Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients

Abstract

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

“…Similarly, Yu et al showed that differences in KF11 evolution between clades B and C were largely the result of differences in immunological features of HLA-B*5701-and -B*5703-restricted responses, with the latter allele being more frequent in clade C-infected populations (47). The temporality of selection can also differ between clades; while TW10 and IW9 selection is similar between clade B and C, the order in which they are selected is opposite (12). Our data show that virological factors (i.e., sequence differences) can also lead to clade-specific es- cape.…”

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…Molecular cloning of HIV-1 genomes is labor intensive and thus limits the number of IMCs that can reasonably be characterized. Moreover, predicting which viral genomes are functional in chronically infected individuals is challenging, because immune escape mutations frequently incur fitness costs (38)(39)(40)(41)(42)(43)(44)(45). Virus isolation represents an alternative to cloning, but bulk cultures cannot account for the biological variation of individual quasispecies members.…”

Distinct HIV-1 Escape Patterns Selected by Cytotoxic T Cells with Identical Epitope Specificity

“…The change from Ala to Pro at residue 146 of Gag (A146P) is a well-analyzed case. A146P is an escape selected by not only HLA-B*57-restricted, ISW9-specific CTLs (22) but also by HLA-B*15:10-restricted and HLA-B*48:01-restricted CTLs (15,23,24), although the latter CTLs selected it by different mechanisms. The replacement of Thr with Asn at residue 242 (T242N) of Gag is another case.…”