Determinants of HIV broadly-neutralizing antibody precursor induction in infants

点击翻译按钮获取中文摘要

ABSTRACT – OVERALL The induction of broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env) is considered vital for an effective HIV vaccine. Rational vaccine design applying native Env-like trimers that target the respective germline B cell receptor have evolved as the most promising strategy. Yet, so far, bNAb precursor yields have not exceeded 50% of vaccinees. The goal of this Program aims to identify early determinants of bNAb precursor induction, with a focus on the role of adjuvants and host microbiota, utilizing broad and integrated omics approaches to decipher the mechanisms associated with bNAb development. In HIV infection, plasma bNAbs develop in a minority of adults and only after several years, whereas bNAbs in infants with HIV can be detected as early as one year post infection. Interestingly, bNAbs isolated from infants appear to require less somatic hypermutations to achieve similar breadth as bNAbs of adults, implying potentially different mechanisms of bNAb development. We present preliminary data that immunization of infant rhesus macaques (RM) with BG505 germline-targeting (GT)1.1 SOSIP trimers adjuvanted with the TLR7,8 adjuvant 3M-052 resulted in the induction of VRC01-like CD4 binding site bNAb precursors in 3 of 5 animals, a frequency comparable to that observed in adult RM (6 of 12). Plasma antibodies of infant RM also targeted a broader array of epitopes compared to adult RM, indicative of greater polyreactivity. Despite additional immunizations, the remaining 2 infant RM did not develop this neutralization signature, suggesting that early events are critical in driving bNAb development. In infants, early immunity is partially defined by the evolving microbiota. The polyreactivity of many, although not all, bNAbs, further supports a potential role of microbiota in bNAb development We hypothesize that the dynamic state of the infant immune system and microbiota can be exploited to optimize the induction of bNAbs by HIV vaccines. Leveraging the infant BG505 GT1.1 SOSIP vaccine model and applying systems biology approaches, we will identify how the developmental pathways of bNAb induction are altered by the modulation of the vaccine prime by different adjuvants (Project 1), the microbiome (Project 2), and the interactions between host immunity and microbiota (Biostatistics and Computational Analysis [BCA] Core). The Projects will be supported by the Nonhuman Primate (NHP) and the B Cell Cores, with organizational and fiscal support by the Administrative Core. In Aims 1 and 2, we will define differences in early immune responses and molecular signatures between vaccinees who do or do not develop bNAbs in response to BG505 GT1.1 SOSIP vaccination by modulating the vaccine prime via adjuvants (Project 1) and microbiota (Project 2). Aim 3 will develop modeling approaches that integrate immune, microbiome, and molecular signatures to predict the development of bnAb precursors. The results of the Program will identify critical determinants in the induction of bNAb precursors. In future studies, we will modulate these factors to optimize HIV vaccine strategies. The newly developed computational models will facilitate vaccine screening for the potential of bNAb development.