Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.
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...
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doaj-d5b2f7046b1541119a744ca5d089a0a52020-11-25T00:02:08ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-07-01127e100574210.1371/journal.ppat.1005742Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.Cecilia RademeyerBette KorberMichael S SeamanElena E GiorgiRuwayhida ThebusAlexander RoblesDaniel J ShewardKshitij WaghJetta GarrityBrittany R CareyHongmei GaoKelli M GreeneHaili TangGama P BandaweJinny C MaraisThabo E DiphokoPeter HraberNancy TumbaPenny L MooreGlenda E GrayJames KublinM Juliana McElrathMarion VermeulenKeren MiddelkoopLinda-Gail BekkerMichael HoelscherLeonard MabokoJoseph MakhemaMerlin L RobbSalim Abdool KarimQuarraisha Abdool KarimJerome H KimBeatrice H HahnFeng GaoRonald SwanstromLynn MorrisDavid C MontefioriCarolyn WilliamsonThe 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.http://europepmc.org/articles/PMC4951126?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cecilia Rademeyer Bette Korber Michael S Seaman Elena E Giorgi Ruwayhida Thebus Alexander Robles Daniel J Sheward Kshitij Wagh Jetta Garrity Brittany R Carey Hongmei Gao Kelli M Greene Haili Tang Gama P Bandawe Jinny C Marais Thabo E Diphoko Peter Hraber Nancy Tumba Penny L Moore Glenda E Gray James Kublin M Juliana McElrath Marion Vermeulen Keren Middelkoop Linda-Gail Bekker Michael Hoelscher Leonard Maboko Joseph Makhema Merlin L Robb Salim Abdool Karim Quarraisha Abdool Karim Jerome H Kim Beatrice H Hahn Feng Gao Ronald Swanstrom Lynn Morris David C Montefiori Carolyn Williamson |
spellingShingle |
Cecilia Rademeyer Bette Korber Michael S Seaman Elena E Giorgi Ruwayhida Thebus Alexander Robles Daniel J Sheward Kshitij Wagh Jetta Garrity Brittany R Carey Hongmei Gao Kelli M Greene Haili Tang Gama P Bandawe Jinny C Marais Thabo E Diphoko Peter Hraber Nancy Tumba Penny L Moore Glenda E Gray James Kublin M Juliana McElrath Marion Vermeulen Keren Middelkoop Linda-Gail Bekker Michael Hoelscher Leonard Maboko Joseph Makhema Merlin L Robb Salim Abdool Karim Quarraisha Abdool Karim Jerome H Kim Beatrice H Hahn Feng Gao Ronald Swanstrom Lynn Morris David C Montefiori Carolyn Williamson Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. PLoS Pathogens |
author_facet |
Cecilia Rademeyer Bette Korber Michael S Seaman Elena E Giorgi Ruwayhida Thebus Alexander Robles Daniel J Sheward Kshitij Wagh Jetta Garrity Brittany R Carey Hongmei Gao Kelli M Greene Haili Tang Gama P Bandawe Jinny C Marais Thabo E Diphoko Peter Hraber Nancy Tumba Penny L Moore Glenda E Gray James Kublin M Juliana McElrath Marion Vermeulen Keren Middelkoop Linda-Gail Bekker Michael Hoelscher Leonard Maboko Joseph Makhema Merlin L Robb Salim Abdool Karim Quarraisha Abdool Karim Jerome H Kim Beatrice H Hahn Feng Gao Ronald Swanstrom Lynn Morris David C Montefiori Carolyn Williamson |
author_sort |
Cecilia Rademeyer |
title |
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. |
title_short |
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. |
title_full |
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. |
title_fullStr |
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. |
title_full_unstemmed |
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization. |
title_sort |
features of recently transmitted hiv-1 clade c viruses that impact antibody recognition: implications for active and passive immunization. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2016-07-01 |
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. |
url |
http://europepmc.org/articles/PMC4951126?pdf=render |
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