Viral escape from the immune system is quintessential for HIV chronic infection. Antiretroviral therapy (ART) has dramatically improved the health of HIV-infected individuals, however, many side-effects are arising from prolonged use showing the urgent need to develop new treatments and ideally, a vaccine against this virus1.
Rare individuals, termed HIV controllers, can control HIV viral load and remain healthy despite the infection in the absence of ART treatment. We previously found that controller CD4+ T cells are able to recognise a prevalent Gag HIV epitope presented by multiple HLA-DR molecules, with high sensitivity and polyfunctionality and that they can eliminate HIV infected antigen presenting cells. Excitingly, these functionally superior HIV-specific CD4+ T cells expressed a shared TCR in HIV controllers, which is striking given the inherent TCR diversity within humans2-4.
Although the same TCR a - and b - chain biased usage is observed in ART treated patients, their CD4+ T cells are of lower affinity and were preferentially restricted by different HLA-DR molecules compared to the controllers. By employing surface plasmon resonance, cell activation assays, and protein crystallography we are investigating the molecular basis of the CD4+ T cell-mediated response from ART treated individuals. Structural analysis and comparison of the TCR-HLA-DRGag293 complex crystal structures reveal the molecular differences between ART treated and HIV controller TCRs.
The link between HIV control and T cells function, if clearly understood, could be harnessed to manipulate this protective immunity for vaccine design or therapeutics, in order to reproduce a controller-like response.