Escape from the Dominant HLA-B27-Restricted Cytotoxic T-Lymphocyte Response in Gag Is Associated with a Dramatic Reduction in Human Immunodeficiency Virus Type 1 Replication (original) (raw)
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Journal of Virology, 2007
Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8 ؉ T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T 242 N substitution in the capsid protein is associated with upstream mutations at residues H 219 , I 223 , and M 228 in the cyclophilin A (CypA)-binding loop in B57 ؉ individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T 242 N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T 242 N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T 242 N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8 ؉ T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.
The Journal of Immunology
It has been hypothesized that sequence variation within CTL epitopes leading to immune escape plays a role in the progression of HIV-1 infection. Only very limited data exist that address the influence of biologic characteristics of CTL epitopes on the emergence of immune escape variants and the efficiency of suppression of HIV-1 by CTL. In this report, we studied the effects of HIV-1 CTL epitope sequence variation on HIV-1 replication. The highly conserved HLA-B14-restricted CTL epitope DRFYKTLRAE in HIV-1 p24 was examined, which had been defined as the immunodominant CTL epitope in a long-term nonprogressing individual. We generated a set of viral mutants on an HX10 background differing by a single conservative or nonconservative amino acid substitution at each of the P1 to P9 amino acid residues of the epitope. All of the nonconservative amino acid substitutions abolished viral infectivity and only 5 of 10 conservative changes yielded replication-competent virus. Recognition of t...
Journal of Virology, 2011
One proposed HIV vaccine strategy is to induce Gag-specific CD8 ؉ T-cell responses that can corner the virus, through fitness cost of viral escape and unavailability of compensatory mutations. We show here that the most variable capsid residues principally comprise escape mutants driven by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms that arise in conjunction with these escape mutations. These covarying polymorphisms are potentially compensatory and are concentrated around three tropism-determining loops of p24, suggesting structural interdependencies. Our results demonstrate complex patterns of adaptation of HIV under immune selection pressure, the understanding of which should aid vaccine design.
AIDS restriction HLA allotypes target distinct intervals of HIV-1 pathogenesis
Nature Medicine, 2005
An effective acquired immune response to infectious agents mediated by HLA-restricted T-cell recognition can target different stages of disease pathogenesis. We show here that three distinct HLA alleles known to alter the overall rate of AIDS progression act during distinct intervals after HIV-1 infection. The discrete timing of HLA allele influence suggests alternative functional mechanisms in immune defense against this dynamic and chronic immunosuppressive disease. HLA-B*27 and HLA-B*57 show robust protection against AIDS progression relative to all other HLA class I alleles, whereas certain HLA-B*35 subtypes (termed B*35-Px) show strong influence on susceptibility to developing AIDS rapidly 1. HIV-1-specific CD8 + T-cell responses restricted by B*27 and B*57 provide a probable mechanism for the epidemiological protection shown in carriers of these alleles. B*27 mediates an immunodominant response against a viral peptide derived from a conserved region of HIV p24 Gag 2,3 , termed KK10, which can lead to the selection of cytotoxic T lymphocyte (CTL) escape variants (R264K/G/T), generally years after initial infection 2,4,5. The basis for B*57 protection also seems to involve, in part, a highly conserved immunodominant epitope in Gag, termed TW10, a response to which seems to confer protection early during acute infection 6. Mutation of TW10 may considerably attenuate viral fitness based on the observed reversion back to the wild-type sequence within months after transmission of the virus to B*57individuals 7. Reversion of the KK10 mutation upon transmission of the virus from B*27 + to B*27individuals does not occur nearly as rapidly 8,9 , if at all. Susceptibility mediated by B*35-Px remains the most enigmatic, but differential correlations of CTL activity with HIV-1 viral load suggest that the peptidebinding signatures of B*35-Px may affect the quality of HIV-specific CTL activity 10 .
Retrovirology, 2012
Background Disassembly of the viral capsid following penetration into the cytoplasm, or uncoating, is a poorly understood stage of retrovirus infection. Based on previous studies of HIV-1 CA mutants exhibiting altered capsid stability, we concluded that formation of a capsid of optimal intrinsic stability is crucial for HIV-1 infection. Results To further examine the connection between HIV-1 capsid stability and infectivity, we isolated second-site suppressors of HIV-1 mutants exhibiting unstable (P38A) or hyperstable (E45A) capsids. We identified the respective suppressor mutations, T216I and R132T, which restored virus replication in a human T cell line and markedly enhanced the fitness of the original mutants as revealed in single-cycle infection assays. Analysis of the corresponding purified N-terminal domain CA proteins by NMR spectroscopy demonstrated that the E45A and R132T mutations induced structural changes that are localized to the regions of the mutations, while the P38A...