Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control

Abstract

Background Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs. Results In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC. Conclusions These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.

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

“…A prophylactic vaccine strategy in NHPs targeting only three CD8 þ T-cell epitopes was sufficient to maintain viral control after SIV challenge and viral escape from these three epitopes occurred concomitantly with loss of control of viral replication [65]. Similarly, viral escape of a single epitope has also been associated with loss of long-term control in a person with HIV [66]. These data suggest that a few well targeted epitopes might be sufficient to induce viral control.…”

HLA‐A*11:01 and HLA‐C*04:01 are associated with severe COVID‐19

“…Interestingly, long‐term nonprogression (LTNP) in HIV+ individuals has also been associated with the HLA‐B*14:02 allele. Specifically, LTNP is linked to an immunodominant response to the viral peptide Env‐EL9 that is presented by HLA‐B14*02 33 and is more protective than the response mediated by the presentation of Gag viral peptides by the HLA‐B*14:01 allele 34 . We hypothesize that HLA‐B*14:02 could have a similar role in SARS‐CoV‐2 infection and could be associated with a faster viral clearance through the presentation of a particular viral peptide that elicits a more effective response.…”

Structural Framework for Analysis of CD4+ T-Cell Epitope Dominance in Viral Fusion Proteins

“…In addition to the neutralizing activity of an antibody binding to the Env trimer, other immune recognition events are important for protection and impose selective pressure on the Env protein sequence. Protective CD8+ T-cell epitopes are well-established in the context of certain class I HLA alleles, but most of these epitopes are located in the Gag gene product; their importance is limited to human populations bearing the relevant HLA alleles, and they are subject to rapid selection of resistant mutations. − An antibody epitope in the V2 domain of Env has been investigated for its potential importance in protection by ADCC, but numerous animal studies and human trials so far have not provided a robust confirmation. , In one of the few examples of association of disease with a CD4+ epitope, Ranasinghe et al reported the positive correlation of viral load with the CD4+ T-cell response to a C2 epitope (corresponding to cluster 3 above) . Mutation of nearby glycosylated residues has been shown to substantially modify presentation of gp120 and alter T-cell responses .…”