Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization
Creators: name: Giorgi, Elena E.
name: Seaman, Michael S.
name: Montefiori, David C.
name: Wagh, Kshitij
name: Gray, Glenda E.
name: Gao, Feng
name: Robb, Merlin L.
name: Rademeyer, Cecilia
name: Hraber, Peter
name: Abdool Karim, Quarraisha
name: Carey, Brittany R.
name: Moore, Penny L.
name: Bandawe, Gama P.
name: Tang, Haili
name: Robles, Alexander
name: Bekker, Linda-Gail
name: Kim, Jerome H.
name: Makhema, Joseph
name: Tumba, Nancy
name: Sheward, Daniel J.
name: Korber, Bette
name: Williamson, Carolyn
name: Diphoko, Thabo E.
name: Kublin, James
name: Abdool Karim, Salim
name: Maboko, Leonard
name: Hahn, Beatrice H.
name: Greene, Kelli M.
name: McElrath, M. Juliana
name: Gao, Hongmei
name: Marais, Jinny C.
name: Morris, Lynn
name: Hoelscher, Michael
name: Vermeulen, Marion
name: Garrity, Jetta
name: Thebus, Ruwayhida
name: Swanstrom, Ronald
name: Middelkoop, Keren
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.