Understanding the interplay between HIV-1 diversity, humoral immune responses and viral fitness

Abstract

HIV-1 antibody dependent cell cytotoxicity (ADCC) and neutralizing antibody (nAb) responses are both thought to be important responses to elicit through vaccination. This thesis characterises neutralizing response in two cohorts in Africa, and in a detailed study of one individual, elucidates the interplay between ADCC and nAb responses in early infection, and the impact of humoral escape on viral fitness. It remains an open question whether different geographically distinct population groups vary in their neutralization responses to HIV-1. We compared neutralizing antibody responses in two African cohorts and found 35% of the Tanzanians in the HIV Superinfection Study (HISIS) cohort had neutralization breath (neutralized >50% of panel viruses) at two years post infection compared to only 9% in the Centres for AIDS Program of Research in South Africa (CAPRISA) cohort. Cumulative viral loads between 3 and 12 months post infection were strongly associated with neutralization breadth (p<0.001), and were higher in the Tanzanian cohort (p=0.046). No association was found between breadth and dual infection, subtype or features of the envelope. One elite neutralizer was identified in the HISIS cohort with responses targeting the CD4 binding site. While neutralizing antibodies are considered central for protection from infection, ADCC activity correlated with reduced risk of HIV-1 acquisition in the RV144 trial. There is limited understanding of the overlapping ADCC and neutralizing antibody functions in early infection. We investigated the kinetics and targets of both responses in one individual from CAPRISA. ADCC responses were detected 4 weeks post infection, with nAbs responses emerging at 7 weeks post infection. We identified five neutralization escape patterns in the V4 region of the envelope by 11 weeks post-infection. Four of these also conferred ADCC escape; however the fifth neutralization escape variant resulted in increased sensitivity to ADCC. This variant was eliminated in vivo by 29 weeks post infection. Finally, we studied the effect of neutralizing and ADCC antibody escape mutations on the virus' ability to mediate fusion, infectivity and replicative fitness. Envelopes bearing immune escape adaptations had lower cell-cell fusion ability compared to the T/F virus. The mutations also resulted in reduced infectivity of infectious molecular clone virus stocks. However, only the largest deletion in the V4 caused reduced growth in peripheral blood mononuclear cells (PBMC). In conclusion, the study finds that neutralizing antibody responses are influenced by community viral loads. The study defined the first ADCC epitope reported in the V4 region, and describes overlapping targets for ADCC and neutralizing antibodies. Where neutralization escape resulted in increased ADCC sensitivity, this was a dead end escape pathway. Finally we find that early V4 escape from both ADCC and nAb responses had a fitness impact on the virus. We thus demonstrate a mechanism through which ADCC and neutralizing antibodies can synergistically influence viral evolution and potentially produce a protective immune response.