Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants

Abstract

Most asymptomatic individuals infected with HIV-1 have a cytotoxic T lymphocyte (CTL) response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14). Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. But peptide variants of class I-restricted epitopes cause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the original epitope. This mirrors similar findings in class II-restricted systems. Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same individuals. The effect is present if the epitopes are derived from synthetic peptides and when they are processed from full-length proteins expressed by either recombinant vaccinia constructs or replicating HIV.

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

“…This is supported by data from Moore et al [25], showing that HIV-1 infected patients harbouring virus with escape mutations had a level of viraemia that was approximately a log higher than individuals infected with HIV-1 that lacked such mutations. In addition, it has been shown that cells expressing mutated HIV-1 peptides can even block the lysis of cells infected with unmutated virus [18]. In our current study however, the combined amino acid variation across the specific peptide regions studied was not associated with peripheral levels of HIV-1.…”

“…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.…”

Fully competent dendritic cells as inducers of T cell anergy in autoimmunity

“…Indeed, positive selection might have occurred if peptide P4, a naturally occurring APL of TPO produced by professional antigen presenting cells, is presented in the thymus. ''Naturally'' occurring epitope variants, with APL characteristics, may have an important role in immune recognition and pathology has been demonstrated in viral infections (36,37). In these latter situations, however, the virus mutates changing amino acids in critical TCR contact sites and thus leading to the generation of ''naturally induced'' APL.…”

Natural epitope variants of the hepatitis C virus impair cytotoxic T lymphocyte activity

“…Other variations, primarily in solvent-accessible residues, may abrogate TCR recognition altogether or alter it in such a way that critical activation signals are not transmitted to the cytotoxic T cells resulting in attenuated responses or even anergy [10,[16][17][18] . Examples of attenuated responses have also been found with HIV and HBV [28][29][30][31][32] . It is thought that by antagonizing T-cell responses to native epitopes, viruses expressing mutant epitopes might aid in the survival of infected cells producing wild-type viruses, which would otherwise be recognized and destroyed by CTL.…”