key: cord-278831-gwnfcfvk
authors: Taniwaki, Sueli Akemi; Figueiredo, Andreza Soriano; Araujo Jr., João Pessoa
title: Virus–host interaction in feline immunodeficiency virus (FIV) infection
date: 2013-08-02
journal: Comp Immunol Microbiol Infect Dis
DOI: 10.1016/j.cimid.2013.07.001
sha: 
doc_id: 278831
cord_uid: gwnfcfvk

Feline immunodeficiency virus (FIV) infection has been the focus of several studies because this virus exhibits genetic and pathogenic characteristics that are similar to those of the human immunodeficiency virus (HIV). FIV causes acquired immunodeficiency syndrome (AIDS) in cats, nevertheless, a large fraction of infected cats remain asymptomatic throughout life despite of persistent chronic infection. This slow disease progression may be due to the presence of factors that are involved in the natural resistance to infection and the immune response that is mounted by the animals, as well as due to the adaptation of the virus to the host. Therefore, the study of virus–host interaction is essential to the understanding of the different patterns of disease course and the virus persistence in the host, and to help with the development of effective vaccines and perhaps the cure of FIV and HIV infections.

The feline immunodeficiency virus (FIV) was initially isolated in 1986 from domestic cats that exhibited signs of immunodeficiency but were seronegative for the feline leukaemia virus (FeLV) [1] . FIV belongs to the family Retroviridae, the subfamily Orthoretrovirinae, and the genus Lentivirus [2] . It exhibits a complex genomic organisation, which includes the structural genes gag, pol, and env, as well as several other genes that encode non-structural proteins. The 5 and 3 ends of the proviral DNA that is integrated into the host cell chromosomes comprise long terminal repeats (LTRs), which are repeated regions that contain information on the start and termination of transcription [3, 4] . Because the genomic organisation and pathogenesis of FIV are similar to those of human immunodeficiency virus (HIV), FIV has been widely used as an experimental model in studies of immunopathogenesis and virus-host interactions and in the development of vaccines and antiretroviral therapies [4] [5] [6] [7] [8] .

FIV is present worldwide and can be classified into five well-characterised subtypes (A-E) [9] [10] [11] [12] [13] . The prevalence of FIV varies from 1% to 44%, depending on the health status of the investigated cats [3, [14] [15] [16] . The prevalence of FIV is influenced by the animals' behaviour. Free-ranging male cats in areas of high population density constitute the risk group mainly because of their greater exposure to bites, which are the main path of disease transmission, during territorial demarcation fights [3] .

Infected cats do not exhibit specific clinical signs, and some animals can remain asymptomatic throughout life. FIV infection causes progressive immunosuppression that results in the development of the acquired immunodeficiency syndrome (AIDS) in cats, which, similar to human HIV infection, increases susceptibility to secondary and opportunistic infections. Concomitantly, FIV also causes immunostimulation, which results in immune-mediated diseases [17, 18] .

FIV infection is one of the most important infectious diseases in cats because it causes persistent infection. The aim of the present review is to discuss the virus-host interaction in FIV infection to better understand the immunopathogenesis of this disease, particularly the immune system dysfunction. In addition, the present review seeks to establish the presence of factors that are involved in the natural resistance to FIV infection, similar to those that have been discovered in HIV-exposed seronegative humans.

Following infection, viral replication occurs in dendritic cells, macrophages, and CD4 + T lymphocytes. A marked viraemia is usually detected in the second week postinfection (pi), with a peak between 8 and 12 weeks, when the virus spreads across the entire organism [3, 4, 18, 19] . During this initial stage, or the acute phase, the animals may exhibit mild to moderate clinical signs, such as fever, transient generalised lymphadenopathy, anorexia, and lethargy [4, 18, 20] . Gag-specific cytotoxic T lymphocytes (CD8 + ) may be detected as early as the second week pi, which is prior to seroconversion [21] Two to eight weeks after infection, specific antibodies against the surface (SU) and transmembrane (TM) proteins of env gene, and the capsid (CA) and matrix (MA) proteins of gag gene might be identified [4, 18] .

Despite the development of a cellular and humoral immune response, the animals are unable to eliminate the virus, which leads to the establishment of persistent FIV infection [4] . Nevertheless, the immune response reduces the circulating viral load, which defines the onset of the asymptomatic stage. The infected cats remain in this stage for many years, or even throughout life, with few clinical signs; however, progressive immunodeficiency with reduction in the number of CD4 + T lymphocytes and an inversion of the CD4 + /CD8 + ratio [3, 18, 19] .

Finally, a proportion of FIV-positive cats reaches the second stage, or terminal phase, which correlates with the generalised lymphadenopathy, pre-AIDS, and AIDS stages of HIV infection [4, 22] . This phase is characterised by severe immunosuppression and a consequent reduction in circulating antibodies, which allows the viral load increase and the development of disease s that are caused by opportunistic or secondary chronic infections, neoplasia, and neurological disorders [4, 19] . Despite the progressive immunodeficiency, the course of the disease depends on the virus-host interaction, which explains why only a fraction of the animals develops the terminal phase.

The cell tropism and the pathogenesis of the viral disease are determined by the specificity of the interaction between the viral surface proteins and the host cell receptors [4, 23] . Similar to HIV infection, infection with FIV requires an initial interaction with a primary receptor and subsequent binding to a co-receptor [24] . In the case of HIV infection, the surface glycoprotein (gp120) interacts with the CD4 receptor expressed on the surface of CD4 + T lymphocytes [25] , which results in a conformational change in gp120 that exposes the co-receptor binding site, thereby allowing binding to the chemokine receptors CXCR4 or CCR5 [23, 25] . The interaction between the coreceptor and gp120 induces a conformational change in the HIV transmembrane glycoprotein (gp41) that exposes its fusion peptide and thus allows the fusion of the viral envelope with the cell membrane [23, 26] . This conformational change in the envelope proteins is an important mechanism for viral escape because the conserved regions of the surface protein, which are the target of neutralising antibodies, are not exposed prior to binding to the receptor and co-receptor [25] .

In contrast to HIV, FIV uses CD134 instead of CD4 as its primary receptor. CD134, which is also known as OX40, is a member of the tumour necrosis factor and nerve growth factor receptor superfamily [24] . A large fraction of the FIV primary strains that have been isolated from infected animals, which are most likely the transmissible viruses, require initial binding to the CD134 receptor and subsequent binding to the CXCR4 chemokine receptor for productive infection [24, 27] . However, some cultureadapted FIV strains do not use the CD134 receptor and are able to interact directly with the CXCR4 co-receptor [23] . The interaction between CD134 and the FIV surface protein gp95 leads to structural changes that expose the binding site of the CXCR4 co-receptor [28] . Binding to the CXCR4 co-receptor induces the exposure of a serpentine region of the FIV transmembrane protein (gp36) that binds to the cell membrane, thereby originating a hairpin structure that allows for viral fusion and entry [29] . These interactions also induce the exposure of the epitopes that are the target of neutralising antibodies [28] . Although the V3 region of gp95 is the principal immunodominant domain of FIV, the antibodies produced exhibit low neutralising activity. However, upon the binding of gp95 to soluble CD134, de Perseval et al. [28] observed that monoclonal antibodies against the surface protein inhibited FIV infections in vitro, which denotes a viral escape mechanism during infection.

In addition to a mechanism of viral protection against the host's immune response, the binding of the virus to cell surface receptors and co-receptors also accounts for the differentiated cell tropism that occurs throughout the course of the disease. In the case of HIV infection, binding via the CD4 receptor allows for entry into all CD4 + T lymphocytes [24] . However, the main viral strains found during the early stages of infection are those that use the co-receptor CCR5, which is only expressed by activated memory T lymphocytes, whereas the strains isolated at later stages tend to use the CXCR4 co-receptor [30] . In the case of FIV infection, all of the viral strains tested to date interact with the CXCR4 co-receptor, which, in cats, is highly expressed in activated T cells, B cells, and monocytes [23, 31] . Nevertheless, the need to interact with the primary receptor CD134, which is more abundantly expressed in activated CD4 + T lymphocytes, constrains the initial infection and consequently results in a depletion of the CD4 + T-cell subgroup that plays a vital role in the development of the antigen-specific cellular immune response [23, 24] .

Therefore, although these viruses use different entry receptors, the initial target of both FIV and HIV is the activated T lymphocytes [24] . However, with the progression of infection, the host's immune response exerts a positive selective pressure on the virus [32] . The high error rate of the reverse transcriptase enzyme, which is involved in retroviral replication, leads to mutations that result in the generation of a wide variety of different viral genomes within a single individual (quasispecies) and allows for a small changes of the surface proteins that alters their recognition by the immune system (antigenic drift) [33] . Kraase et al. [32] found a greater accumulation of mutations in the FIV env gene amongst cats diagnosed with late infection (322 weeks pi) compared with animals with acute infection (12 weeks pi). These mutations were mainly found in the glycosylated regions, which is an additional mechanism that is used by viruses to evade the immune system. In addition, a single mutation involving the loss of a glycosylation site (T271I, N269G, or N269D) might give rise to mutants that are less dependent on the receptor CD134 [32, 34] . Similar to the cultureadapted FIV prototypes, the viral variants that bind directly to the co-receptor CXCR4 are likely more susceptible to neutralising antibodies [32] . Thus, the presence of these viruses in the circulation during the asymptomatic phase must be transient; however, when the animals reach the terminal phase, which is characterised by severe immunosuppression, the viruses begin to circulate again [32] and increase the number of infected cells, including CD4 + and CD8 + T lymphocytes, B lymphocytes, and astrocytes [3, 23, 35 ].

As mentioned above, a cellular and humoral antiviral immune response occurs during the acute phase of the infection, which reduces the viral load. However, the infection persists as a result of the viral evasion mechanisms (e.g., glycosylation of the viral envelope proteins, camouflage of the immunodominant epitopes through structural changes of the envelope glycoproteins after binding to the host cell, and antigenic drift) and the immune dysfunction that occurs after infection. With the progression of the FIV infection, two opposing events occur that result in immune dysfunction: immunosuppression and hyperactivation of the immune system [7] . A summary of the events that promote the immune dysfunction are shown in Fig. 1 .

The immunosuppression caused by FIV infection manifests as a loss of response to viral antigens, a loss of response to mitogens, and the inability to launch a primary immune response against secondary pathogens [7] . Torten et al. [36] observed that, together with the progression of the disease (25-44 months pi), the infected cats exhibited a reduction in their response to T-dependent immunogens but an adequate response to T-independent immunogens. In addition, these researchers observed a reduction in lymphocyte proliferation, which is induced by mitogens in the infected cats. An alteration in cytokine production, immune anergy, and apoptosis, and a hyperactivation of regulatory T cells are the mechanisms that might explain the immune system dysfunction.

Although several studies have quantified the cytokines in FIV-infected cats, the profile of cytokine alteration is not yet well established (Table 1 ). This cytokine alteration is likely related to the infection stage, especially in relation to the reduction of CD4 + T lymphocytes and the inversion of the CD4 + /CD8 + ratio, as well as the different methods that have been used for the quantification of the proteins or transcripts. Lawrence et al. [37] observed a significant increase in the production of interleukin-1 (IL-1), IL-6, and tumour necrosis factor alpha (TNF␣) in peripheral blood mononuclear cells (PBMCs) in response to mitogens (concanavalin A (ConA) and pokeweed mitogen (PWM)) in FIV-positive cats with or without signs of immunosuppression. In addition, a significant reduction of IL-2 was observed in symptomatic animals, which also exhibited reduced lymphocyte proliferation in response to mitogens [37] . An increased bioactivity of TNF␣ and IL-6 was observed in alveolar macrophages before (four weeks pi) and after (10 weeks pi) the inversion of the CD4 + /CD8 + ratio [38] . The same study also observed an increased expression of TNF␣, IL-6, IL-10, and interferon-gamma (IFN␥). An increased expression of IFN␥ and a reduced expression of IL-2 and IL-12 were observed in infected cats after the inversion of the CD4 + /CD8 + ratio 24 weeks pi [39] .

FIV-infected cats do not exhibit a primary immune response against a secondary infection by either Toxoplasma gondii [39] or Listeria monocytogenes [40] . FIV-and T. gondii-co-infected animals exhibit increased expression of IL-10 before and after the infection by the secondary pathogen. The high production of IL-10 suppresses the production of Th1 (IL-2, IL-12, and IFN␥) and Th2 (IL-6) cytokines, which explains the inability to contain the infection by T. gondii [39] . Dean et al. [41] observed that FIV-positive cats, especially animals with chronic infections (after the inversion of the CD4 + /CD8 + ratio), exhibited higher numbers of colony-forming units of L. monocytogenes in the lymph nodes. In addition, the innate immune response of these cats with chronic infection was unable to contain the secondary infection four days after inoculation, unlike animals with acute infection or FIV-negative cats [41] . This reduction in the response to infection by L. monocytogenes might be due to increased IL-10 expression, which inhibits the production of TNF␣ in macrophages [40] . In contrast to Levy et al. [39] , Dean et al. [40] did not observe a reduction in the levels of IL-2 and IFN␥, most likely because the animals from the latter study did not exhibit an alteration of the CD4 + /CD8 + ratio. Nevertheless, both studies observed an increase in the IL-10/IL-12 ratio, which explains the deficient response to the secondary pathogen because IL-12 stimulates IFN␥ and TNF␣ production and IL-10 suppresses the production of IL-12 by dendritic cells [7, 42] . Therefore, there is an important change in cytokine production that results in a deficient response to secondary pathogens.

Both FIV and HIV infections are associated with a progressive loss of T-cell function, which is caused by the suppression of IL-2 production, and an increased programmed cell death (apoptosis) of T cells in the lymph nodes [7] . Immune anergy is the functional inactivation of T or B lymphocytes following antigenic stimulation due to inadequate amounts of co-stimulatory molecules (e.g., B7.1 and B7.2) in antigen-presenting cells or to the presence of inhibitory CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) receptors [43] . The binding of B7 molecules to the CD28 receptor, which is expressed in T lymphocytes, stimulates the release of IL-2 and consequently the clonal expansion that is needed to mount an effective immune response, whereas the binding of B7 to the CTLA4 receptor suppresses the release of IL-2 and thus terminates the immune response [43] . In addition, antigen recognition induces the production of pro-apoptotic proteins, but the activity of these proteins is neutralised by anti-apoptotic proteins in the normal response to microorganisms [43] .

Guiot et al. [44] observed that FIV-infected cats exhibited increased apoptosis that affected all lymphocyte types (CD4 + and CD8 + T lymphocytes, B lymphocytes, and natural killer (NK) cells). This increased apoptosis was directly correlated with an increase in the animal's age and the duration of the infection and with a reduction in the numbers of CD4 + T cells [44] . The increase in the apoptosis of CD4 + and CD8 + T cells in both the lymph nodes and the blood of FIV-positive cats might be related to an increase in the levels of CD4 + and CD8 + T cells with a B7 + CTLA4 + phenotype [45] . An increase in B7 + T cells was observed in animals with acute infection (<6 months), asymptomatic animals (1-5 years), and mainly animals with terminal infection (8-10 years) that exhibit a chronic secondary oral or respiratory infection and, in most cases, the presence of B-cell lymphoma at necropsy [45] . The chronic activation of T cells co-expressing B7 and CTLA-4 and the possibility of a T-T interaction mediated by the binding of B7.1/B7.2 to the CTLA-4 receptor induce a bidirectional suppression of IL-2 that results in anergy and apoptosis [7, 45, 46] . Therefore, this mechanism causes immunosuppression with a progressive loss of T cells and premature termination of the immune response against pathogens [45, 46] . The regulatory T (Treg) cells are mostly CD4 + cells that express high levels of CD25 (alpha chain of the IL-2 receptor), and their function is to regulate the activation of other T cells [43] . The Treg cells depend on the transcription factor Foxp3 and IL-2 to maintain their function and produce cytokines, such as IL-10 and tumour growth factor beta (TGF␤), that block the activation of lymphocytes and macrophages [43] . There are two different types of Treg cells: the thymus-generated natural Treg cells, which are related to the suppression of auto-immune T cells and the maintenance of tolerance to self-antigens, and the adaptive or induced Treg cells, which regulate the response of CD4 + and CD8 + T cells to pathogens (e.g., bacteria, fungi, intracellular parasites, and viruses) and are activated in the peripheral lymphoid tissues [47] [48] [49] . The function of the induced Treg cells is to avoid the tissue damage that is caused by excessive inflammation in response to pathogens [49, 50] . However, certain pathogens modulate the activity of these Treg cells and thus cause persistent chronic infection [48] .

Mexas et al. [49] showed that Treg cells (CD4 + CD25 + ) are the target of acute FIV infection since these cells exhibit high viral mRNA levels two weeks after infection, which correlates with the peak of viraemia. The establishment of persistent chronic infection may be related to the infection of CD4 + CD25 + cells because these cells are activated during acute infection in the presence of the Foxp3 transcription factor and TGF␤ and suppress the production of IL-2, thus inhibiting the antiviral response of the helper T cells [48] . In cats, the CD4 + CD25 + cells are unable to proliferate in response to antigenic or mitotic stimulation due to the lack of IL-2 production, and exhibit the ability to suppress the proliferation of the CD4 + CD25 − cells when activated [51] . In addition, during the disease progression, Treg cells act as a reservoir of infection, where the virus might replicate at low rates without becoming a target of the immune response because these cells exhibit anergic characteristics [49] . Although cats with chronic FIV infection exhibit the same proportion of CD4 + CD25 + cells as FIV-negative animals, the CD4 + CD25 + cells of FIV-positive cats exhibit a greater expression of B7.1 and B7.2 molecules in both the lymph nodes and the blood, as well as a greater CTLA-4 expression in the lymph nodes [51] . The expression of these molecules explain the immunosuppression mechanism associated with the Treg cells (CD4 + CD25 + B7 + CTLA4 + ) that are activated by FIV during the progression of the disease.

In addition to progressive immunosuppression, FIVpositive cats also exhibit marked hyperactivation of B and T cells [7] . The total protein levels are increased in FIV-infected cats due to an increase in the gamma globulins [52] . In one study, two FIV-positive cats with B-cell lymphoma exhibited an increase in B lymphocytes, increased IgG (from the beginning to the end of the follow-up period, which corresponded to 50-300 weeks pi), and a progressive increase in IgA [53] . Takano et al. [54] also observed higher globulin levels in FIV-positive cats at the terminal phase compared with animals in the asymptomatic phase or those that were FIV-negative. An increase in the levels of B cells with surface immunoglobulins (sIg + ) and negative for CD21, which represent cells that are differentiated for antibody production, was observed in the asymptomatic cats and more evident in animals in the terminal phase, which suggests that this finding might be related to the emergence of immunosuppression signs [54] . The activation of B lymphocytes corresponds to a polyclonal and non-virus-specific activation because antibodies against heterologous non-viral antigens were detected six to eight weeks after infection, remained until the end of the study (90 weeks pi), and did not exhibit cross-reactivity with FIV viral recombinant antigens [55] . Furthermore, neither the stimulation of B lymphocytes nor hypergammaglobulinemia were caused by co-infection with other pathogens because the study used specific pathogen free (SPF) animals that were experimentally infected with FIV [55] . Therefore, the hyperactivation caused by FIV is responsible for the appearance of immune-mediated diseases, such as chronic gingivitisstomatitis and glomerulonephritis, myeloproliferative neoplasms, and lymphomas [18] .

The stimulation of CD4 + and CD8 + T cells starts during the acute phase of FIV infection and continues throughout the disease progression [7] . The increase in the number of activated CD8 + T cells (CD8␤ low CD62L − ) suggests that the naïve CD8 + T cells are replaced by the activated CD8 + T cells during FIV infection. The same phenomenon occurs with the CD4 + T cells, which reduce the expression of CD62L during the course of infection (reviewed in [7] ). In addition, and as mentioned above, the increased expression of B7 molecules and CTLA-4 by activated CD4 + and CD8 + T cells might alter the host's immune response [45] . Tompkins and Tompkins [7] suggested that FIV infection activates CD4 + , CD8 + and Treg (CD4 + CD25 + ) T cells. The activation of Treg cells inhibits the production of IL-2 and IFN␥ through the production of TGF␤ and thus reduces the immune response against FIV through the induction of anergy and apoptosis, which allows for continuous viral replication and chronic antigenaemia. In turn, chronic antigenaemia causes hyperactivation of the CD4 + /CD8 + T cells and Treg cells, which results in anergy and apoptosis due to the activity of the Treg cells and an inappropriate T-T cell interaction due to the binding of B7/CTLA-4, which are expressed in larger amounts in activated T cells [7] . This uncontrolled hyperactivation of immune system causes progressive immunosuppression and a reduction in the immune response to secondary infections.

Major efforts have been devoted in recent years to the discovery of novel alternatives to the treatment, and perhaps even cure, of HIV infection. For that purpose, many studies seek to understand the factors that are involved in the natural resistance to HIV-1 infection that occurs in some individuals who, despite a history of frequent (sexual, parenteral, or vertical) exposure to the virus, do not exhibit any serologic evidence of infection or any sign of immunodeficiency [56] . These high-risk exposed but seronegative (ESN) individuals seem to have genetic and immunological factors that reduce their susceptibility to infection, although a single factor individually may not account for this characteristic [57] .

Amongst the genetic factors involved in the slow progression of AIDS and resistance to HIV infection, the following have been identified: alleles of human leucocyte antigen (HLA), the presence of activators or the absence of inhibitors of the genes encoding KIR (killer immunoglobulin-like receptor) molecules, a genetic polymorphism of the chemokines RANTES (regulated on activation normal T-cell expressed and secreted), macrophage inflammatory protein (MIP)-1␣, and MIP-1␤ and their receptors [56, 57] . Amongst these alterations, the deletion of 32 base pairs of the gene encoding the CCR5 receptor (CCR5 32) is strongly correlated with resistance to HIV infection [58] . Dean et al. [59] observed that approximately 10% of the studied population (n > 600), which included healthy controls, ESN individuals, and HIVpositive individuals with and without signs of AIDS, had the CCR5 32 allele. This mutation causes a change in the reading frame of amino acid 185 that generates a non-functional protein with a premature termination codon [58, 59] . Individuals who are homozygous for the CCR5 32 allele are strongly protected against HIV infection because these individuals lack a functional CCR5 co-receptor on their cell surface [59, 60] . All of the CCR5 32/ 32 homozygous individuals were ESN individuals, whereas none amongst the 1343 HIV-positive individuals exhibited this genotype [59] . In addition, CCR5 + / 32 heterozygous individuals exhibited some degree of resistance to infection; and when infected, their viral load is lower, and their progression of AIDS is slower compared with that observed in CCR5 + / + homozygous individuals [59] . There is still no evidence of any mutations in the FIV receptors that confer a natural resistance to infection in cats. Currently, the following are known: the in vitro infectivity of FIV decreases in a large fraction of strains with the use of a feline/human hybrid CD134 receptor, the human CD134 receptor is not functional for FIV entry [61] , and mutations in the human CXCR4 co-receptor (D187A) prevent the in vitro entry of FIV [62] .

Nevertheless, although a deletion in the CCR5 coreceptor gene grants a high natural resistance to HIV infection, this mutation is not found in all ESN individuals. Therefore, other factors might also be involved. The host's innate immunity contributes to the protection against HIV infection mainly through the activity of NK cells and a large production of IFN␥. In addition, an increased production of ␤-chemokines (e.g., CC chemokine ligand (CCL)2, CCL3 (MIP-1␣), CCL4 (MIP-1␤), CCL5 (RANTES), and CCL11), ␣-chemokines (stromal cell-derived factor-1 (SDF-1)), peroxiredoxin II, CD8 + cell antiviral factor (CAF), NK cell stimulatory factor B, IL-22 (cytokine involved in the production of acute-phase proteins), defensins, and ribonucleases have been associated with protective effects [revised in 56, 57] . The innate immune response mediated by cellular restriction factors, such as APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide 3), Trim5␣ (tripartite motif protein), and tetherin, inhibits the viral replication of retroviruses and thus blocks the establishment of infection after the virus has entered the host cell [57, 58] .

APOBEC3 deaminates cytidine residues in RNA and single-stranded DNA, thereby converting cytosine (C) into uracil (U) or thymine (T), which alters the encoding of the viral proteins [8, 63] . According to recent observations in humans, exposure to HIV increases the expression of APOBEC3G, and ESN individuals exhibit a higher expression of this protein compared with non-exposed individuals. In addition, APOBEC3G reduces the susceptibility to HIV infection in vitro [56] [57] [58] . In cats, the action of APOBEC3G was investigated with three exogenous feline retroviruses: FIV, FeLV, and feline syncytium-forming virus (FeSFV), which is different from the first two viruses because it is considered non-pathogenic in nature [8] . FeLV exhibited reduced infectivity in vitro when APOBEC3 proteins were present, which might explain the occurrence of abortive and regressive infection in some of the cats that had contact with the virus [8, 64] . FeLV belongs to the genus Gammaretrovirus and does not have the accessory genes vif and bet, which are found in species that belong to the genera Lentivirus and Spumavirus, respectively [33] , and are associated with the inactivation of APOBEC3 [65] . An exception is the equine infectious anaemia virus (EIAV), which is the only lentivirus that lacks the vif gene, but it exhibits resistance to feline APOBEC3 [8] . Several studies have shown that retroviruses are inhibited by the action of APOBEC3 in non-susceptible species, which explains the host specificity and enables its therapeutic use [63] . Although APOBEC3 exhibits an antiviral effect, viruses have mechanisms that prevent the action of this protein in the natural host, and cause a persistent infection. The same is true with tetherins, which exert an antiviral action by preventing the release of viral particles. Dietrich et al. [66] showed that the release of FIV and HIV-1 particles was inhibited by the transient expression of the feline tetherin. However, FIV replication did not decrease when the expression of tetherin was stable, which probably occurs in natural infection. Furthermore, the cell-to-cell spread of the virus is facilitated by the increase in syncytium formation [66, 67] . According to some studies, the feline Trim5␣ is truncated and does not exhibit any antiretroviral effect [66, 67] . Therefore, further investigation of restriction factors, especially their importance in the prevention and treatment of infection, is warranted because orthologous restriction factors were shown to inhibit infection by retroviruses.

Although acquired immunity, both cellular and humoral, plays a crucial role in the resistance to HIV infection, there is not yet a consensus as to which mechanisms are truly protective. With regard to the cellular immune response in ESN individuals, some reports indicate a strong anti-HIV response by non-cytotoxic CD8 + T cells, the recognition of a different epitope compared with seropositive individuals, and a greater Th1 response that is characterised by an increased production of IL-2 and IFN␥ and a reduced IL-10 production [56, 57] . Nevertheless, a low lymphocyte activation was also shown to reduce the susceptibility to HIV infection because lymphocyte activation is needed for viral replication and is associated with the pathogenesis of the disease [7, 56] . The resistance to infection might be related to the humoral immune response mainly through the production of anti-HIV immunoglobulin A (IgA), which is present in cervicovaginal secretions, saliva, colostrum, and serum, and by the presence of autoantibodies against the CD4 receptor in ESN individuals [56, 57] . In cats, anti-CD134 antibodies were observed in 63% (143/226) of FIV-positive animals, whereas these antibodies were not present in any of the SPF animals (n = 107) and only in 0.44% (1/225) of the diseased cats, some of which were infected by feline herpesvirus (FHV), feline coronavirus (FCoV), or FeLV but were FIV-negative [68] . In addition, the cats with anti-CD134 antibodies exhibited a lower viral load and a better state of health, which indicates the importance of these antibodies in the progression of disease [68] .

The ability of animals to develop an immune response that is sufficiently robust to reduce FIV viral load, although unable to extinguish the FIV infection, may reflect an important factor for reducing the speed of disease progression. However, this factor might also increase the selective pressure and induce the accumulation of a greater number of mutations throughout the course of the infection because the virus has a greater need to adapt to survive in the host. In addition, the early reduction in the number of CD4 + T lymphocytes and the consequent decrease in the CD4 + /CD8 + ratio, which correlates with the emergence of immunosuppression signs, might be related to the presence of virus with mutations that favour its escape or occurs in cats unable to develop a response that restricts viral replication.

Few studies have examined the presence of factors that are involved in the natural resistance to FIV infection in cats. The identification of these factors may contribute to a better understanding of the various patterns of disease progression and help with the development of a FIV/HIV cure. The complexity of the virus-host interaction, particularly the mechanisms of viral persistence, justifies the difficulty in the development of effective vaccines and treatments. Therefore, much of this interaction must still be investigated before a full understanding of FIV infection in cats and HIV infection in humans.

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Constitutive expression of types 1 and 2 cytokines by alveolar macrophages from feline immunodeficiency virus-infected cats

Failure of FIV-infected cats to control Toxoplasma gondii correlates with reduced IL2, IL6, and IL12 and elevated IL10 expression by lymph node T cells

Effect of feline immunodeficiency virus on cytokine response to Listeria monocytogenes in vivo. Veterinary

Cytokine modulation of the innate immune response in feline immunodeficiency virus-infected cats

Multivariate statistical analyses demonstrate unique host immune responses to single and dual lentiviral infection

Imunologia básica: funç ões e distúrbios do sistema imunológico

Spontaneous programmed cell death (PCD) process of lymphocytes of FIV-infected cats: cellular targets and modulation

Feline immunodeficiency virus infection is characterized by B7+CTLA4+T cell apoptosis

A4+T cells engage in T-T cell interactions that mediate apoptosis: a model for lentivirus-induced T cell depletion

Natural versus adaptive regulatory T cells

The role of CD4+CD25+ regulatory T cells in viral infections

CD4+CD25+ regulatory T cells are infected and activated during acute FIV infection

Regulatory cells and infectious agents: détentes cordiale and contraire

Feline immunodeficiency virus infection phenotypically and functionally activates immunosuppressive CD4+CD25+T regulatory cells

Hematology and serum biochemistry of feline immunodeficiency virus-infected and feline leukemia virusinfected cats

Feline immunodeficiency virus (FIV)-associated lymphoma: a potential role for immune dysfunction in tumourigenesis

Comparative study of the plasma globulin level, CD21(−) B-cell counts and FOXP3 mRNA expression level in CD4(+) T-cells for different clinical stages of feline immunodeficiency virus infected cats

Polyclonal Jarrett O. B-cell activation in cats infected with feline immunodeficiency virus

Immunological factors involved in natural resistance to HIV-1 infection

Host factors involved in low susceptibility to HIV infection

Determinants of protection among righ risk HIV seronegative persons: an overview

Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene, Hemophilia Growth and Development Study

The evolutionary history of the CCR5-Delta32 HIV-resistance mutation

Mapping the domains of CD134 as a functional receptor for feline immunodeficiency virus

Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses

Restrictions to cross-species transmission of lentiviral infection gleaned from studies of FIV

Functions, structure, and read-through alternative

Molecular and functional interactions of cat APOBEC3 and feline foamy and immunodeficiency virus proteins: different ways to counteract host-encoded restriction

Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection

Cellular restriction factors of feline immunodeficiency virus

Improved health and survival of FIV-infected cats is associated with the presence of autoantibodies to the primary receptor

This work was supported by the São Paulo Research Foundation (FAPESP) grant 2009/52979-5.