key: cord-0891067-dm8tbxka
authors: Kulmann-Leal, Bruna; Ellwanger, Joel Henrique; Chies, José Artur Bogo
title: CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population
date: 2021-12-10
journal: Front Immunol
DOI: 10.3389/fimmu.2021.758358
sha: 0117396888925bd4670e70dc1a80ead79e2fcc19
doc_id: 891067
cord_uid: dm8tbxka

The genetic background of Brazilians encompasses Amerindian, African, and European components as a result of the colonization of an already Amerindian inhabited region by Europeans, associated to a massive influx of Africans. Other migratory flows introduced into the Brazilian population genetic components from Asia and the Middle East. Currently, Brazil has a highly admixed population and, therefore, the study of genetic factors in the context of health or disease in Brazil is a challenging and remarkably interesting subject. This phenomenon is exemplified by the genetic variant CCR5Δ32, a 32 base-pair deletion in the CCR5 gene. CCR5Δ32 originated in Europe, but the time of origin as well as the selective pressures that allowed the maintenance of this variant and the establishment of its current frequencies in the different human populations is still a field of debates. Due to its origin, the CCR5Δ32 allele frequency is high in European-derived populations (~10%) and low in Asian and African native human populations. In Brazil, the CCR5Δ32 allele frequency is intermediate (4-6%) and varies on the Brazilian States, depending on the migratory history of each region. CCR5 is a protein that regulates the activity of several immune cells, also acting as the main HIV-1 co-receptor. The CCR5 expression is influenced by CCR5Δ32 genotypes. No CCR5 expression is observed in CCR5Δ32 homozygous individuals. Thus, the CCR5Δ32 has particular effects on different diseases. At the population level, the effect that CCR5Δ32 has on European populations may be different than that observed in highly admixed populations. Besides less evident due to its low frequency in admixed groups, the effect of the CCR5Δ32 variant may be affected by other genetic traits. Understanding the effects of CCR5Δ32 on Brazilians is essential to predict the potential use of pharmacological CCR5 modulators in Brazil. Therefore, this study reviews the impacts of the CCR5Δ32 on the Brazilian population, considering infectious diseases, inflammatory conditions, and cancer. Finally, this article provides a general discussion concerning the impacts of a European-derived variant, the CCR5Δ32, on a highly admixed population.

Until the year 1500 CE, Brazil was inhabited only by Native Americans belonging to different linguistic groups, distributed along the coast and hinterland of the country. This scenario changed dramatically after the arrival of the Portuguese explorers in the Brazilian territory that year, affecting many cultural and biological aspects of the native populations. The European colonization of Brazil and the associated influx of Africans had a strong influence on the genetic makeup of the Brazilian population. In Brazil, as well as in other countries colonized by the Europeans, the Native American population deeply declined after colonization (contracted around 90% in the Americas) (1) (2) (3) . The remaining native population underwent a strong process of genetic miscegenation. However, the processes of population change continued throughout Brazilian history, even in more recent times. Over the past 200 years, Brazil has received a large influx of European immigrants from various countries, also described as the last migration pulse, which added another layer to the genetic makeup of the Brazilian population (1) (2) (3) (4) .

In general terms, the genetic background of current Brazilians has Amerindian, African, and European components in different proportions (2, 3, (5) (6) (7) , depending on the Brazilian region under investigation (North, Northeast, Center-West, Southeast, or South). For example, the genetic makeup of Brazilians in the southern region of Brazil was strongly influenced by migratory flows from Europe in the 19th and 20th centuries; although in the Northeast of the country, the African genetic component is high (1, 2, 8) . Of note, the European component is preponderant in different Brazilian regions when the Amerindian, African, and European components are compared, but even observing some regional peculiarities as those mentioned above, the genetic composition of the Brazilian population is rather uniform in its miscegenation in different regions of the country (1) .

Throughout history, Brazil also received migrants from other countries beyond those from Europe and Africa, including countries from Asia and Middle East (7, 9) . The intense migration within the national territory (10) allowed the exchange of genetic information between Brazilians from different regions, ethnic and genetic groups. As a result of the interactions of these different groups, the Brazilian population is currently highly miscegenated, a characteristic evident in the rich genetic and phenotypic diversity observed among the Brazilian population (2, 6, 11, 12) . Considering the scenario mentioned above, the Brazilian population can be considered genetically heterogeneous and admixed, in addition to being relatively uniform throughout the country (1) . Interestingly, admixed Brazilian populations are probable "reservoirs" of the diverse Native American genetic component (3) , currently the least prevalent genetic component in the population (1, 8) .

Y-chromosome haplogroup analysis corroborates the high genetic miscegenation observed in the Brazilian population. Abe-Sandes et al. (13) investigated the frequency of different haplogroups in Brazilian individuals from different ethnicities. A significant frequency of typical European haplotypes in Afro-Brazilians was found, for example, in the Quilombola community of São Goncalo, Bahia state, northeastern Brazil. Abe-Sandes et al. (13) also found the E-SRY4064 haplotype, usually observed in populations from Sub-Saharian Africa and almost absent in populations from Europe and Asia, in white Brazilians, in a notable frequency (13) . Marrero et al. (14) also reported evidence of admixture in Native American populations, showing the presence of non-Amerindian haplotypes in Kaingang and Guarani peoples (14) . Finally, numerous studies analyzing Y-chromosome haplogroups reinforce the miscegenation addressed in this article, pointing to European, Amerindian, African and Asian haplogroups in different ethnicities and population groups from different Brazilian regions (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) .

In the same direction, evaluation of mitochondrial DNA in different populations of Brazil showed the presence of diverse haplogroups characteristic of African, European, Native American and Asian populations, again evidencing the high level of miscegenation in the Brazilian population (14, (29) (30) (31) (32) (33) (34) (35) (36) (37) . Of note, Cardena et al. (38) assessed a population from São Paulo, southeastern state of Brazil, specifically evaluating mtDNA haplogroups and comparing such data with selfdeclared ethnicity. Interestingly, a significant parcel of the individuals classified as whites showed a high percentage of African mtDNA (37.6%), with less participation of Amerindian (31.6%) and European (30.8%) origins. When analyzing other genomic loci of the same individuals, a higher European contribution was noticed (63.3%), evidencing a considerable African participation of maternal origin in individuals simultaneously presenting high non mtDNA European ancestry (38, 39) .

The CCR5D32 polymorphism (reference SNP ID number: rs333) is a genetic variant that originated in the European population (40) , and therefore can be used as an ancestry-informative marker in studies involving population genetics and genome ancestry (41, 42) . This variant represents a 32-base pair deletion in the CCR5 gene (chromosome 3; 3p.21.31), a fundamental component of the immune system responsible for encoding the CCR5 protein, which acts mainly in the regulation of inflammatory cell migration. It is unclear what selective pressures (considering positive selection) were responsible for fixing CCR5D32 in the human genome. Smallpox, bubonic plague, and other infectious diseases have already been suggested, but there is no consensus on this aspect (40) . Neutral evolution is also a possibility (43) . What is somehow certain is that the variant probably originated in the European population at 700-5,000 years ago (43, 44) , potentially even earlier than 5,000 years (45, 46) , and later spread heterogeneously across the world.

The CCR5D32 allele presents a higher frequency in northern Europe (greater than 15% in Norway, Latvia, and Estonia), being less frequent in countries located in the south of the European continent. For example, the frequency of the CCR5D32 allele is 8.1% in Spain, 6.9% in Portugal, 6.2% in Italy, and 5.1% in Greece. The allele frequency is very low or even absent in most Asian and African countries: for example, 0.4% in China, 2.2% in Korea, 0.7% in Cameroon, 0.26% in Eritrea, and 2.9% in Egypt (47) . A recent study reports the absence of the CCR5D32 allele in the Nepalese population (48) . Similarly, CCR5D32 is rare in Native American groups, showing an overall CCR5D32 allele frequency of 0.2%, mostly probably due to miscegenation (42) . In the contemporary Brazilian population, the overall frequency of the CCR5D32 allele usually ranges from 4 to 6% but showing significant variations between different Brazilian regions and ethnic groups (42, 49) , as will be discussed in the next sections of this article.

The main function of the CCR5 is coordinating leukocyte migration during inflammatory reactions through interaction with different chemokines, especially CCL3, CCL4, and CCL5 (40) . Of note, these chemokines were historically called "MIP-1a", "MIP-1b" and "RANTES", respectively, but that denomination has fallen into disuse (50, 51) . The CCR5 protein is expressed on the cell surface and has seven transmembrane domains connected by three extracellular loops and three intracellular loops. Leukocytes are the main cells that express the CCR5 (40), although the protein is also detected in other cell types, such as human embryonic neurons (52), adipocytes (53) , and several types of cancer cells and tissues (54) (55) (56) (57) (58) , indicating that CCR5 performs immune functions that go beyond coordinating the migration of inflammatory cells.

Carriers of the wild-type CCR5 gene have CCR5 expression constitutively, with some variation between individuals. CCR5D32 causes important phenotypic effects, affecting the interaction of the CCR5 with chemokines. Due to the induction of a change in the CCR5 gene reading frame, the CCR5D32 produces a truncated protein that is not expressed on the cell surface, presenting a gene-dosage effect. In brief, the presence of the CCR5D32 allele in heterozygous causes a reduction in the expression of CCR5 at the membrane. The presence of the CCR5D32 allele in homozygosis culminate in virtually no expression of CCR5 molecules on the cell surface (59) (60) (61) (62) (63) . The CCR5D 32-derived molecules are not phosphorylated and remain retained in the endoplasmic reticulum (64) . Interestingly, it was suggested that in addition to the gene-dosage effect associated to CCR5D32, the CCR5D32derived truncated protein could promote the sequestration of the CCR5 and CXCR4 proteins, both HIV-1 co-receptors, from the cell surface (65, 66) .

These changes in the expression of CCR5 associated to CCR5D32 culminate in a disrupted CCR5-mediated immune response, which can be beneficial in some situations or harmful in others (67) since the 'chemokine system' is not completely redundant. The absence of CCR5 can impact the cell signaling coordinated by CCL3, CCL4 and CCL5, thus perturbing the proper CCR5-mediated immune responses (68) . Disruptions in the chemokine system can significantly alter the susceptibility and progression of different diseases. For instance, COVID-19 severe cases are associated with uncontrolled receptor-ligand interactions and consequent inflammatory dysregulation, which characterizes the cytokine storm frequently observed in such severe disease cases (69, 70) . Recently, CCR5D32 deletion was identified as a protective factor in Czech First-Wave COVID-19 subjects (71) . Different CCR5-editing techniques are currently available and can be used to test in vitro the impacts of the CCR5 absence in different conditions, simulating the consequences of CCR5D32 on the immune system and disease conditions (72, 73) . However, it is essential to emphasize that the CCR5-editing in human embryos raises many ethical concerns and may have deleterious consequences (67, 74) .

Looking at the desirable effects, CCR5D32 protects against HIV infection, since the homozygous state of the variant impairs the proper expression of CCR5, preventing the interaction of CCR5 (the main HIV co-receptor) with the virus on the cell surface, thus avoiding infection of the host (75, 76). As mentioned above, CCR5D32-derived molecules (CCR5 truncated proteins) can also have an important protective effect against HIV by sequestrating CCR5 and CXCR4 from cell surface (65, 66) . The discovery of this effect was truly relevant because it gives support to the use of CCR5 blockers for the clinical control of HIV infection. The best example of this case is maraviroc, a noncompetitive CCR5 antagonist that prevents the proper interaction between the HIV envelope glycoprotein and the CCR5. Currently, other CCR5 blockers (e.g., cenicriviroc, leronlimab) are being tested to treat HIV infection and other inflammatory conditions, and maraviroc emerges as a potential drug to treat other diseases involving CCR5, especially some types of cancer (77) . In Brazil, CCR5 blockers represent a good choice for HIV treatment, since most of the circulating viral strains show CCR5 tropism (78) (79) (80) . Based on the scenario presented above, Figure 1 shown an alluvial diagram representing the classic outcomes associated with the CCR5D32, including "desirable" and "undesirable" effects.

Another major achievement involving CCR5D32, and HIV infection was the sustained remission of the infection in the 'Berlin Patient', reported in 2009 (83) and confirmed in 2011 (84) , and in the 'London Patient', reported in 2019 (85) and confirmed in 2020 (86) . Both individuals were HIV positive and developed hematological malignant diseases (acute myeloid leukemia and Hodgkin's lymphoma, respectively), requiring allogeneic hematopoietic stem-cell transplantations. After receiving cell transplantations from CCR5D32 homozygous donors, both showed sustained remission of HIV infection. Other cases like Berlin and London patients are being followed up, such as the 'Düsseldorf patient' (87) . The success of this strategy, although involving few cases, shows that sustained remission of HIV is possible to be achieved and subsequently maintained free of antiretroviral therapy. The Berlin patient, Timothy Ray Brown, passed away on September 29, 2020, due to the recurrence of acute myeloid leukemia, not HIV infection (88, 89) . In addition to having collaborated enormously to advance research involving HIV, T. R. Brown created the Timothy Ray Brown Foundation and contributed significantly to the field of HIV/AIDS research, with a big and admirable impact on global society as an HIV activist (89) (90) (91) .

Currently, it is known that the influence of CCR5 and CCR5D32 goes beyond protection against HIV infection and is much broader than previously believed, influencing the susceptibility and outcome of different conditions, such as other different viral, bacterial, and parasitic diseases (40, 92) , as well as non-infectious inflammatory conditions (93) (94) (95) (96) . This occurs because the lack of CCR5 expression, in humans naturally due to CCR5D32, interferes with multiple aspects of inflammatory responses, including expression of immune system genes, levels of inflammatory markers, and activity of immune cells (97) (98) (99) (100) (101) (102) (103) . On the other hand, now looking at the undesirable aspects of CCR5D32, this genetic variant increases the risk of serious complications caused by the West Nile virus and Tick-borne encephalitis virus (104) (105) (106) (107) (108) (109) .

Although Brazilians form a population of more than 210 million individuals, genetic studies in this population are still limited, with most genetic studies focusing on populations with European ancestry (6, 9) . The Brazilian population can serve as a study case to understand the impact of genetic admixture on the frequency of genetic variants, such as CCR5D32, and its impacts on different conditions and pharmacogenomics (7) . Understanding the extent to which the CCR5D32 variant influences the health of different populations is critical since it indicates which individuals and ethnic groups are more likely to benefit from therapies focused on modulating CCR5 in the context of cancer, infections, and inflammatory diseases. Focusing on HIV, knowing the frequency of CCR5D32 in different human populations is the initial step to guide potential new attempts at sustained remission of HIV infection through stem cell transplantation with CCR5D32 homozygous genotype. Moreover, it is also essential to understand how CCR5D32 impacts the health of the Brazilian population.

Considering that (I) the frequency of CCR5D32 is quite varied among Brazilians from different country's regions and that (II) the role of CCR5D32 in various pathological conditions is an emerging topic with several knowledge gaps, the primary objective of this article is to review the effects of the genetic variant CCR5D32 on the Brazilian population, considering several diseases and clinical conditions. The secondary objective of this article is to discuss the impacts of a Europeanderived variant, the CCR5D32, on a highly mixed population.

For the initial selection of articles, the terms "CCR5", "CCR5 delta 32", "CCR5D32" and "rs333", used in combination with "Brazil" or "Brazilian", were searched on PubMed (https://pubmed.ncbi.nlm. nih.gov/). Subsequently, the same search strategy was used on Scientific Electronic Library Online -SciELO (https://scielo.org/). The articles were initially selected based on the title and abstract. Only articles addressing CCR5D32 in Brazilian populations were included in this review. Articles published in English and Portuguese were considered in the evaluation, without restriction concerning the date of publication. On some specific occasions, the reference list of selected articles was also used as an additional source of published works involving CCR5D32 in the Brazilian population. Additional unstructured searches were performed on PubMed to select the articles cited in the introduction section and additional points of the review.

A study published in 2016 by Silva-Carvalho and collaborators (49) presented a very complete meta-analysis regarding the CCR5D32 frequency in Brazil. In addition to original data from those authors, the meta-analysis included 29 articles reporting the CCR5D32 frequency in Brazil, encompassing populations from ten Brazilian States. The study found an overall allelic frequency of 4% in the country (49) . The frequencies of the CCR5D32 allele in the Brazilian States, including data compiled by , are summarized in Figure 2 .

Henceforward, we expand the information concerning the CCR5D32 frequency in Brazil, highlighting studies not included in the meta-analysis by , and including data obtained from studies with indigenous populations and quilombola communities, as discussed below.

Leboute et al. (112) reported the absence of the CCR5D32 allele in a sample of 300 Amerindians from four indigenous populations of the Brazilian Amazon region, namely: Tikuna (n = 191), Baniwa (n = 46), Kashinawa (n = 29), and Kanamari (n = 34). Based on such data, we can argue that, at least until the date of publication of that work, the studied Amazonian tribes probably did not have a significant degree of miscegenation at a level sufficient for the introduction of the CCR5D32 allele into those indigenous groups. Alternatively, the allele could already be circulating in the groups, but it may not have been detected due to the small sample size (112) .

Carvalhaes et al. (113) also described the frequency of the CCR5D32 allele in different ethnic groups of the Brazilian Amazon region, specifically from ParáState. The sample groups investigated were composed of 394 individuals from Beleḿ (capital of Para), 67 Afro-Brazilian individuals, 89 Amerindian individuals, and 111 Japanese immigrants. The CCR5D32 allele was not observed in Amerindian individuals and Japanese immigrants. In the sample of Afro-Brazilian individuals, only one individual carrying the allele in heterozygous was found, with the allele frequency, in this case, being 0.75%. In the sample of random individuals from Beleḿ, one homozygous individual for the gene deletion and 22 heterozygous individuals were found, resulting in a CCR5D32 allele frequency of 3.04% (113) .

Hünemeier et al. (110) evaluated the frequency of the CCR5D32 allele in Native American populations in Brazil and Paraguay: five Amazonian groups (Tiriyo, Mura, Cinta Larga, Gavião, and Zoro); a group from the Paraguayan Gran Chaco (Lengua); one from the Paraguayan forest (Ache); and one from southern Brazil (Kaingang). The CCR5D32 allele was found only in two groups: Mura (2%) and Kaingang (3%). The presence of the CCR5D32 allele in the samples of these two groups may be due to gene flow, which is explained by previous data showing that both populations have a degree of miscegenation. Thus, the CCR5D32 allele may have been introduced in American-native populations due to European miscegenation (110) .

Vargas et al. (42) investigated the distribution of the CCR5D32 allele in individuals from Alegrete, a city in the western region of Rio Grande do Sul State. The population of Alegrete is highly admixed, with the genetic participation of Spanish, Portuguese, African, and Amerindian peoples. In the study, 103 healthy and unrelated individuals were analyzed, being divided into 'white' (n=59), 'brown' (n=31), and 'black' (n=13). No CCR5D32 homozygous individuals were found, and the frequency of heterozygotes was 14% in whites, 13% in browns, and 8% in blacks. Allele frequencies were 6.8%, 6.4%, and 3.8%, respectively (42) . In Brazil, the classification of ethnicity performed by the government agency Instituto Brasileiro de Geografia e Estatı́stica (Brazilian Institute of Geography and Statistics) is based on skin color, and for this reason many Brazilian studies classify individuals using this criterion. Alternatively, 'white' individuals can be classified as Caucasians, and 'brown' and 'black' can be classified as non-Caucasians.

Ferreira-Fernandes et al. (111) analyzed the CCR5D32 frequency in a sample of the population of the Piauı́State. The sample consisted of 223 elderly individuals from the Network of Research on Frailty in Elderly Brazilians. The CCR5D32 allele was found only in heterozygous in the sample, with an allele frequency of 1.8%. In order to have a more robust investigation, the sample was also stratified according to sex and age (dividing the groups into individuals below or above 73 years old), but the frequencies were not statistically different between groups, ranging from 1.5% to 2.3%. The general CCR5D32 frequency observed is in accordance with other data presented by groups also from northeastern Brazil (111) .

Carvalho et al. (41) evaluated the CCR5D32 frequency in three quilombola communities in the states of Sergipe (Mocambo community) and Bahia (Rio das Rãs and São Goncalo communities). The groups were founded about 150 years ago by individuals from Sub-Saharan Africa and/or their descendants. The study evaluated individuals born in quilombola communities and recent immigrants, with a total of 100 inhabitants from Rio das Rãs, 71 from Mocambo, and 53 from São Goncalo. In these communities, 28 were recent immigrants from Rio das Rãs, 18 from Mocambo, and 15 from São Goncalo. Thus, the total sample size was 224 individuals: 163 born in the quilombos and 61 recent immigrants. In most cases, the oldest person in each family was chosen to participate in the study. The CCR5D32 allele was found in the three communities evaluated, but only in heterozygosis, with allele frequencies of 5.6% in Mocambo, 1% in Rio das Rãs, and 0.9% in São Goncalo. According to the authors, the differences in allele frequencies can be due to several factors, including different proportions of parental populations in the founder's individuals, a foundereffect, and different patterns of inter-ethnic contact (41) .

Finally, we summarized in Figure 2 the frequencies of CCR5D32 allele in thirteen Brazilian States, according to data of ten states compiled by Silva-Carvalho et al. (49) , and the frequencies observed by Hüneimeier et al. (110) in the Mura population (Amazonas State), by Carvalho et al. (41) in individuals from Mocambo community (Sergipe State), and Ferreira-Fernandes et al. (111) in individuals from Piauı. To the best of our knowledge, there are no data available in the literature on CCR5D32 in the other Brazilian States.

CCR5 plays a critical role in the regulation of the immune response against infectious agents, controlling the traffic of immune cells [e.g., Natural Killer (NK) and T-regulatory (Treg) cells] towards inflammation sites. For instance, a recent study with mice showed that CCR5 has a pivotal role in the recruitment of NK cells to the kidney allowing an adequate neutrophil activity during systemic Candida albicans infection, acting as a fundamental molecule for a proper immune response. The absence of CCR5 expression resulted in uncontrolled inflammation and increased renal damage in face of C. albicans infection (114) . Also, Treg cells play a fundamental role in resolving inflammatory conditions, providing an immunosuppressive activity. During infection by different pathogens (e.g., Schistosoma spp.), the poor recruitment of Treg cells to the inflammation sites due to CCR5 absence causes uncontrolled inflammation and related tissue damage (40, 115) . On the other hand, during Rocio virus infection, the CCR5 absence was associated with reduced brain inflammation and better prognosis in animals (116) . Taking together, imbalances in the CCR5-mediated immune responses due to CCR5D32 can cause both reduced and exacerbated inflammation, depending on the type of pathogen responsible for the infection (e.g., fungus, bacteria, virus), the infection site, or the immune cell type affected by the lack or reduction of CCR5 expression (40) . In this context, studies addressing CCR5D32 and viruses in the Brazilian population will be discussed here, including HIV, Human T-lymphotropic virus (HTLV), Dengue, Influenza A, Hepatitis C virus (HCV), Hepatitis B virus (HBV), and Human papillomavirus (HPV).

As explained in the introduction section, CCR5D32 exerts its protective effect against HIV infection through two mechanisms: reduced expression of the CCR5 gene (gene-dosage effect; probably the most important mechanism) (60, 63) and sequestration of CCR5 and CXCR4 from the cell surface (65, 66) . Many studies that evaluated CCR5D32 in the Brazilian population corroborated the protective effect of the variant on susceptibility or clinical aspects of HIV infection (e.g., [117] [118] [119] [120] , although other studies have not evidenced these effects, in some cases probably due to the small sample size (e.g., 121, 122) . The main results of the studies involving CCR5D32 and HIV infection in Brazil are detailed in Table 1 .

Experimental evidence indicated that the course of HTLV (type 1 and 2) infection and HIV/HTLV co-infection may be affected by CCR5 expression patterns, which can be modulated by such viruses (138, 139) . The CCR5 and its ligands can also influence the course of Dengue infection (140, 141) . CCR5D32 was associated with an increased risk of fatal Influenza virus infection in Spanish individuals (142) . However, CCR5D32 has a limited impact on these infections in the Brazilian population. Studying HTLV-1 infection, no statistically significant association was found between CCR5D32 and susceptibility or presence/absence of a symptomatic infection (143) . Only one study was found regarding this evaluation in a non-Brazilian population. Hisada et al. (144) investigated the CCR5D32 frequency in Jamaican HTLV-1-infected individuals and healthy controls. However, the frequency found was too low to further conclusions. That said, no study found an association between the variant and HTLV-1 infection (144) . Also, no statistically significant association was observed when the frequencies of CCR5D32 were compared between severe Dengue cases and controls (145) . A similar study carried out in an Australian population also found no association between the CCR5D32 allele and DENV infection (146) . The CCR5D32 was not associated with hospitalization in individuals infected by Influenza A virus (2009 pandemic H1N1 strain) (147) . Subsequently, a study addressing the same virus also reported no significant effect of CCR5D32 on H1N1 infection severity (148) . A study conducted in a Spanish population identified an association between the CCR5D32 allele and fatality due to Influenza A (H1N1) infection (142) . Also, an association of the variant with disease severity was observed in a Canadian population (149) . Therefore, further studies evaluating the role of this polymorphism in Influenza virus infection are needed. HCV and HBV are associated with the development of hepatocarcinoma and other liver diseases (150) . CCR5 could affect both susceptibility to these viruses and associated diseases due to its regulatory role in inflammatory reactions. Our group evaluated the influence of CCR5D32 on susceptibility to HCV infection and HCV/HIV co-infection. In the same study, we also accessed the potential impact of the CCR5D32 on HCV-related fibrosis, cirrhosis, and hepatocarcinoma. In total, 1352 individuals were included in the study. No statistically significant associations of CCR5D32 with the evaluated criteria were observed (151) . Looking at data reported in other populations [see discussion in reference (151)], we highlight that the association between the CCR5D32 variant and HCV infection can show important biases in some populations, and other studies corroborate our results showing a lack of association between the variant and HCV infection. Importantly, our work had the largest sample evaluated in the context of HCV infection (151) .

More recently, we evaluated the influence of CCR5D32 on susceptibility to HBV infection and HBV/HIV co-infection in a study involving 1113 individuals. We found no significant effect of CCR5D32 on susceptibility to HBV mono-infection. On the other hand, the CCR5D32 allele exerted a protective influence on HBV/HIV co-infection. Of note, this result was potentially due to the known protective effect of CCR5D32 on HIV infection (92) . In a study in the Indian population, the heterozygous genotype (WT/D32) was associated with a higher susceptibility to HBV infection, whereas in a study in the Iranian population, the variant was a protective factor against the infection (152, 153) . Other studies carried out in different populations reported a lack of association between HBV infection and the CCR5D32 variant (154) (155) (156) , which is in agreement with the major finding observed in our previous study (92) .

HPV is strongly associated with the development of cervical cancer (157) and it was suggested that CCR5 could play a role in the context of HPV infection and related diseases. Nevertheless, Mangieri et al. (158) observed no significant effect of CCR5D32 on susceptibility to the infection or cervical lesions (158) . Also, the CCR5D32 was not associated with infection by a particular HPV genotype (159) . In contrast, in a Swedish population, the homozygous genotype for the variant was associated with an increased risk of HPV infection (160) . Given the limited amount of data and the contradictory results concerning the involvement of CCR5 in HPV infection, further evaluation concerning the potential role of the CCR5D32 variant in the context of HPV infection and related diseases in Brazilian and other populations are needed.

The influence of CCR5D32 on parasitic diseases was also investigated in the Brazilian population, including Chagas disease, leishmaniasis, and toxoplasmosis. CCR5 can have two opposite effects on Chagas disease, a disease caused by Trypanosoma cruzi infection. CCR5 mediates the control of acute infection, assuming a favorable role for the host. In opposition, the increased expression of CCR5 during Chagas disease is associated with exacerbated inflammation and related cardiac complications (161) . Thus, the levels of CCR5 expression are critical in the outcome of Chagas disease. However, two other studies found no association between the CCR5D32 variant and 

ART: antiretroviral therapy.

cardiac or digestive manifestations on chronic Chagas disease (162, 163) . In a Peruvian population, the frequency of the D32 allele was not high enough to allow an analysis of association with T. cruzi infection, and a study with individuals from Venezuela did not find an association of the variant with the presence of disease symptoms (164, 165) . Therefore, the potential CCR5D32 allele role in Chagas disease is still under discussion. Brajão de Oliveira et al. (166) and Ribas et al. (167) reported no statistically significant difference between Leishmaniainfected individuals and controls concerning CCR5D32 frequencies (166, 167) . In the study performed by Brajão de Oliveira et al. (166) , the CCR5D32 allele carriers showed a less severe spectrum of clinical manifestations, but without statistical significance (166) . Ribas et al. (167) observed a higher frequency of the CCR5D32 polymorphism among a subgroup of patients with recurrent lesion, but this specific result was based on an exceedingly small cohort (167) . Also, a study performed in a Pakistani population showed no association between the CCR5D32 variant and cutaneous leishmaniasis (168) .

The CCR5D32 wild-type genotype in association with AA or AG genotypes (from the CCR5 rs1799987 polymorphism, an intron A/G SNP) was associated with increased risk of ocular toxoplasmosis, potentially due to the persistent CCR5-mediated inflammation in individuals with normal CCR5 expression (169) . Also evaluating Brazilians, Vallochi et al. (170) found no association between the CCR5D32 and ocular toxoplasmosis (based on a brief description; detailed data not described by such authors) (170) . No other studies evaluating the role of this variant in the context of ocular toxoplasmosis in non-Brazilian populations were found.

Based on the studies discussed above, apart from the protective effect of CCR5D32 on HIV infection, the impacts of CCR5D32 on viral and parasitic infections in Brazilian populations seem quite limited (details of each study are presented in Table 1 and Table 2 ). However, considering the recognized role of CCR5 in the regulation of inflammation, it is possible that potential influences of CCR5D32 on non-HIV infections have not been detected due to the small number of studies carried out in Brazil on these topics, many of them involving a small sample size.

Finally, the impact of the CCR5D32 on fungal infections is unknown in Brazilian populations and quite sparse in other human populations, and therefore research in this field is needed. Of note, Brazil is affected by several endemic mycoses, such as Dermatophytosis, Paracoccidioidomycosis, Histoplasmosis, and Cryptococcosis, among others (171) . Understanding whether and how the CCR5D32 influences the susceptibility or clinical progression of these diseases can provide insights into the potential use of CCR5-based therapies for these diseases.

Considering the critical role of CCR5 in the regulation of the inflammatory response, several authors have been investigating the effect of CCR5D32 on conditions that have their susceptibility or clinical course affected by different types (e.g., systemic, local) and intensity of inflammation. In this topic, we review the role of CCR5D32 on the following inflammatory diseases or inflammation-related clinical conditions: multiple sclerosis, systemic lupus erythematosus, preeclampsia, rheumatoid arthritis, juvenile idiopathic arthritis, periodontitis, osteomyelitis, transplant rejection, and sickle cell disease. Details of each study are described in Table 3 and discussed below.

Multiple sclerosis is an autoimmune, chronic, and inflammatory disease showing heterogeneity in clinical findings. Chemokines and chemokine receptors are molecules involved in the pathogenesis of multiple sclerosis (172, 194) , and the CCR5D32 can influence different aspects of this disease, as shown in studies with non-Brazilian individuals (195) (196) (197) . A meta-analysis carried out in 2014 evaluated the role of this variant in multiple sclerosis in different populations, and concluded that the CCR5D32 is not associated with susceptibility to the development of multiple sclerosis in Europeans, calling attention to the need for further studies involving other populations (198) . In Australian individuals, this variant also did not show a protective role to multiple sclerosis (199) . However, other studies have shown an association of the D32 allele with treatment response, disease severity, and susceptibility to multiple sclerosis (196, (200) (201) (202) . In Brazil, only two papers explored the possible impact of the CCR5D32 on multiple sclerosis. Based on magnetic resonance imaging, Kaimen-Maciel et al. (172) observed a decreased disease progression in patients bearing the CCR5D32 allele (172) . Subsequently, Troncoso et al. (173) described a statistically significant higher CCR5D32 allele frequency in Euro-Brazilian controls (7.4%) compared to Euro-Brazilian patients (3.3%), suggesting a protective role of the variant on the development of multiple sclerosis. Besides, the frequency of the CCR5D32 was higher in Euro-Brazilian patients with progressive multiple sclerosis than Euro-Brazilian patients with relapse remitting multiple sclerosis (173) . Both studies carried out in Brazil show that the CCR5D32 variant can influence both the susceptibility and the clinical outcome of multiple sclerosis.

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease characterized by the large production of autoantibodies, triggering generalized tissue damage. This disease has different clinical manifestations and a complex genetic influence, and chemokines and their receptors, such as CCR5, are implicated in the pathogenesis of lupus (96, 185, 203, 204) . The CCR5D32 variant has already been studied in this context, being previously associated to protection against lupus development and, albeit in a contradictory manner, this polymorphism was also associated to susceptibility to nephritis in lupus patients (203, 204) . In Brazil, two studies evaluated the CCR5D32 variant in lupus.

Schauren et al. (185) investigated the role of the CCR5D32 in healthy patients and controls of Rio Grande do Sul State (185) . A lower frequency of the CCR5D32 allele was found in Euro-Brazilian patients (2.7%) compared to Euro-Brazilian controls (7.5%), suggesting a protective role of the variant against the development of systemic lupus erythematosus. However, in the same study, patients with the CCR5D32 allele had a greater predisposition to the development of class IV nephritis than patients without the allele, which suggests a more severe clinical outcome associated with the genetic variant (185).

Baltus et al. (96) evaluated the frequencies of the CCR5D32 in patients and controls in the ParanáState, also southern Brazil. Unlike the first study, the frequency of the CCR5D32 allele was statistically higher in patients (6.8%) than in controls (1.9%), suggesting the variant as a risk factor for systemic lupus erythematosus. Also, by stratifying the sample according to ethnicity, the researchers identified that Euro-Brazilian individuals carrying the CCR5D32 were more likely to develop systemic lupus erythematosus than Afro-Brazilian patients carrying the variant. In another analysis of the study, CCR5D32 carriers had a lower age of systemic lupus erythematosus onset and higher levels of anti-dsDNA antibodies. Thus, the CCR5D32 allele was associated with increased susceptibility to the development of systemic lupus The frequency of the CCR5D32 variant was significantly higher in healthy euro-Brazilian controls (0.075) than in euro-Brazilian SLE patients (0.027) (p=0.002); Patients carrying the CCR5D32 variant were predisposed to the development of class IV nephritis (p=7E-6) Schauren et al. (185) (Continued) erythematosus and severity in clinical outcomes (96) . Studies performed in different populations have found no association between the variant and the development of systemic lupus erythematosus (205) (206) (207) (208) . Such divergence involving the results mentioned above deserves attention and, therefore, more studies in other populations are required.

Preeclampsia is a hypertensive gestational complication and an important cause of maternal-fetal mortality in Brazil. Relevant clinical findings of the disease, such as edema and proteinuria after the 20th week of pregnancy, are intricate with an excessive inflammatory process and endothelial dysfunction. In preeclampsia, increased systemic production of proinflammatory chemokines was observed, highlighting the role of the chemokine-ligand system in this condition (177, 178, 209) . Two studies evaluating the CCR5D32 variant in preeclampsia were carried out in Brazil, both published by our group, but evaluating samples from different Brazilian regions. Firstly, Telini et al. (177) evaluated the frequency of the CCR5D32 in Brazilian women who developed preeclampsia and women who did not develop this condition during their pregnancies. The group of healthy women had a higher frequency of the CCR5D32 allele (14%) when compared to the group of women who developed preeclampsia (7%). The analysis revealed a protective role of the variant on preeclampsia development (177) . More recently, Kaminski et al. (178) also investigated the role of CCR5D32 in women who developed preeclampsia and in women with healthy pregnancies (178) . In accordance with the results of Telini et al. (177) , healthy pregnant women also showed an increased CCR5D32 allele frequency (4.5%) compared to the group of pregnant women with preeclampsia (1.6%). Thus, the study corroborated the protective role of the CCR5D32 variant on preeclampsia development, endorsing the hypothesis that a reduced inflammatory millieu may contribute to a lower risk of developing preeclampsia (177, 178) . A study conducted in a Turkish population found similar results, strengthening the conclusion here presented (210) .

Rheumatoid arthritis is a systemic autoimmune disease characterized by progressive damage to the joints caused by chronic inflammation in the synovial fluid. Given the intense migration of immune cells to the inflammation sites, the role of CCR5 in rheumatoid arthritis appears to be of great importance (179, 180) . In Brazil, two studies investigating the role of the CCR5D32 variant in rheumatoid arthritis were published. Kohem et al. (179) evaluated the frequency of the allele in healthy patients and controls from the Rio Grande do Sul State, and no statistically significant difference was found between the groups. Of note, the sample group was relatively small, with 92 patients and 160 healthy controls (179). Toson et al. (180) performed a similar study but evaluating the frequency of the CCR5D32 variant in different Brazilian populations, considering four different regions (south, southeast, northeast, and north). Two of the four sample groups, from southern and northern regions, showed a statistically significant difference between rheumatoid arthritis patients and healthy controls (4% vs. 7.5%; 1.1% vs. 3.4%, respectively), being precisely the groups with the largest sample sizes. The difference concerning the northeast region sample was not statistically significant but followed a similar trend to the groups in southern and northern. Only the southeastern sample deviated from the trend, with the small sample size possibly being the reason for the lack of statistical association. In sum, the study suggests a protective role for the CCR5D32 variant against the development of rheumatoid arthritis (180) . A meta-analysis carried out in 2012 concluded that the variant may play a role in protection to rheumatoid arthritis in European populations, corroborating the data found in Brazil (211) .

Juvenile idiopathic arthritis is a chronic inflammatory condition characterized in the synovial joints of young people up to 16 years of age (174, 212) . Scheibel et al. (174) investigated the potential association of the CCR5D32 variant with juvenile idiopathic arthritis subtypes in a sample from Porto Alegre, southern Brazil. A statistically significant difference was found Cilião et al. (186) between patients (9.4%) and healthy controls (3.8%), especially considering the group of patients of the systemic juvenile idiopathic arthritis subtype (25%). The researchers conclude that the CCR5D32 variant, although not a risk factor for the development of juvenile idiopathic arthritis, contributes to the progression and clinical status of patients (174) . Interestingly, the meta-analysis previously mentioned (211) also explored the role of the D32 allele in juvenile idiopathic arthritis, and concluded that the variant was a protective factor for this condition as well (211) . A further study comprising children from different populations found an association between the heterozygous genotype and mild disease course, but no influence on susceptibility to disease development (213) . That said, these controversial results evidence the importance of novel studies investigating the CCR5D32 variant in juvenile idiopathic arthritis. Periodontitis is an oral disease characterized by a chronic infection accompanied by inflammatory processes, causing irreversible and progressive destruction of dental support structures. The CCR5-mediated immune responses affect multiple aspects of periodontitis. For instance, not only CCR5 and its ligands are important in the context of disease protection, but also influence periodontal destruction and bone resorption (176, (214) (215) (216) (217) . Cavalla et al. (176) investigated the CCR5D32 variant and its possible influence on periodontitis development. The CCR5D32 allele was significantly more frequent in individuals classified in the group of chronic gingivitis (11.1%) than in individuals with chronic periodontal disease (5.8%) or aggressive periodontal disease (5.5%). This result suggests a protective role of the variant concerning periodontitis (176) . Other studies carried out in Taiwan and Germany found no association between the variant and periodontitis (218, 219) . Considering the conflicting results, it is interesting to carry out further studies in other populations to better understand the role of CCR5 in the development of periodontitis.

Osteomyelitis is an infectious-inflammatory condition that can occur after bone trauma often following Staphylococcus aureus infection (175, 220) . Souza et al. (175) evaluated the CCR5D32 frequency in patients who were admitted to a hospital in Fortaleza, northeastern Brazil, with bone trauma. The patients were prospectively studied to assess a possible development of osteomyelitis. There was no statistically significant difference between individuals who developed and those who did not develop the disease, but all patients with closed fractures (type I or type II) and who carried the CCR5D32 variant did not developed the condition. The researchers conclude that the lack of statistical significance observed in their study was probably due to the low sample size (175) . No other studies regarding the potential role of the CCR5D32 in osteomyelitis were found in the literature.

The immune response and inflammatory processes that occur after an organ transplant are critical in the process of tissue rejection. Genetic variants related to the immune system can therefore influence the response to transplantation (186, (221) (222) (223) . Studies carried out in non-Brazilian populations observed no association between the CCR5D32 allele and kidney transplant rejection (224) (225) (226) (227) (228) . A study in a multicentric sample from Europe showed a higher survival rate after kidney transplantation in individuals with the CCR5D32 homozygous genotype (222) . In Brazil, Cilião et al. (186) evaluated the CCR5D32 frequency in transplanted individuals who had episodes of rejection comparing to individuals who did not have such episodes. A sample of 246 patients was collected in a referral hospital in Londrina, ParanáState. However, the frequency of the CCR5D32 variant did not vary significantly between the groups (186) .

Sickle cell disease is an inherited disorder caused by a single nucleotide substitution in the beta-globin gene. This mutation originated in Africa and is, therefore, more common in African populations and Afro-descendants. Sickle cell disease can be understood as a chronic inflammatory condition, which may be the cause of associated secondary complications. In this sense, high levels of inflammation in sickle cell disease patients are related to disease morbidity (181) (182) (183) (184) . A study in a population from Egypt found no association between the variant and sickle cell disease (229) . In Brazil, four studies investigated the influence of the CCR5D32 variant in sickle cell disease, all detailed below.

Chies and Hutz (181) assessed the potential role of the CCR5D32 in severe and recurrent infections that could contribute to differentiated survival of sickle cell anemia patients. The study involved individuals from different ethnic groups and the frequencies of the CCR5D32 allele found were 4.4% in Euro-Brazilian controls, 1.3% in Afro-Brazilian controls, and 5.1% in sickle cell anemia patients. When comparing these frequencies between the different groups, no statistically significant difference was found. However, it is important to note that, considering the same ethnic background of the groups of patients and Afro-Brazilian controls, a difference in the allele frequency was evidenced, being the CCR5D32 allele three times more present in the group of sickle cell anemia patients. Given the low frequency of the allele in the sample of Afro-Brazilian controls, a 3-fold increase in the group of patients is quite important. The researchers suggested that the CCR5D32 allele was more frequent in the group of patients for conferring some advantages concerning the clinical course of the disease (181) . As mentioned previously, sickle cell anemia can be considered a chronic inflammatory disease (93) , and patients with the CCR5D32 allele would benefit from developing inflammatory responses at low levels. According to this hypothesis, the CCR5D32 allele was associated with an improvement in the general health status of the patients (93, 181) .

Subsequently, Vargas et al. (182) evaluated CCR5D32 in sickle cell anemia patients from Porto Alegre, Rio Grande do Sul State. No statistically significant difference was observed in the study but, interestingly, the CCR5D32 allele was present only in the group of patients with a severe clinical course (when the pain rate was considered). Such data may indicate a trend towards the development of a severe clinical course associated with the CCR5D32 allele in sickle cell anemia patients (182) . Lopes et al. (183) compared the CCR5D32 frequencies of two groups of patients (pediatric and adult) and between sick adults and healthy controls from Pernambuco, northeastern Brazil. There were no statistically significant differences in any of the comparisons made in the study (183) . Finally, Nascimento et al. (184) evaluated the CCR5D32 frequency in sickle cell anemia patients from Bahia State. However, the CCR5D32 allele was not found in the study (184) .

Chemokines and chemokine receptors have fundamental participation in both antitumor response and pathogenesis of cancer. The migration of regulatory immune cells to tumor sites can create an immunosuppressor environment proper for cancer development. Also, cancer cells can subvert the anti-tumor action of chemokine-ligand interactions (187) (188) (189) (190) (191) . Of note, CD4+ T cells are important modulators of the immune response, acting as drivers for the action of effector cells. Some CD4+ regulatory T cells express the CCR5 molecule, being this a key receptor of the cellular response against tumor development. The presence of the CCR5D32 variant can impair the action of CCR5+/CD4+ T cells, influencing the risk of cancer development. In brief, chemokine receptors can assume multiple roles in different tumoral processes, and more investigation is needed to unravel the connections between CCR5 and cancer (101, 192) . Two meta-analyses published in 2014 evaluated the possible role of the D32 allele in cancer. Ying et al. (230) found no association of the variant with risk of tumorigenesis, while Lee et al. (205) found an association of the allele with susceptibility to cancer in Indians, specifically concerning breast cancer (205, 230) . Further studies found associations of the CCR5D32 variant with improved metastasis-free survival in breast cancer patients and, contradictorily, also with an increased risk for developing breast cancer (231) (232) (233) . In Brazil, the possible role of the CCR5D32 variant in cancer has been addressed ( Table 4 ) and the available data will be presented below.

The action of CD8+ cytotoxic T cells is important in the antitumor immune response. The use of immunomodulators in antitumor treatment is increasingly common, with carboxymethylglucan (CM-G) being one of the best-described immunostimulators (192, 234) . Magnani et al. (192) evaluated the CD3+, CD4+ and CD8+ cell populations of patients with advanced prostate cancer and compared this data with the CCR5 genotype, associating it with the administration of oral CM-G for 28 days. The CCR5D32 variant was found only in a heterozygous genotype, in six patients, at an allelic frequency of 10%. Five patients reported a family history of prostate cancer, two of whom had affected first-degree relatives. Both patients carried the CCR5D32 allele. In general, CCR5D32 non-carriers had higher counts on CD3+ and CD4+ cells when comparing respectively after and before treatment with CM-G, as well as higher counts of CD8+ cells when comparing to CCR5D32 carriers only after treatment with CM-G. In addition, the average CD4+/CD8+ cell ratio showed a worsened antitumor response after treatment in CCR5D32 allele carriers (192) . Zambra et al. (193) also evaluated the CCR5D32 frequency in Brazilian prostate cancer patients, comparing to individuals affected by benign prostatic hyperplasia and healthy subjects. No association was found considering the variant and risk to both conditions, nor with clinical outcomes (193) .

Aoki et al. (188) assessed the CCR5D32 frequency in individuals with breast cancer and healthy women. However, no significant difference was observed between groups. The impact of p53 genotypes, a known tumor suppressor gene, together with the CCR5D32 genotypes, was also evaluated revealing a higher frequency of individuals with the p53 Arg homozygous genotype and the CCR5D32 wild-type genotype amongst controls as compared to patients (188) . Banin-Hirata et al. (189) (193) also evaluated whether the CCR5D32 variant was associated with susceptibility, response to treatment, and clinical course of breast cancer. No association was found between CCR5D32 and the features analyzed (189) . In accordance, Derossi et al. (190) did not found an association between the CCR5D32 and CCL5 levels in breast cancer (190) .

HPV infection is the main cause of cervical cancer. However, factors other than HPV infection, including genetic, immune, and environmental factors, also affect tumorigenesis (159, 235, 236) . In this context, Santos et al. (159) evaluated the CCR5D32 frequency in HPV+ women with and without cervical neoplastic lesions. No association was found between the variant and the presence of cancer or lesions severity (159) .

In addition to the multiple roles of CCR5 in tumorigenesis and antitumor response, this molecule is also an important modulator of neuroinflammation (237) (238) (239) , potentially affecting the development of brain-related diseases. In this sense, Vieira-Filho et al. (191) found an association between the presence of the CCR5D32 allele and susceptibility to neuroblastoma (191) . Lastly, Oliveira et al. (187) investigated the role of the CCR5D32 variant in acute lymphoblastic leukemia, but no association was found between the variant and the disease development (187) . In conclusion, the CCR5 has varied influences in different types of cancer.

At a population level, the effects of CCR5D32 on European populations may be different than those potentially observed in highly admixed populations. However, the population-specific effects of CCR5D32 are not only due to its frequency, but also due to its interaction with different alleles. There are nine widely known CCR5 haplotypes, which are formed by combinations of eight CCR5 polymorphisms (including CCR5D32) and one polymorphism located in the CCR2 gene (40, 70) . The impact of the CCR5 haplotypes on HIV disease progression differs between African Americans and Caucasians since the effects of the CCR5D32 can be modulated by other alleles heterogeneously distributed among the populations (240) . In a broader perspective, this information indicates that the effect of the CCR5D32 observed in Europeans (or other non-Brazilian populations) may be modified by further genetic traits circulating in Brazilians, which may also vary in different regions of the country. In fact, the detection of the real effect of CCR5D32 on different health and disease conditions in the Brazilian population is not a simple task. Of note, gene-disease association studies performed with admixed populations can be difficult due to differential linkage disequilibrium patterns (241) .

Pharmacogenomic approaches, including the use of CCR5 modulators based on the CCR5D32 genotyping, must be considered at an individual level, especially in highly admixed populations, where the frequency of polymorphisms may be quite different from those observed in populations with greater genetic homogeneity (7) . The CCR5D32 genotyping could be considered in pharmacological treatments involving CCR5 blockade in the context of inflammatory diseases or types of cancer. The use of CCR5 modulators in individuals with the CCR5D32 genotype probably has a limited effect due to the natural absence of CCR5 expression on the cell surface. Although the number of individuals with this genotype is exceptionally low in an admixed population such as the Brazilian population, the cost-benefit of this strategy must be considered on a case-by-case basis. Despite the limitations, the area of pharmacogenomics involving CCR5D32 genotyping is expected to progress in the next years, especially considering the increasing use of CCR5 modulators to treat other diseases not associated with HIV infection. Some important advances have already been made. For instance, the CCR5D32 genotyping can help clinicians to predict the progression of human enteroviral cardiomyopathy, also helping the decision making concerning the early use of antiviral interferon-b therapy in such condition (242) .

The CCR5D32 allele frequency is quite variable in Brazil, being extremely low in some regions (e.g., 0.6% in Rondonia), but high in others (e.g., up to 9.3% in Paranáand 7.4% in Rio Grande do Sul). In Native American populations, the allele is absent or occurs at low frequencies. In Brazil, CCR5D32 is not uncommon in non-Caucasian populations, because of the miscegenation that has occurred in the country.

Many studies corroborated the protective effect of the CCR5D32 on susceptibility or clinical aspects of HIV infection in the Brazilian population. On the other hand, there is no evidence pointing to a relevant role for CCR5D32 on Cutaneous leishmaniasis, Chagas disease, HTLV-1, Dengue virus, Influenza A, HPV, HBV and HCV infections, or HCV-HIV co-infection in Brazilians. Limited evidence indicates a potential involvement of CCR5D32 wild-type genotype in ocular toxoplasmosis and a protective effect of the variant on HBV/HIV co-infection.

Considering inflammatory conditions, the CCR5D32 can influence both the susceptibility and the clinical outcome of multiple sclerosis. Of note, CCR5D32 reduces the risk of preeclampsia and periodontitis development, potentially due to the CCR5D32-associated reduced inflammation. Moreover, CCR5D32 can reduce the risk of rheumatoid arthritis, but contributes to the progression and clinical status of juvenile idiopathic arthritis patients. CCR5D32 can also influence sickle cell anemia-related immune conditions. However, the impact of CCR5D32 on systemic lupus erythematosus is controversial. Concerning tumoral development, the CCR5D32 has varying influences on the development of different types of cancer, including prostate cancer and breast cancer. It is not possible to generalize the impact of the variant on cancer development, especially in the Brazilian population.

Understanding the real impact of the CCR5D32 variant in different conditions is essential to indicate in which diseases the use of CCR5 modulators may be relevant. This knowledge is fundamental for the advancement of CCR5-based therapies, especially in populations with a complex genetic structure. Finally, CCR5D32 influences should be assessed within the context of each population, since genetic admixture and interactions with other alleles may alter the expected phenotypic effects attributed to CCR5D32.

BK-L and JE wrote the first version of the manuscript. JC revised and edited the text. All authors contributed to the article and approved the submitted version. 

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The Genetic Diversity of the Americas

Reconstructed Lost Native American Populations From Eastern Brazil Are Shaped by Differential Je/Tupi Ancestry

Genomic Insight Into the Origins and Dispersal of the Brazilian Coastal Natives

Genetic Composition of Brazilian Population Samples Based on a Set of Twenty-Eight Ancestry Informative SNPs

Brazilian Urban Population Genetic Structure Reveals a High Degree of Admixture

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Historical Genetics: Spatiotemporal Analysis of the Formation of the Brazilian Population

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Analysis of Y Chromosome SNPs in Alagoas, Northeastern Brazil

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The Phylogeography of Brazilian Y-Chromosome Lineages

Y Chromosome Diversity in Brazilians: Switching Perspectives From Slow to Fast Evolving Markers

Y-Chromosome STR Haplotype Diversity in Brazilian Populations

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Resistance to HIV-1 Infection in Caucasian Individuals Bearing Mutant Alleles of the CCR-5 Chemokine Receptor Gene

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Determination of Viral Tropism by Genotyping and Phenotyping Assays in Brazilian HIV-1-Infected Patients

Frequency of Coreceptor Tropism in PBMC Samples From HIV-1 Recently Infected Blood Donors by Massively Parallel Sequencing: The REDS II Study

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Ccr5D32 (Rs333) Polymorphism is Associated With the Susceptibility to Systemic Lupus Erythematosus in Female Brazilian Patients

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The Effect of the CCR5-Delta32 Deletion on Global Gene Expression Considering Immune Response and Inflammation

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CCR5 Deficiency Increases Risk of Symptomatic West Nile Virus Infection

Genetic Deficiency of Chemokine Receptor CCR5 is a Strong Risk Factor for Symptomatic West Nile Virus Infection: A Meta-Analysis of 4 Cohorts in the US Epidemic

A Deletion in the Chemokine Receptor 5 (CCR5) Gene is Associated With Tickborne Encephalitis

CCR5 Deficiency is a Risk Factor for Early Clinical Manifestations of West Nile Virus Infection But Not for Viral Transmission

Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 Genes are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population

Host Immunogenetics in Tick-Borne Encephalitis Virus Infection-The CCR5 Crossroad

T-Cell and Chemokine Receptor Variation in South Amerindian Populations

Prevalence of CCR5-D32 and CCR2-V64I Polymorphisms in a Mixed Population From Northeastern Brazil

Absence of the Deltaccr5 Mutation in Indigenous Populations of the Brazilian Amazon

Distribution of CCR5-[Delta]32, CCR2-64I, and SDF1-3'a Mutations in Populations From the Brazilian Amazon Region

CCR5-Mediated Recruitment of NK Cells to the Kidney Is a Critical Step for Host Defense to Systemic Candida Albicans Infection

Experimental Infection With Schistosoma Mansoni in CCR5-Deficient Mice is Associated With Increased Disease Severity, as CCR5 Plays a Role in Controlling Granulomatous Inflammation

Influence of the CCR-5/MIP-1 a Axis in the Pathogenesis of Rocio Virus Encephalitis in a Mouse Model

Effects of CCR5 Genetic Polymorphism and HIV-1 Subtype in Antiretroviral Response in Brazilian HIV-1-Infected Patients

Frequency of CCR5-D32 Deletion in Human Immunodeficiency Virus Type 1 (HIV-1) in Healthy Blood Donors, HIV-1-Exposed Seronegative and HIV-1-Seropositive Individuals of Southern Brazilian Population

Better CD4+ T Cell Recovery in Brazilian HIV-Infected Individuals Under HAART Due to Cumulative Carriage of SDF-1-3'a, CCR2-V64I, CCR5-D32 and CCR5-Promoter 59029A/G Polymorphisms

Novel Genetic Associations and Gene-Gene Interactions of Chemokine Receptor and Chemokine Genetic Polymorphisms in HIV/AIDS

Frequencies of CCR5-D32, CCR2-64I and SDF1-3'A Mutations in Human Immunodeficiency Virus (HIV) Seropositive Subjects and Seronegative Individuals From the State of Paráin Brazilian Amazonia

Ancestralidade Genômica, Nıvel Socioeconômico E Vulnerabilidade Ao HIV/aids Na Bahia, Brasil

Prevalence of the CCR5Delta32 Mutation in Brazilian Populations and Cell Susceptibility to HIV-1 Infection

CCR5 Genotype and Plasma Beta-Chemokine Concentration of Brazilian HIV-Infected Individuals

Frequency of Polymorphisms of Genes Coding for HIV-1 Co-Receptors CCR5 and CCR2 in a Brazilian Population

CCR5 Promoter Polymorphisms and HIV-1 Perinatal Transmission in Brazilian Children

CCR5 Genotypes and Progression to HIV Disease in Perinatally Infected Children

Distribution of CCR5 Genotypes and HLA Class I B Alleles in HIV-1 Infected and Uninfected Injecting Drug Users From Rio De Janeiro, Brazil

The Effect of Combined Polymorphisms in Chemokines and Chemokine Receptors on the Clinical Course of HIV-1 Infection in a Brazilian Population

Analysis of Immunological, Viral, Genetic, and Environmental Factors That Might Be Associated With Decreased Susceptibility to HIV Infection in Serodiscordant Couples in Florianoṕolis, Southern Brazil

Frequency of CCR5 Genotypes in HIV-Infected Patients in Roraima, Brazil

TRIM5 Gene Polymorphisms in HIV-1-Infected Patients and Healthy Controls From Northeastern Brazil

Pace of Coreceptor Tropism Switch in HIV-1-Infected Individuals After Recent Infection

Immunological and Virological Characterization of HIV-1

Viremia Controllers in the North Region of Brazil

Young Adults HIV-1 Infected by Vertical Transmission in Southern Brazil -Clinical, Demographic, and Virological Features

HLA-C Single Nucleotide Polymorphism Associated With Increased Viral Load Level in HIV-1 Infected Individuals From Northeast Brazil

CCR5 Genotype and Pre-Treatment CD4+ T-Cell Count Influence Immunological Recovery of HIV-Positive Patients During Antiretroviral Therapy

Recombinant Human T-Cell Leukemia Virus Types 1 and 2 Tax Proteins Induce High Levels of CC-Chemokines and Downregulate CCR5 in Human Peripheral Blood Mononuclear Cells

High Levels of CC-Chemokine Expression and Downregulated Levels of CCR5 During HIV-1/HTLV-1 and HIV-1/HTLV-2 Coinfections

Role of CC Chemokine Receptor 1 and Two of its Ligands in Human Dengue Infection. Three Approaches Under the Cuban Situation

Dengue Virus Requires the CC-Chemokine Receptor CCR5 for Replication and Infection Development

CCR5 Deficiency Predisposes to Fatal Outcome in Influenza Virus Infection

Frequency of the CCRdelta32 Allele in Brazilians: A Study in Colorectal Cancer and in HTLV-I Infection

Chemokine Receptor Gene Polymorphisms and Risk of Human T Lymphotropic Virus Type I Infection in Jamaica

Single Nucleotide Polymorphisms in Candidate Genes and Dengue Severity in Children: A Case-Control, Functional and Meta-Analysis Study

Primary Acute Dengue and the Deletion in Chemokine Receptor 5 (CCR5D32)

The Ccr5D32 (Rs333) Polymorphism is Not a Predisposing Factor for Severe Pandemic Influenza in the Brazilian Admixed Population

Human Ccr5D32 (Rs333) Polymorphism has No Influence on Severity and Mortality of Influenza A(H1N1)pdm09 Infection in Brazilian Patients From the Post Pandemic Period

Chemokine Receptor 5 D32 Allele in Patients With Severe Pandemic (H1N1)

The Contributions of Hepatitis B Virus and Hepatitis C Virus Infections to Cirrhosis and Primary Liver Cancer Worldwide

Ccr5D32 in HCV Infection, HCV/HIV Co-Infection, and HCV-Related Diseases

CCR5 Polymorphism as a Protective Factor for Hepatocellular Carcinoma in

Hepatitis B Virus-Infected Iranian Patients

Host Genetic Factors and HBV Induced Liver Disease: Association of Vitamin D Receptor, CCR5, TNF-A and TNF-B Gene Polymorphisms With Viral Load and Disease Severity

Chemokine Receptor 5 (CCR5) Polymorphism in Chronic Hepatitis B Patients Treated With Three Different Nucleos(T)Ide Analogues

CCR5 D 32 Mutation is Not Prevalent in Iranians With Chronic HBV Infection

Common Polymorphic Effectors of Immunity Against Hepatitis B and C Modulate Susceptibility to Infection and Spontaneous Clearance in a Moroccan Population

Understanding the HPV Integration and its Progression to Cervical Cancer

CCR5 Genetic Variants and Epidemiological Determinants for HPV Infection and Cervical Premalignant Lesions

CCR2 and CCR5 Genes Polymorphisms in Women With Cervical Lesions From Pernambuco, Northeast Region of Brazil: A Case-Control Study

Genetic Polymorphism of Chemokine Receptors CCR2 and CCR5 in Swedish Cervical Cancer Patients

The Role of CCR5 in Chagas Disease -a Systematic Review

CCR5 Chemokine Receptor Gene Variants in Chronic Chagas' Disease

Genetic Susceptibility to Cardiac and Digestive Clinical Forms of Chronic Chagas Disease: Involvement of the CCR5 59029 a/G Polymorphism

Is the CCR5-59029-G/G Genotype a Protective Factor for Cardiomyopathy in Chagas Disease?

Analysis of the CC Chemokine Receptor 5 Delta32 Polymorphism in a Brazilian Population With Cutaneous Leishmaniasis

Effect of the Chemokine Receptor CCR5 in the Development of American Cutaneous Leishmaniasis in a Southern Brazilian Population

CC Chemokine Receptor 5 D32 Polymorphism: Association Analysis and Allele Distribution Among Cutaneous Leishmaniasis Patients From Pakistan

Molecular Markers of Susceptibility to Ocular Toxoplasmosis, Host and Guest Behaving Badly

Social, Environmental and Microbiologic Aspects of Endemic Mycoses in Brazil

CCR5-D32 Genetic Polymorphism Associated With Benign Clinical Course and Magnetic Resonance Imaging Findings in Brazilian Patients With Multiple Sclerosis

Ccr5D32 -A Piece of Protection in the Inflammatory Puzzle of Multiple Sclerosis Susceptibility

Differential CCR5Delta32 Allelic Frequencies in Juvenile Idiopathic Arthritis Subtypes: Evidence for Different Regulatory Roles of CCR5 in Rheumatological Diseases

A New Look at Osteomyelitis Development-Focus on CCR5delta32. Study in Patients From Northeast Brazil

Ccr5D32 (Rs333) Polymorphism is Associated With Decreased Risk of Chronic and Aggressive Periodontitis: A Case-Control Analysis Based in Disease Resistance and Susceptibility Phenotypes

The Ccr5D32 Polymorphism as a Pre-Eclampsia Susceptibility Marker: An Evaluation in Brazilian Women

Influence of NKG2C Gene Deletion and CCR5D32 in Pre-Eclampsia-Approaching the Effect of Innate Immune Gene Variants in Pregnancy

The Chemokine Receptor CCR5 Genetic Polymorphism and Expression in Rheumatoid Arthritis Patients

Ccr5D32 and the Genetic Susceptibility to Rheumatoid Arthritis in Admixed Populations: A Multicentre Study

High Frequency of the CCR5delta32 Variant Among Individuals From an Admixed Brazilian Population With Sickle Cell Anemia

Polymorphisms of Chemokine Receptors and eNOS in Brazilian Patients With Sickle Cell Disease

The Ccr5D32 Polymorphism in Brazilian Patients With Sickle Cell Disease

Genomic Ancestry Evaluated by Ancestry-Informative Markers in Patients With Sickle Cell Disease

CCR5delta32 in Systemic Lupus Erythematosus: Implications for Disease Susceptibility and Outcome in a Brazilian Population

Association of UGT2B7, UGT1A9, ABCG2, and IL23R Polymorphisms With Rejection Risk in Kidney Transplant Patients

Absence of Association Between CCR5 Rs333 Polymorphism and Childhood Acute Lymphoblastic Leukemia

CCR5 and P53 Codon 72 Gene Polymorphisms: Implications in Breast Cancer Development

CCR2-V64I Genetic Polymorphism: A Possible Involvement in HER2+ Breast Cancer

CCL5 Protein Level: Influence on Breast Cancer Staging and Lymph Nodes Commitment

CCR5 and CXCL12 Allelic Variants: Possible Association With Childhood Neuroblastoma Susceptibility?

Analysis of Peripheral T Cells and the CC Chemokine Receptor (CCR5) Delta32 Polymorphism in Prostate Cancer Patients Treated With Carboxymethyl-Glucan (CM-G)

CCR2 and CCR5 Genes Polymorphisms in Benign Prostatic Hyperplasia and Prostate Cancer

Systemic Sclerosis

Matrix Metalloproteinase-9 and Disease Activity in Multiple Sclerosis

Loṕez de Munain A. Influence of CCR5-Delta32 Genotype in Spanish Population With Multiple Sclerosis

CCL5 and CCR5 Genotypes Modify Clinical, Radiological and Pathological Features of Multiple Sclerosis

A Meta-Analysis of the Relation Between Chemokine Receptor 5 Delta32 Polymorphism and Multiple Sclerosis Susceptibility

The CCR5 Deletion Mutation Fails to Protect Against Multiple Sclerosis

Ccr5D32 Polymorphism Associated With a Slower Rate Disease Progression in a Cohort of RR-MS Sicilian Patients

Association of CCR5 D32 Deletion With Early Death in Multiple Sclerosis

Immune Response Genes Receptors Expression and Polymorphisms in Relation to Multiple Sclerosis Susceptibility and Response to INF-b Therapy

CCR5-Delta32: Implications in SLE Development

Chemokine Receptor 5 (CCR5) Delta 32 Polymorphism in Lupus Nephritis: A Large Case-Control Study and Meta-Analysis

Chemokine Receptor 5 D32 Polymorphism and Systemic Lupus Erythematosus, Vasculitis, and Primary Sjogren's Syndrome

Lack of Association of C-C Chemokine Receptor 5 D32 Deletion Status With Rheumatoid Arthritis, Systemic Lupus Erythematosus, Lupus Nephritis, and Disease Severity

Evaluation of CCR5D32 Polymorphism in Patients With Systemic Lupus Erythematosus and Healthy Individuals

The Role of MECP2 and CCR5 Polymorphisms on the Development and Course of Systemic Lupus Erythematosus

Genetic Variants in Preeclampsia: Lessons From Studies in Latin-American Populations

Association of the CC Chemokine Receptor 5 (CCR5) Polymorphisms With Preeclampsia in Turkish Women

Considerations About the Role of the CCR5 Gene in Juvenile Idiopathic Arthritis -Look at the Whole or Put All Parts Together?

A130: Is the CCR5-Delta32 Mutation Protective Against Systemic-Onset Juvenile Idiopathic Arthritis?

Characterization of Cellular Infiltrate, Detection of Chemokine Receptor CCR5 and Interleukin-8 and RANTES Chemokines in Adult Periodontitis

Patterns of Chemokines and Chemokine Receptors Expression in Different Forms of Human Periodontal Disease

CCR5 Mediates Pro-Osteoclastic and Osteoclastogenic Leukocyte Chemoattraction

Involvement of CCR5 in Bone Resorption Associated to Apical Periodontitis

Prevalence of the Chemokine Receptor CCR5-Delta32 Gene Mutation in Periodontal Disease

Association of CCL5 and CCR5 Gene Polymorphisms With Periodontitis in Taiwanese

Staphylococcus Aureus Osteomyelitis: Bad to the Bone

Gene Polymorphisms and Transplantation

CC Chemokine Receptor 5 and Renal-Transplant Survival

CC Chemokine Receptor 5delta32 Polymorphism-a Risk Factor for Ischemic-Type Biliary Lesions Following Orthotopic Liver Transplantation

Chemokine Receptor Polymorphism and Risk of Acute Rejection in Human Renal Transplantation

Chemokine Receptor 2-V64I and Chemokine Receptor 5-Delta32 Polymorphisms and Clinical Risk Factors of Delayed Graft Function and Acute Rejection in Kidney Transplantation

The Effect of Chemokine Receptor Gene Polymorphisms (CCR2V64I, CCR5-59029g>A and CCR5D32) on Renal Allograft Survival in Pakistani Transplant Patients

Impact of Chemokine Receptor CCR2 and CCR5 Gene Polymorphism on Allograft Outcome in North Indian Renal Transplant Recipients

Analysis of CC Chemokine Receptor 5 and 2 Polymorphisms and Renal Transplant Survival

Association of the CCR5D32 Mutant Genotype With Sickle Cell Disease in Egyptian Patients

Delta32 Polymorphisms and Cancer Risk: A Meta-Analysis Based on 20,625 Subjects

Association Analysis and Allelic Distribution of Deletion in CC Chemokine Receptor 5 Gene (CCR5D32) Among Breast Cancer Patients of Pakistan

Improved Metastasis-Free Survival in Nonadjuvantly Treated Postmenopausal Breast Cancer Patients With Chemokine Receptor 5

Del32 Frameshift Mutations

Evaluating the Association Between CCR5delta32 Polymorphism (Rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population

CD8+ Cytotoxic T Lymphocytes in Cancer Immunotherapy: A Review

The Role of TLRs in Cervical Cancer With HPV Infection: A Review

MicroRNA-Related Polymorphisms in Infectious Diseases-Tiny Changes With a Huge Impact on Viral Infections and Potential Clinical Applications

CCR5 Expression on Monocytes and T Cells: Modulation by Transmigration Across the Blood-Brain Barrier In Vitro

The Chemokine Receptor CCR5 in the Central Nervous System

CCR5 Blockade for Neuroinflammatory Diseases-Beyond Control of HIV

Race-Specific HIV-1 Disease-Modifying Effects Associated With CCR5

Confounding and Heterogeneity in Genetic Association Studies With Admixed Populations

CCR5del32 Genotype in Human Enteroviral Cardiomyopathy Leads to Spontaneous Virus Clearance and Improved Outcome Compared to Wildtype CCR5

Conflict of Interest: JE is Guest Associate Editor of Frontiers in Immunology but he was not involved in editing this article.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.