HIV-1 has a remarkable capacity to adapt to individual human hosts by escaping cytotoxic T lymphocyte (CTL) responses mediated by human leukocyte antigen (HLA) recognition. Though HLA types are highly polymorphic, and there is site-specific functional constraint to change in the virus, HIV-1 appears to escape HLA-restricted CTL (and possibly CD4 T helper cell) responses by genetic mutation. Here, the study of HLA-driven adaptation at a population level will be used to understand determinants of HIV-1 disease severity in the HIV-1 infected individual and to guide design of a vaccine that would most effectively overcome the adaptability of HIV-1 in human populations.
The specific aims are to: 1) Characterize HIV-1 adaptation to HLA at a (host) population level to identify immune escape/adaptations across full length HIV-1 sequences in a large drug-naive cohort that has HLA and viral diversity representative of populations in the US; 2) Correlate HLA-driven adaptation to viral load; 3) Determine immunological and virological determinants of HLA-driven adaptation and viral load. The sites of HLA-associated selection will mark out in vivo epitope targets of immune responses and the viral load effects of escape at these sites serve as a quantitative measure of the balance between host immune pressure and genetic barrier to mutation unique to every specific escape/adaptation. The information will be used to (i) correlate in-vivo HLA class I selection effects with assayed ex-vivo CTL responses (ii) define novel CTL and CD4 T helper epitopes (ii) measure magnitude, phenotype and T cell receptor (TCR) characteristics of T cells that favour or mitigate specific adaptations and (iii) measure the replicative fitness cost that constrains immune selection at these sites; 4) Design a 'population-optimised' HIV-1 vaccine. The results will be used to determine how well the immune responses induced by a given vaccine would recognise diverse, variably HLA-adapted HIV-1 strains at those epitopes most critical for the prevalent HLA types of the study cohort.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI060460-03
Application #
7022268
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Wassef, Nabila M
Project Start
2004-03-15
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
3
Fiscal Year
2006
Total Cost
$244,125
Indirect Cost
Name
Murdoch University
Department
Type
DUNS #
740094610
City
Perth
State
Country
Australia
Zip Code
6150
Yagita, Yuichi; Kuse, Nozomi; Kuroki, Kimiko et al. (2013) Distinct HIV-1 escape patterns selected by cytotoxic T cells with identical epitope specificity. J Virol 87:2253-63
Hertz, Tomer; Oshansky, Christine M; Roddam, Philippa L et al. (2013) HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection. Proc Natl Acad Sci U S A 110:13492-7
Bronke, Corine; Almeida, Coral-Ann M; McKinnon, Elizabeth et al. (2013) HIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes. AIDS 27:899-905
Apps, Richard; Qi, Ying; Carlson, Jonathan M et al. (2013) Influence of HLA-C expression level on HIV control. Science 340:87-91
Li, Hui; Blair, Lily; Chen, Yalu et al. (2013) Molecular mechanisms of HIV type 1 prophylaxis failure revealed by single-genome sequencing. J Infect Dis 208:1598-603
Carlson, Jonathan M; Brumme, Chanson J; Martin, Eric et al. (2012) Correlates of protective cellular immunity revealed by analysis of population-level immune escape pathways in HIV-1. J Virol 86:13202-16
Keane, Niamh M; Roberts, Steven G; Almeida, Coral-Ann M et al. (2012) High-avidity, high-IFN?-producing CD8 T-cell responses following immune selection during HIV-1 infection. Immunol Cell Biol 90:224-34
Brockman, Mark A; Chopera, Denis R; Olvera, Alex et al. (2012) Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity. J Virol 86:6913-23
Phillips, Elizabeth J; Chung, Wen-Hung; Mockenhaupt, Maja et al. (2011) Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol 127:S60-6
Dong, Tao; Zhang, Yonghong; Xu, Ke Yi et al. (2011) Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China. Blood 118:98-106

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