AIDS virus–specific CD8+ T lymphocytes against an immunodominant cryptic epitope select for viral escape

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The association between particular major histocompatibility complex class I (MHC-I) alleles and control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication implies that certain CD8؉ T-lymphocyte (CD8-TL) responses are better able than others to control viral replication in vivo. However, possession of favorable alleles does not guarantee improved prognosis or viral control. In rhesus macaques, the MHC-I allele Mamu-B*17 is correlated with reduced viremia and is overrepresented in macaques that control SIVmac239, termed elite controllers (ECs). However, there is so far no mechanistic explanation for this phenomenon. Here we show that the chronic-phase Mamu-B*17-restricted repertoire is focused primarily against just five epitopes-VifHW8, EnvFW9, NefIW9, NefMW9, and env ARF cRW9-in both ECs and progressors. Interestingly, Mamu-B*17-restricted CD8-TL do not target epitopes in Gag. CD8-TL escape variation occurred in all targeted Mamu-B*17-restricted epitopes. However, recognition of escape variant peptides was commonly observed in both ECs and progressors. Wild-type sequences in the VifHW8 epitope tended to be conserved in ECs, but there was no evidence that this enhances viral control. In fact, no consistent differences were detected between ECs and progressors in any measured parameter. Our data suggest that the narrowly focused Mamu-B*17-restricted repertoire suppresses virus replication and drives viral evolution. It is, however, insufficient in the majority of individuals that express the "protective" Mamu-B*17 molecule. Most importantly, our data indicate that the important differences between Mamu-B*17-positive ECs and progressors are not readily discernible using standard assays to measure immune responses.

Section: Mamusupporting

confidence: 92%

Section: Methodsmentioning

confidence: 97%

Comprehensive Immunological Evaluation Reveals Surprisingly Few Differences between Elite Controller and ProgressorMamu-B*17-Positive Simian Immunodeficiency Virus-Infected Rhesus Macaques

Maness

Yant²,

Chung³

et al. 2008

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“…The nine defined human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) proteins have long been thought to be the sole sources of virus-derived, MHC-I bound epitopes because researchers assume the classical viral protein annotations to represent the totality of the viral translation products despite increasing evidence to the contrary. Our laboratory and others have shown that MHC-I-bound epitopes can be derived from translation of viral alternate reading frames (ARFs), termed cryptic epitopes (2,4,6,10,15,16). Collectively, these data indicate that cryptic CD8 ϩ T cell responses might be more common, and more important, than previously appreciated.…”

Section: Cd8mentioning

confidence: 92%

“…Responses were considered positive if the response exceeded 50 SFC per 10 6 cells and were determined using a one-tailed t test and an alpha of 0.05, where the null hypothesis (H 0 ) is as follows: background level Ն treatment level. An asterisk indicates that these percentages (from ARF10 and the total) include the results for five additional animals that responded to the RW9 epitope in ARF10, as part of a previous study (16), but that were not tested for responses against the other ARFs due to lack of samples. Hence, these percentages are calculated as the fraction of 117 animals showing responses (rather than for 112 animals for the other ARFs).…”

Section: Mamu-b*17mentioning

confidence: 99%

CD8 ⁺ T Cell Recognition of Cryptic Epitopes Is a Ubiquitous Feature of AIDS Virus Infection

Maness

Walsh

Piaskowski

et al. 2010

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Vaccines designed to elicit AIDS virus-specific CD8؉ T cells should engender broad responses. Emerging data indicate that alternate reading frames (ARFs) of both human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) encode CD8 ؉ T cell epitopes, termed cryptic epitopes. Here, we show that SIV-specific CD8 ؉ T cells from SIV-infected rhesus macaques target 14 epitopes in eight ARFs during SIV infection. Animals recognized up to five epitopes, totaling nearly one-quarter of the anti-SIV responses. The epitopes were targeted by high-frequency responses as early as 2 weeks postinfection and in the chronic phase. Hence, previously overlooked ARF-encoded epitopes could be important components of AIDS vaccines.

“…We previously infected rhesus macaques with a mutant SIVmac239 virus bearing escape mutations in three of these epitopes (14). The Mamu-A1*00101-restricted Tat [28][29][30][31][32][33][34][35] SL8 escape mutant was maintained in Mamu-A1*00101-negative macaques.…”

mentioning

confidence: 99%

CD8 ⁺ T Cell Escape Mutations in Simian Immunodeficiency Virus SIVmac239 Cause Fitness Defects In Vivo , and Many Revert after Transmission

Mudd

Ericsen

Walsh

et al. 2011

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Virus-specific CD8؉ T lymphocytes select for escape mutations in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). To assess the effects of these mutations on viral fitness, we introduced escape mutations into 30 epitopes (bound by five major histocompatibility complex class I [MHC-I] molecules) in three different viruses. Two of these MHC-I alleles are associated with elite control. Two of the three viruses demonstrated reduced fitness in vivo, and 27% of the introduced mutations reverted. These findings suggest that T cell epitope diversity may not be such a daunting problem for the development of an HIV vaccine.