Abstract

Most HIV vaccine designs are currently based on studies of chronic HIV-1 subtype B infection. However, the prevailing dominance of HIV-1 subtype C (HIV-1 C) in the worldwide AIDS epidemic, and the efficient, albeit temporary, containment of the virus during acute HIV infection necessitates a comprehensive analysis of primary HIV-1 C infection with regard to vaccine design. Assuming that the level of viral set point is dictated by virus-host interactions, we postulated that (i) the kinetics of viral replication, viral diversity, and immune responses vary between primary HIV-1 infections; (ii) virological and immunological determinants in acute HIV-1 infection are related to viral set point, and (iii) virological and immunological parameters in acute HIV-1 infection associated with low viral set point could be identified and targeted for vaccine development. We hypothesize that a combination of functional Gag p24-specific T cell responses and low viral diversity within tat and nef in primary HIV-1 C infection is associated with low viral set point, while lack of functional p24-specific immune response coupled with high tat and nef diversity are markers of high viral set point. To test this hypothesis a prospective study on acute and early HIV-1 infection in Botswana has been designed. There are two Specific Aims in the study: 1. To characterize the magnitude, breadth and kinetics of virological and immunological determinants during primary HIV-1 C infection including transient changes in viral evolution and immune responses. Viral load (RNA and DNA), viral diversity (p24, tat, env, and nef), virus-specific CD4+ and CD8+ T cell immune responses, expression of CCR5 and CXCR4, and levels of beta-chemokine production (MIP-1a, MIP-1B and RANTES) will be analyzed. 2. To assess the association between virological and immunological markers in primary HIV-1 C infection with viral set point. To develop a multivariate model of the inter-relationship of these factors with viral set point.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057027-04
Application #
7422344
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Young, Janet M
Project Start
2005-05-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
4
Fiscal Year
2008
Total Cost
$430,744
Indirect Cost

  Institution

Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Moyo, Sikhulile; Wilkinson, Eduan; Vandormael, Alain et al. (2017) Pairwise diversity and tMRCA as potential markers for HIV infection recency. Medicine (Baltimore) 96:e6041
Rossenkhan, Raabya; MacLeod, Iain J; Brumme, Zabrina L et al. (2016) Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection. AIDS Res Hum Retroviruses 32:1031-1045
Mann, Jaclyn K; Chopera, Denis; Omarjee, Saleha et al. (2014) Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure. Virology 468-470:214-25
Novitsky, Vlad; Wang, Rui; Rossenkhan, Raabya et al. (2013) Intra-host evolutionary rates in HIV-1C env and gag during primary infection. Infect Genet Evol 19:361-8
Rossenkhan, Raabya; MacLeod, Iain J; Sebunya, Theresa K et al. (2013) tat Exon 1 exhibits functional diversity during HIV-1 subtype C primary infection. J Virol 87:5732-45
Rossenkhan, Raabya; Novitsky, Vladimir; Sebunya, Theresa K et al. (2012) Viral diversity and diversification of major non-structural genes vif, vpr, vpu, tat exon 1 and rev exon 1 during primary HIV-1 subtype C infection. PLoS One 7:e35491
Novitsky, Vladimir; Wang, Rui; Baca, Jeannie et al. (2011) Evolutionary gamut of in vivo Gag substitutions during early HIV-1 subtype C infection. Virology 421:119-28
Wright, Jaclyn K; Novitsky, Vladimir; Brockman, Mark A et al. (2011) Influence of Gag-protease-mediated replication capacity on disease progression in individuals recently infected with HIV-1 subtype C. J Virol 85:3996-4006
Novitsky, Vladimir; Ndung'u, Thumbi; Wang, Rui et al. (2011) Extended high viremics: a substantial fraction of individuals maintain high plasma viral RNA levels after acute HIV-1 subtype C infection. AIDS 25:1515-22
Novitsky, Vladimir; Wang, Rui; Margolin, Lauren et al. (2010) Dynamics and timing of in vivo mutations at Gag residue 242 during primary HIV-1 subtype C infection. Virology 403:37-46

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