HLA-E–restricted HIV-1–specific CD8+ T cell responses in natural infection

Abstract

MHC-E, a non-classical MHC molecule, restricted CD8 T-cell responses have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E restricted CD8 T-cell responses in HIV infection however remains unknown. In this study, CD8 T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in-vitro assays, we observed HLA-E restricted T-cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immuno-dominant Gag-KF11 epitope in T-cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8 T-cell responses. KF11 presented via HLA-E in HIV infected cells was recognized by antigen specific CD8 T cells. Importantly, bulk CD8 T cells obtained from HIV infected individuals recognized infected cells via HLA-E presentation. Ex-vivo analyses at the epitope level showed a higher responder frequency of HLA-E restricted responses to KF11 compared to KL9.Taken together, our findings of HLA-E restricted HIV specific immune responses offer intriguing and possibly paradigm shifting insights into factors that contribute to the immuno-dominance of CD8 T-cell responses in HIV infection.

Learning to Be Elite: Lessons From HIV-1 Controllers and Animal Models on Trained Innate Immunity and Virus Suppression

“…Moreover, only 2 HLA-E alleles are mostly represented in humans ( 148 ), so HLA-E-mediated NK responses can be triggered regardless of highly polymorphic classical MHC genotypes ( 149 ). A recent study demonstrated HLA-E-restricted HIV-1-specific CD8+ T cells responses in PLWH ( 150 ), and a CMV-based vector vaccine was able to elicit MHC-E-mediated SIV-specific CD8+ T cell responses associated with protection in a rhesus macaque model ( 151 ), further validating that HLA-E-mediated responses are therapeutically inducible. HIV-1 infection also increased the percentage of NKG2C+ NK cells, which is linked to effective viremic control ( 15 ).…”

CD8+ T-cell responses in HIV controllers: potential implications for novel HIV remission strategies

“…Strikingly, cytomegalovirus (CMV)-vectored SIV vaccines can elicit broad HLA-E-restricted SIV-specific CD8 + T cell responses that are associated with the prevention of an established chronic infection in ∼50% of animals upon viral challenge [37,38]. HLA-E-restricted responses have been detected in people with HIV but have not yet been associated with viral control [39 ▪ ,40]. Implications:…”

PGE2 expression by HPV6/11‐induced respiratory papillomas blocks NK cell activation in patients with recurrent respiratory papillomatosis

“…However, this strategy leaves tumor cells vulnerable to NK‐cell activation and NK‐cell‐induced cytolysis. Thus, tumors and some virally infected immune cells, such as HIV‐infected CD4 + T‐cells, have devised strategies to inhibit both CTL and NK‐cell activation by selectively suppressing some, or all classical class I MHC expression (HLA‐A and HLA‐B), while maintaining less‐efficient class I MHC molecule expression (HLA‐C) and nonclassical class I MHC molecules (HLA‐E and HLA‐G) [42–49].…”