The circulating and memory B-antibody responses in HIV-infected patients

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DESCRIPTION (provided by applicant): The candidate is an Assistant Professor of Medicine and Infectious Diseases at the Institute of Human Virology (IHV) at the University of Maryland School of Medicine. The candidate's long-term goal is to become an independent clinical investigator specializing in the field of humoral immunity in HIV infection. The purpose of this proposal is to provide the candidate with the appropriate tools and environment to reach this goal. The IHV was built on the premise of bringing a strong collaborative atmosphere between clinicians and laboratory researchers to promote translating basic scientific discoveries into clinically relevant applications. Through the mentorship of researchers from both the basic science (Vaccine Division) and clinical research divisions of the IHV, along with a career development program focused on Immunology, the candidate will receive a solid foundation upon which to build an independent career in academic medicine. The candidate's short-term goals are encapsulated in the research proposal, which is presented below. Vaccine efforts for HIV-1 have been hampered by the biological reality that humans can never completely clear HIV-1 once infected; consequently, finding immune correlates of humoral protection have proven to be difficult. However, within the HIV-infected population, about 1% can effectively control the replication of the virus to minimal levels without antiretrovirals. We have recently described such a cohort of HIV-1 infected individuals, Natural Viral Suppressors (NVS). The NVS and similar cohorts (Elite Controllers) represent the best available model of natural immunity to HIV-1. Much of the research focus until now has been placed on circulating antibodies in the plasma. However, as we will demonstrate, standardized plasma neutralization may not provide an accurate composite picture in these individuals. By contrast, memory B cells provide an archival record of humoral responses for the lifetime of the host. The specific hypothesis of this proposal is that effective humoral immunity (memory B cell frequency and neutralization derived from memory B cell antibodies), correlates with the HIV-1 viral suppression seen in the NVS (but not HIV-controls). We propose that detailed antibody analysis of memory B cells (which archive every antibody ever made) rather than the circulating pool (what is normally tested) in the NVS (HIV-infected persons who control the virus without medication) will reveal an association between memory B cell antibodies and being NVS. If this is correct, then NVS will be a model of antibody control for designing the antibody part of an HIV vaccine.