title: Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.
abstract: 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.
authors.affiliation: 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.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rademeyer
authors.affiliation: Los Alamos National Laboratory and New Mexico Consortium, Los Alamos, New Mexico, United States of America.
authors.forename: Bette
authors.initials: B
authors.lastname: Korber
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.affiliation: Los Alamos National Laboratory and New Mexico Consortium, Los Alamos, New Mexico, United States of America.
authors.forename: Elena E
authors.initials: EE
authors.lastname: Giorgi
authors.affiliation: 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.
authors.forename: Ruwayhida
authors.initials: R
authors.lastname: Thebus
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Robles
authors.affiliation: 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.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sheward
authors.affiliation: Los Alamos National Laboratory and New Mexico Consortium, Los Alamos, New Mexico, United States of America.
authors.forename: Kshitij
authors.initials: K
authors.lastname: Wagh
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Jetta
authors.identifier: 0000-0002-2458-0519
authors.initials: J
authors.lastname: Garrity
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Carey
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Greene
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Haili
authors.initials: H
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Gama P
authors.identifier: 0000-0001-8888-8048
authors.initials: GP
authors.lastname: Bandawe
authors.affiliation: 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.
authors.forename: Jinny C
authors.initials: JC
authors.lastname: Marais
authors.affiliation: Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
authors.forename: Thabo E
authors.initials: TE
authors.lastname: Diphoko
authors.affiliation: Los Alamos National Laboratory and New Mexico Consortium, Los Alamos, New Mexico, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Hraber
authors.affiliation: National Institute for Communicable Diseases (NICD), NHLS & University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Nancy
authors.initials: N
authors.lastname: Tumba
authors.affiliation: 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.
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg and South African Medical Research Council, Cape Town, South Africa.
authors.forename: Glenda E
authors.initials: GE
authors.lastname: Gray
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Kublin
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: South African National Blood Service, Weltevreden Park, South Africa.
authors.forename: Marion
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Desmond Tutu HIV Centre, Department of Medicine and Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa.
authors.forename: Keren
authors.initials: K
authors.lastname: Middelkoop
authors.affiliation: Desmond Tutu HIV Centre, Department of Medicine and Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa.
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.affiliation: Department for Infectious Diseases & Tropical Medicine, Klinikum University of Munich, LMU and German Center for Infection Research (DZIF) partner site Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
authors.affiliation: NIMR-Mbeya Medical Research Center, Mbeya, Tanzania.
authors.forename: Leonard
authors.initials: L
authors.lastname: Maboko
authors.affiliation: Botswana-Harvard AIDS Institute Partnership, Gaborone, Botswana.
authors.forename: Joseph
authors.initials: J
authors.lastname: Makhema
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Quarraisha
authors.initials: Q
authors.lastname: Abdool Karim
authors.affiliation: 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.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ronald
authors.initials: R
authors.lastname: Swanstrom
authors.affiliation: 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.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: 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.|Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology; D000080908:Broadly Neutralizing Antibodies; D002986:Clinical Trials as Topic; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D010802:Phylogeny; D014611:Vaccination / Q000379:methods
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C578595:VRC01 monoclonal antibody