Origins and dynamics of HIV gp120 specific B cell memory in HIV negative high-risk individuals

PROJECT SUMMARY Decades of global effort have yet to result in a robust and effective preventative vaccine for HIV, although it has yielded remarkable insights into the likely requirements for immunogen design and potential correlates of vaccine mediate protection. The encouraging results of RV144 unfortunately were not reproduced in its adaptation to

South Africa with HVTN 702, however both have demonstrated that a finely tuned antibody (Ab) response to gp120, particularly V1V2 will likely be key to an effective vaccine. Similarly, the VRC01 efficacy trial established the defining threshold for a gp120 CD4 binding site broadly neutralizing Ab to mediate protection, and numerous

highly engineered gp120-based immunogens in clinical trials attempting to induce precise germline and B cell receptor development pathways, demonstrate the necessity of clearly defining gp120 specific B cell memory development. Development of a protective Ab response to HIV is likely dependent on the characteristics of the

pre-existing B cell population present prior to HIV infection or vaccination, referred to as pre-immune B cells. We and others have demonstrated increased HIV-specific plasma Abs in individuals at high-risk for HIV acquisition (HR) and recently we have demonstrated that HIV gp120-specific pre-immune B cells include as expected naïve

B cells, but also a substantial non-naïve proportion consisting of IgA, IgG, and IgM memory B cells. Following HIV Env vaccination, both pre-immune B cell populations respond and undergo somatic hypermutation and affinity maturation to give rise to high affinity HIV Env-specific Abs. Although the composition of the naïve pre-

immune HIV Env-specific repertoire is driven by germline genetics and likely to be highly similar amongst individuals, the composition of non-naïve pre-immune HIV Env-specific repertoire is likely to be more heterogenous. Its composition is likely driven by exposure to cross-reactive antigens such as microflora and

potentially in the instance of HR, bystander B cell activation resulting from other sexually transmitted infections, and unproductive exposures to HIV such as with individuals with on PrEP, and subsequently more heterogenous than the naïve pre-immune compartment. Such heterogeneity and memory bias of the pre-immune repertoire,

similar to the consequences of imprinting observed with responses to other viruses (e.g. influenza, dengue), could result in inconsistent HIV vaccine efficacy among HR. We hypothesize that the composition and responsiveness of the gp120 pre-immune B cell compartment is altered in HR and contributes to inconsistent

vaccine responses. To address this hypothesis, we will leverage existing longitudinal samples from US-based HR that are or are not using PrEP and control individuals at low-risk for HIV acquisition (LR) obtained through the NIH-funded MWCCS, a prospective Chlamydia trachomatis infection cohort, and South Africa-based HR and

LR that participated in the HVTN 702 vaccine efficacy trial to complete the following aims 1) determine the molecular and phenotypic features of pre-immune gp120+ B cells, 2) define the mobilization of pre-immune gp120+ B cells following vaccination, and 3) identify drivers of pre-immune gp120+ memory B cell development.