Abstract
In HIV infection, some closely associated human leukocyte antigen (HLA) alleles are correlated with distinct clinical outcomes although presenting the same HIV epitopes. The mechanism that underpins this observation is still unknown, but may be due to the essential features of HLA alleles or T cell receptors (TCR). In this study, we investigate how T18A TCR, which is beneficial for a long-term control of HIV in clinic, recognizes immunodominant Gag epitope TL9 (TPQDLTML180-188) from HIV in the context of the antigen presenting molecule HLA-B*81:01. We found that T18A TCR exhibits differential recognition for TL9 restricted by HLA-B*81:01. Furthermore, via structural and biophysical approaches, we observed that TL9 complexes with HLA-B*81:01 undergoes no conformational change after TCR engagement. Remarkably, the CDR3β in T18A complexes does not contact with TL9 at all but with intensive contacts to HLA-B*81:01. The binding kinetic data of T18A TCR revealed that this TCR can recognize TL9 epitope and several mutant versions, which might explain the correlation of T18A TCR with better clinic outcomes despite the relative high mutation rate of HIV. Collectively, we provided a portrait of how CD8+ T cells engage in HIV-mediated T cell response.
Highlights
HIV replication can be suppressed efficiently to an undetectable level by antiretroviral therapy (ART), because of the persistence of latent viral reservoirs, it is difficult to thoroughly eradicate the virus by ART [1,2,3,4,5,6]
The T18A T cell receptors (TCR) accommodated peptide-human leukocyte antigen (HLA) complexes in a similar traditional diagonal manner, with a total buried surface area (BSA) [43] of 1732.6 Å2 in HLA-B*81:01 background which fell within the range of known BSA [44]
In the interaction between T18A TCR and HIV-1 Gag-TL9 epitope presented by HLA-B*81:01, CDR2b and CDR3a were the dominant contributors, which were characterized by strong hydrogen bond interactions involving multiple asparagine
Summary
HIV replication can be suppressed efficiently to an undetectable level by antiretroviral therapy (ART), because of the persistence of latent viral reservoirs, it is difficult to thoroughly eradicate the virus by ART [1,2,3,4,5,6]. The activation of latent HIV infected T cells in the presence of ART has been proposed to cure HIV infection, but failed [7]. The global T cell activation could be induced by some agents, which are generally too toxic to put into clinical use [8,9,10]. Studies have shown that the immune control of HIV infections is associated with TCR clonotypes and CD8+ T cell clonotypes have the greater ability to cross-react with viral epitope variants [13, 14]
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