HIV-1 Variation Diminishes CD4 T Lymphocyte Recognition

Abstract

Effective long-term antiviral immunity requires specific cytotoxic T lymphocytes and CD4+ T lymphocyte help. Failure of these helper responses can be a principle cause of viral persistence. We sought evidence that variation in HIV-1 CD4+ T helper epitopes might contribute to this phenomenon. To determine this, we assayed fresh peripheral blood mononuclear cells from 43 asymptomatic HIV-1+ patients for proliferative responses to HIV-1 antigens. 12 (28%) showed a positive response, and we went on to map dominant epitopes in two individuals, to p24 Gag restricted by human histocompatibility leukocyte antigen (HLA)-DR1 and to p17 Gag restricted by HLA-DRB52c. Nine naturally occurring variants of the p24 Gag epitope were found in the proviral DNA of the individual in whom this response was detected. All variants bound to HLA-DR1, but three of these peptides failed to stimulate a CD4+ T lymphocyte line which recognized the index sequence. Antigenic variation was also detected in the p17 Gag epitope; a dominant viral variant present in the patient was well recognized by a specific CD4+ T lymphocyte line, whereas several natural mutants were not. Importantly, variants detected at both epitopes also failed to stimulate fresh uncultured cells while index peptide stimulated successfully. These results demonstrate that variant antigens arise in HIV-1+ patients which fail to stimulate the T cell antigen receptor of HLA class II–restricted lymphocytes, although the peptide epitopes are capable of being presented on the cell surface. In HIV-1 infection, naturally occurring HLA class II–restricted altered peptide ligands that fail to stimulate the circulating T lymphocyte repertoire may curtail helper responses at sites where variant viruses predominate.

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

“…These results suggest, in contrast to other reports that have shown a negative effect of viral variation on CD4 T-cell recognition [26,27], that CD4 responses may be somewhat tolerant of viral variation. T-helper cells may have been reactive to more than one of the peptides in the cocktail, and although limitations of small blood volumes from the HIV-1 infected children in this study did not allow peptide responses to be tested individually, this approach would be important in future studies to provide more insight into immunogenic epitopes.…”

“…They observed that the interaction of gp120 epitopes with CD4 T-cell receptors and MHC is precise and poorly cross-reactive, with even one conservative substitution drastically reducing recognition. In another study, by Harcourt et al [27], PBMC from asymptomatic HIV-1 infected patients were assayed for proliferative responses to HIV-1 antigens. Two individuals who showed positive responses were further analysed, and a dominant CD4 T-lymphocyte response was localised to p17 Gag and p24 Gag epitopes, with proviral DNA sequencing revealing substantial sequence variation within both these peptide epitopes.…”

“…Although in general, epitope variation did not diminish binding to class II molecules, several of the viral variants failed to stimulate both fresh PBMC and cultured CD4 T-lymphocyte cell lines, indicating that variant antigens arise in HIV-1 infected patients that fail to stimulate the T-cell antigen receptor of HLA classII-restricted CD4 T-lymphocytes, even though the peptide epitopes can be presented on the cell surface. These authors postulate that these naturally occurring variants that fail to stimulate the circulating Tcell repertoire may curtail helper responses at sites where variant viruses predominate such as the lymph nodes [27].…”

Immunisation with recombinant modified vaccinia virus Ankara expressing HIV‐1 gag in HIV‐1‐infected subjects stimulates broad functional CD4+ T cell responses

“…In the murine LCMV model, transgenic virus-specific CD4 + T cells selected for T helper epitope mutants that evaded recognition [44]. However, while viral evolution in CD4 + T cell epitopes in untreated HIV-1-infected persons abrogated T cell responses in vitro, viral variants did not have a clear survival advantage [45]. More recently, no variation in epitopes targeted by circulating IFN-c-secreting CD4 + T cells was detected by sequencing of plasma HIV-1 RNA, in a cross-sectional study of chronically infected untreated subjects [46].…”

Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS

“…A hallmark of HIV infection is its ability to generate immune escape mutations in epitopes (14)(15)(16)(17) and their flanking regions (18,19). CTL escape mutants have been found in population studies, in which they correlate with higher viral loads (20), and they can be transmitted from mother to child (21,22) as well as between sexual partners (ref.…”