Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ T cell antiviral responses

Abstract

Persistence of HIV through integration into host DNA in CD4 + T cells presents a major barrier to virus eradication. Viral integration may be curtailed when CD8 + T cells are triggered to kill infected CD4 + T cells through recognition of histocompatibility leukocyte antigen (HLA) class I-bound peptides derived from incoming virions. However, this has been reported only in individuals with ''beneficial'' HLA alleles that are associated with superior HIV control. Through interrogation of the pre-integration immunopeptidome, we obtain proof of early presentation of a virion-derived HLA-A*02:01-restricted epitope, FLGKIWPSH (FH9), located in Gag Spacer Peptide 2 (SP2). FH9-specific CD8 + T cell responses are detectable in individuals with primary HIV infection and eliminate HIV-infected CD4 + T cells prior to virus production in vitro. Our data show that non-beneficial HLA class I alleles can elicit an effective antiviral response through early presentation of HIV virion-derived epitopes and also demonstrate the importance of SP2 as an immune target.

Therapeutic vaccination following early antiretroviral therapy elicits highly functional T cell responses against conserved HIV-1 regions

“…Moreover, the increased CD4+ and CD8+ T cell PFS to HIVconsv Pool 1 + 2, which covers Gag sequences within HIVconsv, suggest that Gag-specific T cell functionality was enhanced by vaccination. We have shown previously that CD8+ T cell targeting of functionally constrained regions within Gag proteins is a major driver of CD8+ T cell antiviral activity 14 , 20 . We surmise, therefore, that the superior CD8+ T cell antiviral effect in the ART + V + V arm was due to a combination of re-focusing, ie.…”

Unbiased serology reveals autoimmunity and HIV antibody signatures in HIV CNS Escape

“…In addition to these conserved envelope peptides, we also found a gag peptide at AA position 433 that is significantly enriched in NS escape subjects relative to AS escape subjects. This peptide maps to the gag spacer peptide 2 (p1) domain, which is a recently discovered, protective T-cell epitope 28 . Notably, all three of these epitopes (env AA positions 289 and 577, gag AA position 433) in the CSF of PLWH were also identified by Eshleman et al 36 in their VirScan study profiling anti-HIV antibodies in sera from 57 PLWH.…”

“…However, we found that there was a significant enrichment of HIV gag peptides in NS escape (median rpK 41,770, IQR 20,493-54051 rpK) compared to AS escape cases (median rpK 2,953, IQR 673-12848 rpK) (p<0.001) (Figure 3d). The difference in HIV gag protein enrichment in NS escape subjects was largely driven by peptides starting at AA position 433, mapping to the gag spacer peptide 2 (p1) domain, which is a recently discovered, protective T-cell epitope 28 .…”