An effective HIV-1 vaccine designed to prevent acquisition of infection will require elicitation of effective antibody responses to the envelope glycoprotein (Env) that mediates virus entry. Env-specific antibodies will need to prevent the initial infection of host cells, likely by neutralizing activity, or by limiting the early events of viral dissemination by other effector functions, such as antibody-dependent cell-mediated cytotoxicity. However, as a target of such inhibitory antibodies, HIV-1 Env displays a high degree of genetic and structural variability, requiring the elicitation of broadly reactive antibody responses to functionally conserved Env elements. As a vaccine component, HIV-1 Env elicits limited neutralizing breadth and potency in most pre-clinical and clinical studies to date.
Recent progress in isolating potent, broadly neutralizing monoclonal antibodies (MAbs) from HIV-infected individuals and characterization of their cognate epitopes has increased the number of potential Env antibody targets. These include the most clear-cut example of a functional region that overlaps with an accessible neutralizing determinant, namely the gp120 CD4 binding site (CD4bs) that is critical for virus engagement of the host cell receptor, CD4. The recent isolation of several broadly neutralizing CD4bs MAbs demonstrates that the human B cell repertoire can generate broadly neutralizing antibodies (bNAbs) targeting this conserved Env region. These bNAbs exist in the serum of a subset of HIV-1 infected individuals at significant titers, suggesting that it is feasible to elicit protective serum titers by vaccination. Other sites on HIV-1 Env that are targets of bNabs include the membrane proximal external region (MPER) on the gp41 subunit of Env, the V1V2- and V3-glycan sites, and the more recently defined sites that bridge between gp41 and gp120.
We are actively delineating the B cell in vivo evolution pathways that produce bNAbs, and through a combined approach with structural and functional studies, identifying factors that either promote or limit the elicitation of bNAb responses. These include antibody germ-line gene usage restriction, tolerance control mechanisms on antibody development, and interference by dominant non-neutralizing antibody responses. Efforts are underway to replicate the bNab development process that occurs in natural infection in a vaccine setting. In parallel, atomic-level design of native HIV-1 Env mimetics is being pursued to improve induction of vaccine-elicited bNAb responses.