Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8<sup>+</sup>T Cell Responses

Budde, Melisa L.; Lhost, Jennifer J.; Burwitz, Benjamin J.; Becker, Ericka A.; Burns, Charles M.; O’Connor, Shelby L.; Karl, Julie A.; Wiseman, Roger W.; Bimber, Benjamin N.; Zhang, Guanglan; Hildebrand, William H.; Brusic, Vladimir; O’Connor, David H.

doi:10.1128/jvi.02355-10

Cited by 48 publications

(64 citation statements)

References 56 publications

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“…Notably, detection of CD8 T cells specific for these epitopes were rarely detected in the blood by IFN-␥ ELISPOT (Table 8). Even though it has been shown that epitopes in category C are restricted by M3 MHC class I molecules (20), our results call into question their immunogenicity during a natural SIV infection. It is possible that category C epitopes are not presented well by MHC molecules, CD8 T cells specific for category C epitopes are located in inaccessible sites, or the immune system is too compromised at the later stage of infection, when category C epitopes could otherwise be successfully targeted.…”

Section: Preservation Of Category B T Cell Responses In Mhcheterozygocontrasting

confidence: 40%

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Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Gellerup

Balgeman

Nelson

et al. 2016

J Virol

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Anti-HIV CD8 T cells included in therapeutic treatments will need to target epitopes that do not accumulate escape mutations.Identifying the epitopes that do not accumulate variants but retain immunogenicity depends on both host major histocompatibility complex (MHC) genetics and the likelihood for an epitope to tolerate variation. We previously found that immune escape during acute SIV infection is conditional; the accumulation of mutations in T cell epitopes is limited, and the rate of accumulation depends on the number of epitopes being targeted. We have now tested the hypothesis that conditional immune escape extends into chronic SIV infection and that epitopes with a preserved wild-type sequence have the potential to elicit epitope-specific CD8 T cells. We deep sequenced simian immunodeficiency virus (SIV) from Mauritian cynomolgus macaques (MCMs) that were homozygous and heterozygous for the M3 MHC haplotype and had been infected with SIV for about 1 year. When interrogating variation within individual epitopes restricted by M3 MHC alleles, we found three categories of epitopes, which we called categories A, B, and C. Category B epitopes readily accumulated variants in M3-homozygous MCMs, but this was less common in M3-heterozygous MCMs. We then determined that chronic CD8 T cells specific for these epitopes were more likely preserved in the M3-heterozygous MCMs than M3-homozygous MCMs. We provide evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are homozygous for a set of MHC alleles are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. IMPORTANCEAnti-HIV CD8 T cells that are part of therapeutic treatments will need to target epitopes that do not accumulate escape mutations. Defining these epitope sequences is a necessary precursor to designing approaches that enhance the functionality of CD8 T cells with the potential to control virus replication during chronic infection or after reactivation of latent virus. Using MHChomozygous and -heterozygous Mauritian cynomolgus macaques, we have now obtained evidence that epitopes known to escape from chronic CD8 T cell responses in animals that are MHC homozygous are preserved and retain immunogenicity in a host that is heterozygous for the same MHC alleles. Importantly, our findings support the conditional immune escape hypothesis, such that the potential to present a greater number of CD8 T cell epitopes within a single animal can delay immune escape in targeted epitopes. As a result, certain epitope sequences can retain immunogenicity into chronic infection.

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Section: Preservation Of Category B T Cell Responses In Mhcheterozygocontrasting

confidence: 40%

“…ϩ MCMs (9,12,18,(20)(21)(22). Some of these 14 epitopes accumulate variants during acute SIV infection, some accumulate variants during chronic infection, and some rarely accumulate variants.…”

Section: Resultsmentioning

confidence: 99%

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Gellerup

Balgeman

Nelson

et al. 2016

J Virol

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“…Because of the division in major and minor transcripts, the overall expression on peripheral blood lymphocytes in rhesus macaques appears to be quite similar to humans. Certainly, from a T-cell receptor point of view it appears that only the majors are restricting immune responses [53]. Perhaps with this expansion a division of labors has also occurred, while some loci, like Mamu-A1, (-A7), and certain Mamu-B, may encode molecules whose functions have remained relatively conserved.…”

Section: Discussionmentioning

confidence: 99%

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

et al. 2011

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NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5]. It is the shift in equilibrium of inhibitory and activating receptor signaling that ultimately leads to NK-cell activation in the form of cytokine production, cytotoxicity, or priming of the adaptive immune system [6].Killer cell immunoglobulin-like receptors (KIRs) may influence this balance through interactions with their ligands, the MHC molecules, which are called human leukocyte antigens 2719(HLA) in humans. Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13]. Moreover, certain human pathogens or their simiantrophic family members have adapted to primates as their natural host, and may show a host-specific pathology. Since in an experimental setting the onset of disease or the actual challenge with a pathogen can be controlled, it is possible to stu...

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“…A previous study conducted in Mauritian cynomolgus macaques, together with a retrospective analysis of studies with Indian-origin rhesus macaques, demonstrated that transcriptionally abundant MHC-I alleles play a crucial role in presenting CTL epitopes in SIV infection (43). We developed an in-house bioinformatics pipeline to study associations between the four MHC-I haplotypes for each macaque across the nearly 10,000-bp-long SIV genome, as described in Materials and Methods and shown in Fig.…”

Section: Mhc-i Typing Of 44 Pig-tailed Macaques By Pyrosequencingmentioning

confidence: 99%

Linking Pig-Tailed Macaque Major Histocompatibility Complex Class I Haplotypes and Cytotoxic T Lymphocyte Escape Mutations in Simian Immunodeficiency Virus Infection

Gooneratne

Alinejad‐Rokny

Ebrahimi

et al. 2014

J Virol

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The influence of major histocompatibility complex class I (MHC-I) alleles on human immunodeficiency virus (HIV) diversity in humans has been well characterized at the population level. MHC-I alleles likely affect viral diversity in the simian immunodeficiency virus (SIV)-infected pig-tailed macaque (Macaca nemestrina) model, but this is poorly characterized. We studied the evolution of SIV in pig-tailed macaques with a range of MHC-I haplotypes. SIV mac251 genomes were amplified from the plasma of 44 pig-tailed macaques infected with SIV mac251 at 4 to 10 months after infection and characterized by Illumina deep sequencing. MHC-I typing was performed on cellular RNA using Roche/454 pyrosequencing. MHC-I haplotypes and viral sequence polymorphisms at both individual mutations and groups of mutations spanning 10-amino-acid segments were linked using in-house bioinformatics pipelines, since cytotoxic T lymphocyte (CTL) escape can occur at different amino acids within the same epitope in different animals. The approach successfully identified 6 known CTL escape mutations within 3 Mane-A1*084-restricted epitopes. The approach also identified over 70 new SIV polymorphisms linked to a variety of MHC-I haplotypes. Using functional CD8 T cell assays, we confirmed that one of these associations, a Mane-B028 haplotype-linked mutation in Nef, corresponded to a CTL epitope. We also identified mutations associated with the Mane-B017 haplotype that were previously described to be CTL epitopes restricted by Mamu-B*017:01 in rhesus macaques. This detailed study of pig-tailed macaque MHC-I genetics and SIV polymorphisms will enable a refined level of analysis for future vaccine design and strategies for treatment of HIV infection. IMPORTANCECytotoxic T lymphocytes select for virus escape mutants of HIV and SIV, and this limits the effectiveness of vaccines and immunotherapies against these viruses. Patterns of immune escape variants are similar in HIV type 1-infected human subjects that share the same MHC-I genes, but this has not been studied for SIV infection of macaques. By studying SIV sequence diversity in 44 MHC-typed SIV-infected pigtail macaques, we defined over 70 sites within SIV where mutations were common in macaques sharing particular MHC-I genes. Further, pigtail macaques sharing nearly identical MHC-I genes with rhesus macaques responded to the same CTL epitope and forced immune escape. This allows many reagents developed to study rhesus macaques to also be used to study pigtail macaques. Overall, our study defines sites of immune escape in SIV in pigtailed macaques, and this enables a more refined level of analysis of future vaccine design and strategies for treatment of HIV infection.

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Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8⁺T Cell Responses

Cited by 48 publications

References 56 publications

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

Linking Pig-Tailed Macaque Major Histocompatibility Complex Class I Haplotypes and Cytotoxic T Lymphocyte Escape Mutations in Simian Immunodeficiency Virus Infection

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Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8+T Cell Responses

Cited by 48 publications

References 56 publications

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

Linking Pig-Tailed Macaque Major Histocompatibility Complex Class I Haplotypes and Cytotoxic T Lymphocyte Escape Mutations in Simian Immunodeficiency Virus Infection

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Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8⁺T Cell Responses