Haynes: Broad Neutralizing Antibody Consortium
The human immune system is capable of producing antibodies against HIV-1 envelope, yet these antibodies that are readily made fail to broadly neutralize a wide spectrum of transmitted/founder viruses. The HIV-1 envelope has several conserved vulnerable regions, but with natural infection and with envelope immunization, the B-cell arm of human and animal immune systems do not recognize these vulnerable envelope regions to make neutralizing antibodies. The researchers in the Haynes-led project are determining why broadly reactive neutralizing antibodies are not made, and studying how to design immunogens and adjuvants in vaccine formulations to overcome these roadblocks. Some species of broadly neutralizing anti-HIV-1 antibodies are polyreactive autoantibodies that can be directed at neutralizing viral molecules. The researchers are exploring the role of the immune system in silencing anti-HIV-1 antibodies, a process termed immune tolerance. They are exploring the hypothesis that a successful way to induce broadly reactive neutralizing antibodies to HIV-1 is to vaccinate with novel viral envelope structures reflective of conserved vulnerable envelope regions in formulations that will safely and transiently break tolerance to HIV-1, or to vaccinate with viral epitopes that cross react with host molecules, or with target host molecules that are selectively expressed on the surface of HIV-1 virions and infected cells.
- To determine the spectrum of endogenous antigens to which broadly neutralizing antibodies bind, and determine the structure of neutralizing antibody Fab binding to autoantigens and to HIV-1 Env.
- To develop new immunization strategies to promote survival and expansion of the antibody-producing B cells that produce antibodies against broadly reactive neutralizing determinants on HIV-1 Env.
- To evaluate the immunogenicity of HIV-2 gp41 membrane proximal external region (MPER) epitopes in HIV-2 infected humans compared to HIV-1 infected subjects, and to determine the breadth, potency and epitope specificity of MPER-directed neutralizing antibodies elicited by natural infection and vaccination.
The CAVD team has been successful and demonstrated that central and peripheral tolerance mechanisms control the expression of gp41 membrane proximal external region (MPER) neutralizing antibodies in knock-in mice, that non-neutralizing MPER antibodies bind to the post-fusion six helix bundle of gp41, and that germline antibodies bind to a host protein in both mouse and human with sequences homologous to the HIV gp41 MPER. Most importantly, this team originated the concept of B Cell Lineage Vaccine Design wherein precursors of desired antibodies are targeted by vaccine design. We have found that tolerance deletion is not complete and B cells making broad neutralizing antibodies (bnAbs) survive in the peripheral immune organs for activation by vaccines. From this work, what is required for induction of bnAbs is directed affinity maturation of a gp41 neutralizing antibody response, as well as breaking peripheral anergy of otherwise unresponsive B cells. MPER peptides in membrane liposomes have been designed to mimic virions, and potent adjuvants have been incorporated into MPER-liposomes. Thus, one lead candidate as an MPER immunogen is liposomes with viral lipids containing the gp41 intermediate form of the MPER that may be primed with an endogenous MPER homologous host antigen. Our work focused on immunization studies in rhesus macaques to focus the antibody response on the MPER neutralizing epitopes, and on MPER second generation immunogen design. For gp120 epitopes, this CAVD has identified 3 transmitted founder Envs as candidate vaccines that are both superior as antigenic and immunogenic Envs compared to 28 others tested. Finally, the CAVD team worked to define the correlates of protective immunity to HIV in the RV144 trial samples.