key: cord-0753270-chf4erxl
authors: Nicholas, Rachel E.; Sandstrom, Kjell; Anderson, Jennifer L.; Smith, Willow R.; Wetzel, Molly; Banerjee, Priyankana; Janaka, Sanath Kumar; Evans, David T.
title: KIR3DL05 and KIR3DS02 Recognition of a Nonclassical MHC Class I Molecule in the Rhesus Macaque Implicated in Pregnancy Success
date: 2022-03-23
journal: Front Immunol
DOI: 10.3389/fimmu.2022.841136
sha: ddd2469bda18bcc8df5f0b97777d4adf02938eec
doc_id: 753270
cord_uid: chf4erxl

Knowledge of the MHC class I ligands of rhesus macaque killer-cell Ig-like receptors (KIRs) is fundamental to understanding the role of natural killer (NK) cells in this species as a nonhuman primate model for infectious diseases, transplantation and reproductive biology. We previously identified Mamu-AG as a ligand for KIR3DL05. Mamu-AG is a nonclassical MHC class I molecule that is expressed at the maternal-fetal interface of the placenta in rhesus macaques similar to HLA-G in humans. Although Mamu-AG and HLA-G share similar molecular features, including limited polymorphism and a short cytoplasmic tail, Mamu-AG is considerably more polymorphic. To determine which allotypes of Mamu-AG serve as ligands for KIR3DL05, we tested reporter cell lines expressing five different alleles of KIR3DL05 (KIR3DL05*001, KIR3DL05*004, KIR3DL05*005, KIR3DL05*008 and KIR3DL05*X) for responses to target cells expressing eight different alleles of Mamu-AG. All five allotypes of KIR3DL05 responded to Mamu-AG2*01:01, two exhibited dominant responses to Mamu-AG1*05:01, and three had low but detectable responses to Mamu-AG3*03:01, -AG3*03:02, -AG3*03:03 and -AG3*03:04. Since KIR3DL05*X is the product of recombination between KIR3DL05 and KIR3DS02, we also tested an allotype of KIR3DS02 (KIR3DS02*004) and found that this activating KIR also recognizes Mamu-AG2*01:01. Additional analysis of Mamu-AG variants with single amino acid substitutions identified residues in the α1-domain essential for recognition by KIR3DL05. These results reveal variation in KIR3DL05 and KIR3DS02 responses to Mamu-AG and define Mamu-AG polymorphisms that differentially affect KIR recognition.

MHC class I molecules play a central role in both innate and adaptive immunity. In addition to presenting peptides derived from intracellular antigens on the cell surface for recognition by CD8 + T cells, MHC class I molecules serve as ligands for killer cell Ig-like receptors (KIRs) on natural killer (NK) cells (1, 2) . Whereas the extensive polymorphism of classical MHC class I molecules ensures the presentation of a diverse repertoire of peptides derived from intracellular pathogens to CD8 + T cells, the limited polymorphism of nonclassical MHC class I molecules reflects their more specialized functions.

Macaques and other Old World monkeys express an expanded array of polymorphic MHC class I genes that correspond to the classical HLA-A and -B genes of humans (3) (4) (5) . However, these species lack an ortholog of HLA-C as a consequence of the recent evolutionary origin of HLA-C as a duplication of an ancestral MHC-B gene that occurred after the divergence of apes and Old World monkeys (3, 6) . Old World monkeys have accordingly expanded their lineage II KIR, which encode KIR3D receptors for MHC-A and -B, but lack lineage III KIR that encode KIR2D receptors for HLA-C in humans (7) (8) (9) (10) (11) (12) (13) . Old World monkeys also have orthologs of each of the human nonclassical HLA-E, -F and -G genes. MHC-E and -F are well-conserved and broadly expressed in primates (14) (15) (16) . However, the MHC-G genes of Old World monkeys have accumulated multiple stop codons and no longer encode functional proteins (17, 18) . In the absence of a functional MHC-G locus, Old World monkeys have evolved another nonclassical MHC class I gene, designated MHC-AG, which appears to serve a similar function (19) (20) (21) (22) .

Macaques, vervets, and baboons express MHC-AG molecules with similar molecular features and tissue distribution as HLA-G (22, 23) . MHC-AG sequences are more similar to MHC-A than to MHC-G as a consequence of their evolutionary origins as an MHC-A gene duplication (19) (20) (21) (22) . However like HLA-G, MHC-AG exhibits limited polymorphism, a truncated cytoplasmic tail, and is only expressed on placental trophoblasts that form the barrier between the mother and the developing fetus (19, 20, 23) . Hence, Mamu-AG is believed to serve a similar function as HLA-G, namely contributing to pregnancy success through interactions with NK cells and myeloid cells that promote placental vascularization, tolerance to the haploidentical fetus, and protect the maternal-fetal interface from invading pathogens (23, 24) .

The rhesus macaque (Macaca mulatta) is an important animal model for infectious diseases such as HIV/AIDS, CMV, Zika virus and SARS-CoV-2 (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) , transplantation (36, 37) , and reproductive biology (23, 38) . We previously identified Mamu-AG as a ligand for KIR3DL05 (39) . Here we show that KIR3DL05 recognizes certain allotypes of Mamu-AG, but not others, and define residues in the a1and a2-domains of Mamu-AG essential for interactions with this receptor. We further identify Mamu-AG as a ligand for the activating receptor KIR3DS02. These observations provide an essential foundation for investigating the role of NK cells in the rhesus macaque as a nonhuman primate model for infectious diseases and reproductive biology. These findings also illustrate how polymorphisms in the a1-domain can lead to variation in KIR recognition of closely related MHC class I ligands.

Codon-optimized cDNA sequences encoding Mamu-AG molecules were synthesized by GenScript. These sequences were then cloned into the retroviral vector pQCXIP. Retroviral vectors were packaged into VSV-G-pseudotyped murine leukemia virus (MLV) particles by co-transfecting GP2-293 cells with pQCXIP-Mamu-AG constructs and pVSV-G (Clontech Laboratories). The cell culture supernatant was collected two days after transfection and cellular debris was removed by centrifugation followed by filtration through a 0.45 µm nylon membrane. HLA-null 721.221 cells were transduced by spinoculation for one hour with supernatant collected from the transfected GP2-293 cells. After two days, the transduced cells were placed under antibiotic selection with RPMI medium supplemented with 10% FBS, Lglutamine, penicillin, streptomycin (R10) and 0.4 µg/ml puromycin (Calbiochem). The concentration of puromycin in the medium was gradually increased to 1.0 µg/ml over 3-4 weeks to eliminate untransduced parental 721.221 cells. After 3-4 weeks of selection, cell lines were maintained in medium containing 0.4 µg/ml puromycin. Mamu-AG expression was confirmed by flow cytometry via surface staining with a PEconjugated, pan-MHC class I-reactive monoclonal antibody (W6/ 32, Life Technologies). Mamu-AG-transduced 721.221 cell lines were maintained in R10 medium containing 0.4 µg/ml puromycin. The GenBank accession numbers for Mamu-AG alleles are as follows: Mamu-AG2*01:01 (U84783.1), -AG3*02:01:01:01 (U84785.1), -AG3*02:02:01 (U84786.1), -AG3*03:01:01:01 (U84787.1), -AG3*03:02 (U84789.1), -AG3*03:03 (KF855159.1), -AG3*03:04 (KF855160.1), and -AG1*05:01 (FJ409466). Only partial-length cDNA sequences were available for Mamu-AG3*03:03, -AG3*03:04, and -AG1*05:01. For constructs expressing these alleles, sequences encoding the a3-, transmembrane and cytoplasmic domains were therefore inferred from the Mamu-AG consensus sequence.

Constructs for the expression of chimeric KIR-CD3z receptors with an N-terminal Flag-tag were engineered by cloning cDNA sequences into pQCXIP encoding the D0, D1, D2 and stem domains of KIR3DL05 downstream of sequences for the KIR3DL05*008 leader peptide and Flag-tag (DYKDDDDK) and upstream of sequences coding for the transmembrane and cytoplasmic domains of CD3z. Retroviral vectors were packaged into VSV-G-pseudotyped MLV particles as described above. Jurkat NFAT luciferase (JNL) cells (Signosis) were transduced by spinoculation for one hour with filtered supernatant from transfected GP2-293 cells. Two days after transduction, the JNL cells were placed under antibiotic selection in R10 medium containing 100 µg/ml hygromycin to maintain the luciferase reporter gene and 0.5 µg/ml puromycin to select for KIR-CD3z expression. The puromycin concentration in the medium was gradually increased to 1.0 µg/ml over 3-4 weeks to eliminate untransduced cells and then maintained at a concentration of 0.4 µg/ml. GenBank accession numbers for rhesus macaque KIR sequences are as follows: KIR3DL05*001/KIR3DLW36*001 (EU419045), KIR3DL05*004 (EU419066.1), KIR3DL05*005/ KIR3DLW37*001 (EU419069), KIR3DL05*X (EU419067.1), KIR3DL05*008 (GU112291), and KIR3DS02*004 (EU419026).

KIR-CD3z + JNL cells (1x10 5 ) were co-cultured with Mamu-AG + or parental 721.221 cells (1x10 5 ) overnight at 37°C and 5% CO 2 in triplicate wells of white 96-well plates in 100 µl R10 medium without antibiotics. As a positive control, KIR-CD3z + JNL cells were treated with 5 µg/ml of an anti-Flag-tag monoclonal antibody (GenScript) and 10 µg/ml of a goat anti-mouse secondary antibody (Poly4053, Biolegend). After 12-18 hours, 100 µl of BriteLite Plus luciferase substrate (PerkinElmer) was added to each well and luciferase activity in relative light units (RLU) was measured using a VICTOR X4 multiplate reader (PerkinElmer). 

The RLU data was analyzed by one-way ANOVA followed by Dunnett's test for multiple comparisons of mean KIR-CD3z + JNL cell responses to each of the Mamu-AG + 721.221 cells with mean responses to the parental 721.221 cells as a negative control. For analysis of responses to the Mamu-AG2*02:01 variants, mean RLU values in response to 721.221 cells expressing each variant were compared with mean RLU values in response to 721.221 cells expressing wild-type Mamu-AG2*02:01 using an unpaired t test. Statistical analyses were performed using GraphPad Prism for Mac OS version 9.2.0.

Mamu-AG2*01:01 was previously identified as a ligand for KIR3DL05*008 (39) . However, Mamu-AG and KIR3DL05 are both polymorphic, raising the possibility of allelic variation in ligand recognition. To assess the impact of polymorphisms in these molecules on receptor-ligand interactions, five allotypes of KIR3DL05 were tested for the recognition of eight allotypes of Mamu-AG. KIR3DL05*001, *004, *005, *X and *008 were selected from a previous study showing differences in KIR3DL05 binding to Mamu-A1*002-peptide complexes (40) ( Figure 1 ) and Mamu-AG2*02:01, -AG3*02:01, -AG3*02:02, -AG3*03:01, -AG3*03:02, -AG3*03:03, -AG*03:04 and -AG1*05:01 were selected as representative allomorphs of predicted Mamu-AG loci ( 

KIR3DL05*X is the product of a recombination event that resulted in a hybrid receptor with D0 and D1 domains corresponding to KIR3DS02 and a D2 domain typical of KIR3DL05. We therefore tested KIR3DS02*004, which shares identical D0 and D1 domains with KIR3DL05*X, to determine if this activating KIR could also recognize Mamu-AG ( Figure 4A) . JNL cells expressing a KIR3DS02*004-CD3z fusion responded to 721.221 cells expressing Mamu-AG2*01:01, but not to cells expressing other Mamu-AG alleles ( Figures 4B, C) . These results identify Mamu-AG2* 01:01 as a ligand for KIR3DS02*004 and suggest that the more restricted pattern of responses to Mamu-AG compared to KIR3DL05*X reflects differences in the D2 domain.

To define Mamu-AG polymorphisms that account for differences in KIR3DL05 recognition, amino acid substitutions were introduced into Mamu-AG2*01:01 at positions that differ from Mamu-AG3*02:01 and -AG3*03:01. 721.221 cells expressing these variants were then tested for recognition by KIR3DL05-CD3z+ JNL cells ( Figure 5 ). The replacement of any one of three amino acids in the a1-domain of Mamu-AG2*01:01 with the corresponding residues of Mamu-AG3*02:01 (W18G, E19Q or V76E) partially or completely impaired KIR3DL05 recognition ( Figure 5A) . Likewise, individually exchanging three amino acids of Mamu-AG2*01:01 with the corresponding residues of Mamu-AG3*03:01 (S11A, R75Q or I95F) significantly impaired interactions with KIR3DL05 ( Figure 5A ). Conversely, a combination of three amino acid changes in the a1-domain of Mamu-AG3*02:01 (G18W, Q19E and E76V) was sufficient to restore interactions with KIR3DL05 to a similar level as Mamu-AG2*01:01 ( Figure 5A) . Thus, similar to the KIR recognition of classical MHC class I ligands, the specificity of KIR3DL05 is primarily determined by polymorphisms in the a1-domain of Mamu-AG.

The amino acid residues of Mamu-AG2*01:01 that participate in interactions with KIR3DL05 were modeled by in silico replacement of the corresponding residues in a threedimensional structure of Mamu-A1*002. Mamu-A1*002 was selected for modeling due to its general sequence similarity with Mamu-AG and because it is also a ligand for KIR3DL05 (43) . All of the polymorphic residues that affect KIR3DL05 recognition are in close proximity to the Bw4 motif (residues 77-83) at the C-terminal end of the a1-domain ( Figure 6 ). Residues 75 and 76, for which the R75Q and V76E polymorphisms had the greatest impact on KIR3DL05 responses, are part of the a-helical region directly adjacent to the Bw4 motif ( Figure 6 ). Residues 18 and 19 are located in an underlying loop that was previously identified as a KIR contact site based on the crystal structure of human KIR3DL1 in complex with HLA-B*5701 ( Figure 6 ) (41). The side chains of these residues are surface exposed in a region where the W18G and E19Q polymorphisms would be expected to contribute to a patch of sequence diversity together with polymorphisms at positions 75 and 76. In contrast, residues 11 and 95 are located in the floor of the peptide binding pocket and are unlikely to be surface exposed. The partial effects of the S11A and I95F on KIR3DL05 responses may therefore reflect differences in peptide binding and/or conformational changes to the peptide-MHC class I complex. Overall, these results are consistent with the structure of KIR3DL1 in complex with HLA-B*5701 showing extensive contacts between the D0 and D1 domains of the KIR and the a1-domain of the MHC class I molecule (41) . These findings also illustrate that while polymorphisms in residues 77-83 may determine broad patterns of KIR recognition (e.g. Bw4 specificity), polymorphisms in adjoining regions can contribute to variation in responses to closely related MHC class I allotypes. interactions in the rhesus macaque, Mamu-AG2*01:01 was identified as a ligand for KIR3DL05*008 (39) . Although Mamu-AG does not have a direct human ortholog, it shares similar molecular features and tissue distribution as HLA-G (19, 20, 23) . However, Mamu-AG is considerably more polymorphic than HLA-G owing to allelic variation at multiple loci (44) . KIR3DL05 is also polymorphic with at least 33 different KIR3DL05 alleles identified so far (45) . To gain a better understanding of the determinants of KIR3DL05 specificity for Mamu-AG, we investigated the impact of Mamu-AG polymorphisms on this receptor-ligand interaction.

Our findings reveal three general patterns of Mamu-AG recognition among the KIR3DL05 allotypes selected for this study. We also tested an allotype of KIR3DS02 with identical D0 and D1 domains to KIR3DL05*X. KIR3DS02*004 recognized Mamu-AG2*01:01, but did not respond to other Mamu-AG allotypes. These results identify Mamu-AG2*01:01 as a ligand for this activating KIR and indicate that differences in the D2 domains of KIR3DS02*004 and KIR3DL05*X account for differences in their responses to other Mamu-AG molecules.

An analysis of single amino acid variants identified Mamu-AG polymorphisms that affect KIR3DL05 recognition. In humans, HLA-G is expressed by fetal trophoblasts that invade the uterine endometrium during early stages of pregnancy and on extravillous trophoblasts that remodel spiral arteries of the developing placenta (46) . HLA-G is a ligand for KIR2DL4 (47, 48) , which is an unusual 2 domain KIR with both activating and inhibitory features. KIR2DL4 has a positively charged arginine residue in the transmembrane domain for pairing with FceRIg to transduce activating signals and a long cytoplasmic tail with an immunotyrosine-based inhibitory motif (ITIM) (49) . This receptor interacts with a soluble isoform of HLA-G in endosomes to stimulate the release of proinflammatory and pro-angiogenic factors by decidual NK cells that promote placental vascularization (50) (51) (52) . Although the presence of HLA-E on extravillous trophoblasts is thought to play a dominant role in maintaining fetal tolerance via inhibitory interactions with CD94/NKG2A on decidual NK cells, HLA-G may facilitate tolerance through additional interactions with inhibitory receptors and by serving as a source of leader peptides bound by HLA-E (52, 53) .

The ortholog of HLA-G (Mamu-G) in rhesus macaques is a pseudogene (17) . However, macaques express another nonclassical MHC class I molecule with similar tissue distribution (19) . Like HLA-G, Mamu-AG is expressed on fetal cytotrophoblasts that invade the endometrium and on syncytiotrophoblasts of the placental chorionic villi (23) . While it has been difficult to experimentally verify the function of HLA-G in humans, passive transfer of a Mamu-AG-specific monoclonal antibody to pregnant macaques was shown to disrupt leukocyte responses to implantation, vascularization, and placental development (38) . Thus, Mamu-AG appears to serve a similar function as HLA-G.

The identification of Mamu-AG as a ligand for KIR3DL05 and KIR3DS02 reveals that certain macaque KIRs are capable of mediating functional interactions with this nonclassical molecule. While macaques express a recognizable ortholog of KIR2DL4 (KIR2DL04) (7, 54) , there is no reason to believe that this receptor interacts with Mamu-AG, which bears no homology to HLA-G. Nevertheless, it is likely that there are other receptors for Mamu-AG that are yet to be identified. These may include additional KIRs or other types of receptors that react more broadly with MHC class I molecules, such as the Ig-like transcripts 2 and 4 (ILT-2 and ILT-4) that are known to serve as receptors for HLA-G in humans (55) .

A complex and precarious balance of NK cell activating and inhibitory receptor interactions is essential for normal placental development, fetal tolerance, and immune surveillance of the maternal-fetal interface. Precisely how KIR3DL05 and KIR3DS02 interactions with Mamu-AG contribute to this balance in macaques is presently unclear. The ligation of activating receptors on decidual NK cells may stimulate the release of pro-inflammatory and pro-angiogenic factors that promote placental vascularization and increase blood supply to the developing fetus, similar to the interactions of KIR2DL4 with soluble HLA-G or lineage III KIRs (KIR2Ds) with HLA-C in humans (52, 56) . In the absence of HLA-G or HLA-C, it is conceivable that macaques depend on Mamu-AG recognition by activating KIRs such as KIR3DS02 to stimulate placental vascularization. Mamu-AG may also facilitate fetal tolerance through interactions with inhibitory KIRs such as KIR3DL05 or by providing leader peptides that stabilize Mamu-E on the surface of trophoblasts for inhibitory signaling through CD94/ NKG2A (57) .

Recent studies have demonstrated a role for decidual NK cells in protecting the maternal-fetal interface. Extravillous trophoblasts are susceptible to a number of pathogens that are transmitted in utero, including Zika virus (ZiKV), cytomegalovirus (CMV), and Toxoplasma gondii (58) (59) (60) (61) (62) (63) . In the case of ZiKV, infection of extravillous trophoblasts causes ER stress that results in the downregulation of HLA-C and -G, which renders these cells susceptible to killing by decidual NK cells (60) . Similar antimicrobial functions of decidual NK cells have been reported for CMV and Listeria monocytogenes (64-66). Thus, disruption or alteration of Mamu-AG expression on macaque trophoblasts may trigger decidual NK cell responses through inhibitory or activating KIRs. KIR3DL05 and KIR3DS02 may thereby contribute to pregnancy success by protecting the maternal-fetal interface from invading microorganisms. Furthermore, polymorphic differences in these KIRs and Mamu-AG could account for individual variation in resistance to placental transmission of viral and bacterial pathogens.

The rhesus macaque has become an increasingly valuable animal model for studying viral pathogens such as CMV and Zika virus that are frequently transmitted to the developing fetus during pregnancy (67) (68) (69) (70) . Hence, the molecular interactions between macaque NK cell receptors and their MHC class I ligands that occur at the maternal-fetal interface may be especially important for understanding viral transmission and pathogenesis in this context. The present study defines many of the Mamu-AG ligands recognized by diverse allotypes of KIR3DL05 and identifies KIR3DS02*004 as an activating receptor for Mamu-AG2*01:01. These findings afford greater insight into NK cell recognition of a nonclassical molecule implicated in pregnancy and provide a broader foundation for investigating NK cell biology in the rhesus macaque as a nonhuman primate model for infectious diseases and reproductive biology. FIGURE 6 | Location of amino acid polymorphisms in Mamu-AG that affect recognition by KIR3DL05. The side chains of Mamu-AG2*01:01 residues that affect recognition by KIR3DL05*008 (red) were modeled on a three-dimensional crystal structure of Mamu-A1*002 (grey) in complex with peptide (blue) and b2microglobulin (green) (PDB 3jtt) using PyMol software.

The GenBank accession numbers for the sequences presented in this study are provided in the Materials and Methods. All of the data presented in this study are included in the article. Further inquires can be directed to the corresponding author.

RN, JA, WS, MW, and PB performed the experiments and analyzed the data. KS and SJ designed the experiments. DE conceived the project and wrote the manuscript. All of the authors contributed to the manuscript and approved the submitted version.

This work was supported by Public Health Service Grants AI095098, AI161816, AI121135, AI148379 and AI098485 (to DE) and OD011106 (to the WNPRC).

MHC Class I Molecules and KIRs in Human History, Health and Survival

NK Cell Recognition

The MHC Class I Genes of the Rhesus Monkey: Different Evolutionary Histories of the MHC Class I and II Genes in Primates

Unparalleled Complexity of the MHC Class I Region in Rhesus Macaques

Haplessly Hoping: Macaque Major Histocompatibility Complex Made Easy

Species-Specific Evolution of MHC Class I Genes in the Higher Primates

Single Haplotype Analysis Demonstrates Rapid Evolution of the Killer Immunoglobulin-Like Receptor (KIR) Loci in Primates

Diversity of the Killer Cell Ig-Like Receptors of Rhesus Monkeys

Complete Characterization of Killer Ig-Like Receptor (KIR) Haplotypes in Mauritian Cynomolgus Macaques: Novel Insights Into Nonhuman Primate KIR Gene Content and Organization

Characterization of Rhesus Macaque KIR Genotypes and Haplotypes

The Mosaic of KIR Haplotypes in Rhesus Macaques

Evolutionary Patterns of Killer Cell Ig-Like Receptor Genes in Old World Monkeys

The Killer-Cell Immunoglobulin-Like Receptors of Macaques

The MHC E Locus in Macaques Is Polymorphic and Is Conserved Between Macaques and Humans

The MHC-E Locus Is the Most Well Conserved of All Known Primate Class I Histocompatibility Genes

Characterization of the Rhesus Macaque (Macaca Mulatta) Equivalent of HLA-F

Identifiction of the Rhesus Monkey HLA-G Ortholog. Mamu-G Is a Pseudogene

Allelic Diversity at the Primate Mhc-G Locus: Exon 3 Bears Stop Codons in All Cercopithecinae Sequences

Identification of a Novel MHC Class I Gene, Mamu-AG, Expressed in the Placenta of a Primate With an Inactivated G Locus

Evolution of a New Nonclassical MHC Class I Locus in Two Old World Primate Species

Baboon Placentas Express Soluble and Membrane-Bound Paan-AG Proteins Encoded by Alternatively Spliced Transcripts of the Class Ib Major Histocompatibility Complex Gene

Characterization of Cynomolgus and Vervet Monkey Placental MHC Class I Expression: Diversity of the Nonhuman Primate AG Locus

Placental Expression of the Nonclassical MHC Class I Molecule Mamu-AG at Implantation in the Rhesus Monkey

HLA-G: Function, Polymorphisms and Pathology

Therapeutic Efficacy of Potent Neutralizing HIV-1-Specific Monoclonal Antibodies in SHIV-Infected Rhesus Monkeys

In Vivo Delivery of a DNA-Encoded Monoclonal Antibody Protects Non-Human Primates Against Zika Virus

Fc Receptor But Not Complement Binding Is Important in Antibody Protection Against HIV

Low-Titer Antibody Protection Against Low-Dose Repeated Mucosal SHIV Challenge in Macaques

Fetal Demise and Failed Antibody Therapy During Zika Virus Infection of Pregnant Macaques

Adeno-Associated Virus Delivery of Anti-HIV Monoclonal Antibodies Can Drive Long-Term Virologic Suppression

Vaccine-Induced Protection From Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers

Passive Transfer of Modest Titers of Potent and Broadly Neutralizing Anti-HIV Monoclonal Antibodies Block SHIV Infection in Macaques

Vectored Delivery of Anti-SIV Envelope Targeting mAb via AAV8 Protects Rhesus Macaques From Repeated Limiting Dose Intrarectal Swarm SIVsmE660 Challenge

Comparison of Nonhuman Primates Identified the Suitable Model for COVID-19

Animal Models of Congenital Cytomegalovirus Transmission: Implications for Vaccine Development

Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated With Allograft TGF-Beta 1+CD4+ T Regulatory Cell Infiltrates

Tomotherapy Applied Total Lymphoid Irradiation and Allogeneic Hematopoietic Cell Transplantation Generates Mixed Chimerism in the Rhesus Macaque Model

Passive Immunization Against the MHC Class I Molecule Mamu-AG Disrupts Rhesus Placental Development and Endometrial Responses

Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-Like Receptors of the Rhesus Macaque

KIR Polymorphisms Modulate Peptide-Dependent Binding to an MHC Class I Ligand With a Bw6 Motif

Killer Cell Immunoglobulin-Like Receptor 3DL1-Mediated Recognition of Human Leukocyte Antigen B

Transfer of Cloned Human Class I Major Histocompatibility Complex Genes Into HLA Mutant Human Lymphoblastoid Cells

X-Ray Crystallographic Characterization of Rhesus Macaque MHC Mamu-A*02 Complexed With an Immunodominant SIV-Gag Nonapeptide

Genetic Divergence of the Rhesus Macaque Major Histocompatibility Complex

Nomenclature Report for Killer-Cell Immunoglobulin-Like Receptors (KIR) in Macaque Species: New Genes/Alleles, Renaming Recombinant Entities and IPD-NHKIR Updates

HLA-G: At the Interface of Maternal-Fetal Tolerance

Tetrameric Complexes of Human Histocompatibility Leukocyte Antigen (HLA)-G Bind to Peripheral Blood Myelomonocytic Cells

A Human Histocompatibility Leukocyte Antigen (HLA)-G-Specific Receptor Expressed on All Natural Killer Cells

KIR2DL4 (CD158d), an NK Cell-Activating Receptor With Inhibitory Potential

Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G

Endosomal Signaling and a Novel Pathway Defined by the Natural Killer Receptor KIR2DL4 (CD158d)

Mediated NK Cell Senescence Promotes Vascular Remodeling: Implications for Reproduction

Protein Expression and Peptide Binding Suggest Unique and Interacting Functional Roles for HLA-E, F, and G in Maternal-Placental Immune Recognition

Evidence for Balancing Selection Acting on KIR2DL4 Genotypes in Rhesus Macaques of Indian Origin

Human Inhibitory Receptors Ig-Like Transcript 2 (ILT2) and ILT4 Compete With CD8 for MHC Class I Binding and Bind Preferentially to HLA-G

Maternal Activating KIRs Protect Against Human Reproductive Failure Mediated by Fetal HLA-C2

Non-Classical MHC-E (Mamu-E) Expression in the Rhesus Monkey Placenta

Zika Virus Targets Different Primary Human Placental Cells, Suggesting Two Routes for Vertical Transmission

Pathogens and the Placental Fortress

Decidual NK Cells Kill Zika Virus-Infected Trophoblasts

Intracellular Organisms as Placental Invaders

Intracellular Bacteria in Placental Basal Plate Localize to Extravillous Trophoblasts

Modeling of Human Cytomegalovirus Maternal-Fetal Transmission in a Novel Decidual Organ Culture

Expression of KIR2DS1 by Decidual Natural Killer Cells Increases Their Ability to Control Placental HCMV Infection

Human Cytomegalovirus Infection Elicits New Decidual Natural Killer Cell Effector Functions

Decidual NK Cells Transfer Granulysin to Selectively Kill Bacteria in Trophoblasts

Rhesus Monkeys for a Nonhuman Primate Model of Cytomegalovirus Infections

Intrahost Cytomegalovirus Population Genetics Following Antibody Pretreatment in a

Monkey Model of Congenital Transmission

Immune Profile of the Normal Maternal-Fetal Interface in Rhesus Macaques and Its Alteration Following Zika Virus Infection

African-Lineage Zika Virus Replication Dynamics and Maternal-Fetal Interface Infection in Pregnant Rhesus Macaques

We thank Roger Wiseman at the Wisconsin National Primate Research Center for his assistance with changes to the nonhuman primate KIR and MHC class I nomenclature. DE is an Elizabeth Glaser Scientist of the Elizabeth Glaser Pediatric AIDS Foundation.

Conflict of Interest: The 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.