Statement of Work The HIV-1 pandemic is a global threat and effective vaccination is the most likely pathway to its control. While vaccines that induce broadly neutralizing antibodies (bNAbs) against HIV could be transformative for intervening in the HIV pandemic, no vaccine has been shown to induce HIV-1 bNAbs. Indeed, we do not even understand how bNAb responses arise in rare, HIV-1 infected patients. In part our failure to understand HIV-1 immunity and the generation of bNAb responses can be traced to the absence of a suitable experimental model to study virus:host interaction. Most simian-human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains do not infect rhesus macaques (RMs). This failure reflects low affinity for rhesus CD4 (rhCD4) resulting in impaired virus entry into rhCD4+ cells. We have solved the issue of Env-rhCD4 binding and demonstrated productive infection in RMs by SHIVs with T/F Env glycoproteins, including those that elicit broadly neutralizing antibodies (bnAbs) in humans. The goal of this study is to study infection and immunity in rhesus macaques infected with molecular clones of T/F SHIVs to determine whether patterns of co-evolution by virus and host immunity in individual macaques are similar or unique. This issue is crucial in predicting the efficacy of ?lineage design? vaccines.
HIV-1 infection and AIDS is a global threat not only to the health of individuals but to societies and nations. It is clear that vaccines capable of eliciting broadly neutralizing HIV-1 antibody (bNAb) could be highly effective in stemming the HIV pandemic, at present no vaccine has been shown to induce HIV-1 bNAbs. A widely used approach to induce bnAb production by vaccination is the development of ?designer? immunogens that recreate known pathways of bnAb evolution. This approach, however is always based on the bnAb response of rare individuals. The experiments proposed in this application will determine whether immune response to identical T/F viruses are similar between individual RMs or highly distinct. This is a crucial point for ?lineage design? vaccines: if immune responses are highly variable to identical infections, then the recapitulation of any single bnAb lineage in diverse individuals is unlikely.
|McCarthy, Kevin R; Watanabe, Akiko; Kuraoka, Masayuki et al. (2018) Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires. Immunity 48:174-184.e9|