Current HIV-1 vaccine strategies are based on the assumption that persistent immune control will be possible, but the extent to which this occurs in natural infection is not known. Emerging data provide convincing evidence that the cellular immune system contributes to containing HIV replication. We now propose to build on the previous 15 years of this grant to perform a detailed analysis of immunologic, host genetic and viral factors associated with spontaneous control of viremia in a unique subset of HIV-infected persons who are able to achieve persistent viral control without antiviral therapy. Through a nationwide collaborative effort with academic institutions and primary care physicians, we will expand our existing cohort of 90 persons we term """"""""controllers"""""""", namely persons who maintain viral loads of less than 2000 and often less than 50 RNA copies/ml plasma despite never having been treated with antiviral therapy. This cohort will provide a unique opportunity to determine the extent to which persistent immunologic control is possible in HIV infection, and the extent to which viral and host genetic factors contribute to long-term control of viremia. Comparison to a second cohort comprised of progressors with untreated infection and uncontrolled viremia, as well as longitudinal follow up to examine controllers who ultimately progress will provide the opportunity to determine the factors associated with control and loss of control of viremia. The results of these studies have critical implications not only for understanding HIV immunopathogenesis, but also for current vaccine strategies. Specifically, we propose to a) Establish a cohort of untreated HIV infected persons who control viremia and determine host and viral genetic factors associated with successful in vivo restriction of viral replication; b) Characterize the HLA allele-specific dominant and subdominant CD8 T cell responses associated with successful control of HIV viremia, and compare this to uncontrolled infection; and c) Determine the replicative fitness of clinical isolates collected from persons who spontaneously control viremia to investigate the role of viral attenuation in containment of HIV replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028568-20
Application #
7391746
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
1989-07-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
20
Fiscal Year
2008
Total Cost
$366,256
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Kiezun, Adam; Garimella, Kiran; Do, Ron et al. (2012) Exome sequencing and the genetic basis of complex traits. Nat Genet 44:623-30
McLaren, Paul J; Ripke, Stephan; Pelak, Kimberly et al. (2012) Fine-mapping classical HLA variation associated with durable host control of HIV-1 infection in African Americans. Hum Mol Genet 21:4334-47
Pasaniuc, Bogdan; Rohland, Nadin; McLaren, Paul J et al. (2012) Extremely low-coverage sequencing and imputation increases power for genome-wide association studies. Nat Genet 44:631-5
Brumme, Zabrina L; Li, Chun; Miura, Toshiyuki et al. (2011) Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers. J Acquir Immune Defic Syndr 56:100-8
International HIV Controllers Study (see original citation for additional authors) (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330:1551-7
Brockman, Mark A; Brumme, Zabrina L; Brumme, Chanson J et al. (2010) Early selection in Gag by protective HLA alleles contributes to reduced HIV-1 replication capacity that may be largely compensated for in chronic infection. J Virol 84:11937-49
Miura, Toshiyuki; Brumme, Zabrina L; Brockman, Mark A et al. (2010) Impaired replication capacity of acute/early viruses in persons who become HIV controllers. J Virol 84:7581-91
Julg, B; Williams, K L; Reddy, S et al. (2010) Enhanced anti-HIV functional activity associated with Gag-specific CD8 T-cell responses. J Virol 84:5540-9
Miura, Toshiyuki; Brockman, Mark A; Schneidewind, Arne et al. (2009) HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J Virol 83:2743-55
Miura, Toshiyuki; Brumme, Chanson J; Brockman, Mark A et al. (2009) HLA-associated viral mutations are common in human immunodeficiency virus type 1 elite controllers. J Virol 83:3407-12

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