Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS

Abstract

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

An Endogenous HIV Envelope-derived Peptide without the Terminal NH3+ Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules

“…In addition, some loci such as HLA-B35 (8) and -B27 (9) are individually associated with faster and slower development of AIDS, respectively. The virus escapes this CTL response (10,11), which confirms that CD8 ϩ T lymphocytes exert an immunological pressure (12). This evidence indicates a protective role of CTL in preventing and controlling HIV infection.…”

CD8 + T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

“…However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells. HIV is able to evade immune responses by developing mutations that mediate escape from CTL recognition (6)(7)(8)(9)(10)(11)(12). In addition, the expression of certain HLA class I molecules by HIV-infected patients, such as HLA-B*27, HLA-B*57, HLA-B*58:01, HLA-B*81:01, and HLA-A*74: 01, is associated with better clinical disease outcomes in some population settings (3,(13)(14)(15)(16)(17)(18).…”

“…Moreover, among controllers with or without protective HLA class I alleles, the infection is dynamic such that loss of viral control is observed at least in a subset of individuals who were previously elite controllers. The best-studied examples of progression in elite controllers are of HLA-B*27-positive subjects in whom escape within the immunodominant Gag epitope appears to precipitate loss of viremic control (10,31). However, the mechanisms underlying the loss of viral control in previous controllers are largely undetermined, and few studies have addressed this issue.…”

Detection of Human Immunodeficiency Virus Type 1 Envelope Peptide- Stimulated T-helper Cell Responses and Variations in the Corresponding Regions of Viral Isolates among Vertically Infected Children

“…The rapid replication kinetics and the low-fidelity RT enzyme of HIV-1 allow a high mutation rate, which enables the virus to evade host immune surveillance. Studies with CTLs have shown that mutations, even single amino acid changes, of viral sequences that specify immunogenic epitopes can lead to escape from CD8 T-cell recognition [18][19][20][21]25], impairing the ability of the host to control infection. Little data exists however on the influence of HIV-1 antigenic variation on HLA class II-restricted CD4 T-cell responses.…”

“…Although the role of antigenic variation in HLA class I-restricted epitopes has been widely studied [18][19][20][21], work on the influence of HIV-1 antigenic variation on HLA class II-restricted CD4 T-cell responses has been limited, probably due to the difficulty of detecting these responses in HIV-1 infected individuals at any stage of infection. The objective of this study was to determine whether differences in the amino acid sequences of envelope glycoproteins from HIV-1 isolates of infected children would influence the ability to detect Env-specific Thelper cell responses.…”