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Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination.

ABSTRACT: Although human immunodeficiency virus type 1 (HIV-1) clade C continues to dominate the pandemic, only two infectious clade C proviral DNA clones have been described (N. Mochizuki, N. Otsuka, K. Matsuo, T. Shiino, A. Kojima, T. Kurata, K. Sakai, N. Yamamoto, S. Isomura, T. N. Dhole, Y. Takebe, M. Matsuda, and M. Tatsumi, AIDS Res. Hum. Retrovir. 15:1321-1324, 1999; T. Ndung'u, B. Renjifo, and M. Essex, J. Virol. 75:4964-4972, 2001). We have generated an infectious molecular clone of a pediatric clade C strain, HIV1084i, which was isolated from a Zambian infant infected either intrapartum or through breastfeeding. HIV1084i is an R5, non-syncytium-inducing isolate that bears all known clade C signatures; gag, pol, and env consistently mapped within clade C. Interestingly, gag resembled Asian isolates, whereas pol and env resembled African isolates, indicating that HIV1084i probably arose from an intraclade recombination. As a recently transmitted clade C strain, HIV1084i will be a useful vaccine development tool.

SUBMITTER: Grisson RD

PROVIDER: S-EPMC533957 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination.

Grisson Ricky D RD Chenine Agnès-Laurence AL Yeh Lan-Yu LY He Jun J Wood Charles C Bhat Ganapati J GJ Xu Weidong W Kankasa Chipepo C Ruprecht Ruth M RM

Journal of virology 20041201 24

Although human immunodeficiency virus type 1 (HIV-1) clade C continues to dominate the pandemic, only two infectious clade C proviral DNA clones have been described (N. Mochizuki, N. Otsuka, K. Matsuo, T. Shiino, A. Kojima, T. Kurata, K. Sakai, N. Yamamoto, S. Isomura, T. N. Dhole, Y. Takebe, M. Matsuda, and M. Tatsumi, AIDS Res. Hum. Retrovir. 15:1321-1324, 1999; T. Ndung'u, B. Renjifo, and M. Essex, J. Virol. 75:4964-4972, 2001). We have generated an infectious molecular clone of a pediatric c ...[more]

PMID: 15564517

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Project 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.

Project description:Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies.IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

Dataset Information

Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination.

Publications

Infectious molecular clone of a recently transmitted pediatric human immunodeficiency virus clade C isolate from Africa: evidence of intraclade recombination.

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