ANTIBODY NEUTRALIZATION AND ESCAPE IN SUBTYPE C HIV-1

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neutralizing antibodies in HIV-1 infection are directed against the envelope (Env) glycoproteins gp120 and gp41. However, HIV-1 Env utilizes highly effective, but poorly defined, mechanisms to evade antibody-mediated neutralization. The objective of these studies is to indentify the initial B cell targets and define mechanisms of viral escape in subjects that are newly infected with subtype A and C HIV-1 in Rwanda and Zambia, respectively. In year 03 of this R01, through collaboration with Dr. Guido Silvestri, we compared neutralizing antibody (Nab) responses against the autologous virus in HIV-1 infection vs. SIV infection of a natural host species, the sooty mangabey (Li et al). We demonstrated that high titer Nab develops in early HIV-1 infection and persists into the chronic stage of infection. However, SIV infection of sooty mangabeys does not elicit high titer Nab responses against the autologous virus. This finding suggests fundamental differences in the B cell response in pathogenic vs. nonpathogenic infection, and we are continuing to investigate the biology underlying this observation. We have demonstrated that B cells in chronic HIV-1 infection express increased levels of PD-1 and decreased levels of BTLA, compared to healthy human subjects (Boliar et al.). Expression of these markers was linked to increased immune activation throughout the B cells subsets and to the aberrant production of immunoglobulin. We are continuing to investigate how these abnormalities contribute to disease progression and failure of the humoral immune response in HIV-1 infection. FUNDING SOURCE: NIH