Viral escape from the immune system is quintessential for HIV-I chronic infection. This is due to the genetic diversity as well as the state of latency of the virus after infection whereby the virus can “hide” and create a reservoir. Antiretroviral therapy (ART) has dramatically improved the health of HIV-infected individuals, however, many side-effects are arising from prolonged use.
Rare individuals, termed HIV controllers, can control HIV viral load and remain healthy despite the infection in the absence of ART. We previously found that controller CD4+ T cells targeted a prevalent Gag HIV epitope with high sensitivity and polyfunctionality and that they can eliminate HIV infected antigen presenting cells. Excitingly, thesefunctionally superior HIV-specific CD4+ T cells expressed ashared TCR in HIV controllers (F24 TCR), which is striking given the inherent TCR diversity within humans.
We are now focused on newly isolated clonotypes with different CDR3b loops that possess similar affinity to the F24 TCR. By employing surface plasmon resonance and X-ray crystallography we are investigating the impact of CDR3bloop variation, TCR affinity and HIV inhibition by CD4+ T cells. The understanding of the key structural and functional determinants of HIV-specific protective CD4+ T cells, including cytotoxicity, affinity, TCR recognition, and peptide cross-recognition, will be highly beneficial for translational applications to manipulate the immune response to HIV.