HIV-1 Nef is preferentially recognized by CD8 T cells in primary HIV-1 infection despite a relatively high degree of genetic diversity

Abstract

These data show that despite relatively high sequence variability, viral regions within the clade B consensus sequence of Nef are preferentially recognized during primary HIV-1 infection. Later diversification of responses to other proteins during prolonged antigen exposure provides evidence of the initial preferential immunogenicity of Nef epitopes compared to similarly conserved regions within other viral proteins.

Magnitude, Breadth, and Functional Profile of T-Cell Responses during Human Immunodeficiency Virus Primary Infection with B and BF Viral Variants

“…2A and B). This observation has also been reported previously for subtype B and other subtypes (22,26,28,35,43,45). However, in this study, clade-specific differences in targeted Nef domains were observed.…”

“…Previous studies have determined that during primary HIV infection Nef-specific CD8 T-cell responses represented a significant ratio (46% to 94%) of the total magnitude of the HIV-specific T-cell response (43). In our B/BF cohort, we characterized the Nef-specific T-cell response by employing a peptide matrix-based IFN-␥ ELISPOT assay followed by confirmation of individual peptide response in a further ELISPOT assay.…”

“…These assays were performed shortly after seroconversion in order to avoid the confounders associated with viral diversification, selection of escape mutants, and superinfection. Overlapping peptides spanning the Nef protein were chosen as antigens because of the following: (i) Nef is halfway along the spectrum of variability found in HIV proteins; (ii) during primary HIV infection, Nef-specific CTLs represent between 46% and 94% of the total magnitude of the HIV T-cell response (43); (iii) Nef has, together with Gag, the highest epitope density (1,39). This study also contributes to minimizing the problem of breadth underestimation during CTL screening and provides insights into discrepancies of CD8 T-cell effector function.…”

Synonymous Substitution Rates Predict HIV Disease Progression as a Result of Underlying Replication Dynamics

“…The envelope protein is able to evade nAb responses by accumulating multiple amino acid changes, especially in the hypervariable regions, while maintaining full functionality for viral cell entry. CTL responses, however, target epitopes in other viral genes (such as gag and nef) more strongly and/or more frequently, particularly during the initial stages of HIV infection [8][9][10]. Although HIV infection often results in the evolution of viral variants that escape CTL responses [11], recent evidence from transmission pair studies and in vitro growth rate studies suggests that some escape mutations might occur at the expense of viral fitness [12,13].…”

Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection

“…Selection to use the CXCR4 coreceptor plays a part in generating diversity in HIV-1 env; however, CXCR4 usage evolves late into infection, is not observed in all individuals (13,24,25), and involves a small number of residues within env (26)(27)(28)(29). Evolution of escape to cellular immune responses may also play a role in driving the rapid divergence of env, although cellular responses may be stronger and͞or more common to other genes such as gag, nef, and tat, especially during recent HIV infection (30)(31)(32). In contrast, selection by neutralizing antibody responses has been shown to result in rapid, continuous in vivo evolution of viral escape at the phenotypic level (33)(34)(35)(36), and therefore may contribute to the rapid evolution of HIV-1 envelope.…”