A major goal of this proposal is to understand the role that cytotoxic T lymphocyte (CTL) escape plays in HIV transmission and disease pathogenesis. An understanding of the impact of CTL escape mutations on viral evolution and fitness is only beginning to unfold and the studies proposed in this application represent a unique opportunity to examine how HIV adapts as it moves from one HLA environment to another. These studies focus on linked heterosexual transmission pairs to extensively characterize CTL escape mutations in the setting of shared and disparate HLA class I alleles and to follow these longitudinally after HIV-1 transmission, possible reasons for delayed or non-transmission will also be examined in an equivalent group of discordant couples. Specifically we will: 1.Perform a cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses at a population and individual level to determine if HIV-1 polymorphisms associated with HLA alleles cluster within known HLA class I specific CD8+ CTL epitopes and if we can identify novel epitopes that are specific to African HLA alleles. The epitopes and escape mutations will be validated biologically. These approaches will be extended to determine the relative contribution of HLA allele frequency and viral replicative fitness to fixation of escape mutation in the population consensus sequence, and analyses of class II MHC and Kir allele contributions to immune control of HIV. 2. In 150 couples where we have documented recent transmission, we will determine the kinetics of CTL epitope reversion and escape as the virus adapts to moving from the HLA class I environment of the donor to that of the recipient. We will determine the biological consequences of persistence, escape and reversion in epitope-specific gag and nef sequences by analysis of viral load and in vitro fitness. 3. In approximately 40 high-risk non-transmitting couples we will determine if the long-term non-transmitting partners display a bias in escape signatures that may contribute to lack of transmission. These studies will further allow the application and development of models that address the impact of CTL escape mutations on viral load and viral fitness and their relevance to vaccine development. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI064060-01
Application #
6892706
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Young, Janet M
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2005-02-15
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$1,178,018
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Boppana, Sushma; Goepfert, Paul (2018) Understanding the CD8 T-cell response in natural HIV control. F1000Res 7:
Powers, Kimberly A; Price, Matthew A; Karita, Etienne et al. (2018) Prediction of extended high viremia among newly HIV-1-infected persons in sub-Saharan Africa. PLoS One 13:e0192785
Connolly, Sarah; Wall, Kristin M; Tang, Jianming et al. (2018) Fc-gamma receptor IIA and IIIA variants in two African cohorts: Lack of consistent impact on heterosexual HIV acquisition, viral control, and disease progression. Virology 525:132-142
Wiener, Howard W; Shrestha, Sadeep; Lu, Hailin et al. (2018) Immunogenetic factors in early immune control of human immunodeficiency virus type 1 (HIV-1) infection: Evaluation of HLA class I amino acid variants in two African populations. Hum Immunol 79:166-171
Peng, Binghao J; Carlson, Jonathan M; Liu, Michael K P et al. (2018) Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection. J Virol 92:
Woodson, Evonne; Goldberg, Alec; Michelo, Clive et al. (2018) HIV transmission in discordant couples in Africa in the context of antiretroviral therapy availability. AIDS 32:1613-1623
Ende, Zachary; Deymier, Martin J; Claiborne, Daniel T et al. (2018) HLA Class I Downregulation by HIV-1 Variants from Subtype C Transmission Pairs. J Virol :
Haddad, Lisa B; Wall, Kristin M; Kilembe, William et al. (2018) Bacterial vaginosis modifies the association between hormonal contraception and HIV acquisition. AIDS 32:595-604
Joseph Davey, Dvora Leah; Wall, Kristin M; Kilembe, William et al. (2018) Difficult decisions: Evaluating individual and couple-level fertility intentions and HIV acquisition among HIV serodiscordant couples in Zambia. PLoS One 13:e0189869
Joseph Davey, Dvora L; Wall, Kristin M; Kilembe, William et al. (2017) HIV Incidence and Predictors of HIV Acquisition From an Outside Partner in Serodiscordant Couples in Lusaka, Zambia. J Acquir Immune Defic Syndr 76:123-131

Showing the most recent 10 out of 74 publications