The Differential Ability of HLA B^*5701⁺Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous ViralgagSequences

Abstract

Although the HLA B * 5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57؉ progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8 ؉ T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B * 57 ؉ patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8؉ T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4 ؉ T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8 ؉ T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B * 5701 ؉ HIV-infected patients. Qualitative features of the virus-specific CD8 ؉ T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B * 5701 ؉ LTNPs and progressors to restrict virus replication.

Despite Biased TRBV Gene Usage against a Dominant HLA B57-Restricted Epitope, TCR Diversity Can Provide Recognition of Circulating Epitope Variants

“…The HLA B57-restricted epitope KF11 is both dominantly recognized and highly conserved (15). In this study.…”

“…HLA B57 has shown the strongest association with control of viremia, and subjects with this allele typically have robust HLA B57-restricted CD8 ϩ T cell responses (12)(13)(14)(15). Furthermore, several HLA B57 epitopes have been fine-mapped, including a dominantly recognized, highly conserved epitope located in p24 Gag (KAFSPEVIPMF; KF11) (15,16).…”

HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently

“…There is evidence to support this hypothesis. B57-KAF-specific CD8 responses are maintained for long periods in HLA-B57 ϩ individuals (9,47) and the sequence variants of this epitope that have been reported (33,46) are recognized efficiently by KAF-specific responses in slow-progressing B57 ϩ individuals (33). Similarly, escape from B27-KRW-specific responses typically occurs only after many years (6,7).…”

Control of Simian Immunodeficiency Virus SIVmac239 Is Not Predicted by Inheritance of Mamu-B * 17 -Containing Haplotypes

“…Though many groups have examined proviral SIV (23) and HIV (1,20) sequences from individuals who control virus, the relationship between these sequences and replicating virus is questionable (2). We coupled ultrasensitive viral RNA extraction with reverse transcription-PCR using amplification primers flanking the Nef IW9 epitope sequence to extract viral sequence from plasma virus.…”