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PLoS Pathog. 2016 Jul 19;12(7):e1005742. doi: 10.1371/journal.ppat.1005742. eCollection 2016 Jul.

Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.

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Division of Medical Virology & Institute of Infectious Diseases and Molecular Medicine, University of Cape Town and National Health Laboratory Service (NHLS), Cape Town South Africa.
Los Alamos National Laboratory and New Mexico Consortium, Los Alamos, New Mexico, United States of America.
Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
National Institute for Communicable Diseases (NICD), NHLS & University of the Witwatersrand, Johannesburg, South Africa.
Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg and South African Medical Research Council, Cape Town, South Africa.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
South African National Blood Service, Weltevreden Park, South Africa.
Desmond Tutu HIV Centre, Department of Medicine and Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa.
Department for Infectious Diseases & Tropical Medicine, Klinikum University of Munich, LMU and German Center for Infection Research (DZIF) partner site Munich, Munich, Germany.
NIMR-Mbeya Medical Research Center, Mbeya, Tanzania.
US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
International Vaccine Institute, Seoul, Republic of Korea.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.


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.

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