Conditional CD8<sup>+</sup>T Cell Escape during Acute Simian Immunodeficiency Virus Infection

O’Connor, Shelby L.; Becker, Ericka A.; Weinfurter, Jason T.; Chin, Emily; Budde, Melisa L.; Gostick, Emma; Correll, Michael; Gleicher, Michael; Hughes, Austin L.; Price, David A.; Friedrich, Thomas C.; O’Connor, David H.

doi:10.1128/jvi.05511-11

Cited by 31 publications

(60 citation statements)

References 30 publications

(32 reference statements)

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“…The catalog of potential epitopes presented by MHC class I alleles in MCMs that are MHC identical and infected with clonal SIV can be defined (9,12,19). Fourteen SIV epitopes that are restricted by MHC class I molecules expressed by the M3 MHC class I haplotype and the CD8 T cell responses targeting these epitopes have been identified in M3…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…We found that the accumulation of variants in a single epitope targeted by a CD8 T cell response shared by multiple animals was delayed when there existed additional acute-phase epitope-specific CD8 T cell responses in an animal (9). Subsequent sequence changes that accumulate in the second wave of targeted epitopes need to be compatible with these initial adaptive mutations.…”

Section: Importancementioning

confidence: 93%

“…All animals were used in previous studies (9,11,12). They were purchased from Charles River Laboratories or Bioculture Group, and cared for by the Wisconsin National Primate Research Center (WNPRC) according to protocols approved by the University of Wisconsin Graduate School Animal Care and Use Committee.…”

Section: Animalsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Importancementioning

confidence: 93%

Section: Animalsmentioning

confidence: 99%

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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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“…Single nucleotide polymorphisms (SNPs) relative to each stock's consensus sequence were found using the SNP calling tool in Geneious Pro by applying the following settings: minimum coverage of 50, minimum variant frequency of 5%, and maximum variant P value of 10 Ϫ60 . Amino acid variation present in CD8 ϩ T cell epitopes was analyzed using a custom data analysis pipeline, as previously described (29). Briefly, FASTQ files extracted from the original SFF file were trimmed in order to remove MID, adapter, and transposon sequences.…”

Section: Methodsmentioning

confidence: 99%

Comparative Characterization of Transfection- and Infection-Derived Simian Immunodeficiency Virus Challenge Stocks for In Vivo Nonhuman Primate Studies

Prete¹,

Scarlotta²,

Newman³

et al. 2013

J Virol

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103

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h Simian immunodeficiency virus (SIV) stocks for in vivo nonhuman primate models of AIDS are typically generated by transfection of 293T cells with molecularly cloned viral genomes or by expansion in productively infected T cells. Although titers of stocks are determined for infectivity in vitro prior to in vivo inoculation, virus production methods may differentially affect stock features that are not routinely analyzed but may impact in vivo infectivity, mucosal transmissibility, and early infection events. We performed a detailed analysis of nine SIV stocks, comprising five infection-derived SIVmac251 viral swarm stocks and paired infection-and transfected-293T-cell-derived stocks of both SIVmac239 and SIVmac766. Representative stocks were evaluated for (i) virus content, (ii) infectious titer, (iii) sequence diversity and polymorphism frequency by single-genome amplification and 454 pyrosequencing, (iv) virion-associated Env content, and (v) cytokine and chemokine content by 36-plex Luminex analysis. Regardless of production method, all stocks had comparable particle/infectivity ratios, with the transfected-293T stocks possessing the highest overall virus content and infectivity titers despite containing markedly lower levels of virion-associated Env than infection-derived viruses. Transfected-293T stocks also contained fewer and lower levels of cytokines and chemokines than infection-derived stocks, which had elevated levels of multiple analytes, with substantial variability among stocks. Sequencing of the infection-derived SIVmac251 stocks revealed variable levels of viral diversity between stocks, with evidence of stock-specific selection and expansion of unique viral lineages. These analyses suggest that there may be underappreciated features of SIV in vivo challenge stocks with the potential to impact early infection events, which may merit consideration when selecting virus stocks for in vivo studies.

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HIV-1 Sequencing

O’Connor

2016

HIV-1 Proteomics

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Conditional CD8⁺T Cell Escape during Acute Simian Immunodeficiency Virus Infection

Cited by 31 publications

References 30 publications

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Comparative Characterization of Transfection- and Infection-Derived Simian Immunodeficiency Virus Challenge Stocks for In Vivo Nonhuman Primate Studies

HIV-1 Sequencing

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Conditional CD8+T Cell Escape during Acute Simian Immunodeficiency Virus Infection

Cited by 31 publications

References 30 publications

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Comparative Characterization of Transfection- and Infection-Derived Simian Immunodeficiency Virus Challenge Stocks for In Vivo Nonhuman Primate Studies

HIV-1 Sequencing

Contact Info

Product

Resources

About

Conditional CD8⁺T Cell Escape during Acute Simian Immunodeficiency Virus Infection