HIV disease progression varies widely among individuals. Although some genetic or HIV protein factors have been identified that affect disease progression, these do not explain slow HIV disease progression in most cases. We and others found an association between infection with GB virus C (GBV-C) infection, a common, nonpathogenic human flavivirus, and prolonged survival in several cohorts of HIV-infected people. GBV-C infection is also associated with decreased maternal-fetal HIV transmission. These epidemiological associations are strengthened by in vitro studies demonstrating that GBV-C infection of CD4 cells potently inhibits HIV replication by modulating host cellular gene expression resulting in decreased HIV entry and facilitating CD4 survival. HIV leads to qualitative and quantitative immune dysfunction. Although HIV directly kills CD4 cells, the number of cells infected with HIV is insufficient to explain the overall CD4 depletion. The precise mechanism(s) by which HIV depletes CD4+ T cells is incompletely understood. Immune activation induced by infection with HIV itself or other microbes (e.g. GI bacteria), appears to be critical for CD4 depletion. Recent data found that GBV-C infection dampens CD4 and CD8 T cell activation in vivo and in vitro, suggesting that GBV-C may influence HIV disease in this manner. In addition, GBV-C infection was associated with a lack of CD4 expansion among people who received recombinant IL-2 therapy (rIL-2) in a blinded, prospective, multicenter trial. Although the study was small and some data were missing, the results were striking. If confirmed in larger cohorts, GBV-C infection would be a critical variable in the interpretation of rIL-2 therapy and potentially other immunomodulatory trials. We hypothesize that GBV-C interacts with IL-2, potentially via the IL-2 receptor to dampen T cell activation and proliferation, resulting in delayed HIV disease progression. To test this hypothesis we propose three aims. First, we will confirm our initial epidemiological findings in a larger cohort (ESPRIT). Secondly, we will examine the effect of GBV-C on changes in T cell activation and proliferation in lymphocytes from HIV-infected and uninfected people in relation to IL-2 activation. Finally, we will characterize the GBV-C protein(s) and protein domains involved in cellular interactions dampening T cell activation in vitro. Understanding factors that delay HIV disease is critical for understanding disease variability in HIV infection, and identification of the mechanisms by which CD4 cells are preserved during HIV infection may be exploited to identify novel approaches of cellular-based HIV therapeutics.

Public Health Relevance

- Stapleton This project is designed to characterize the effect of GB virus C infection on CD4 T cell proliferation and activation. Clinical and laboratory studies indicate that GBV-C decreases two key factors of HIV disease progression (T cell activation and proliferation). Understanding how GBV-C interferes with these processes should facilitate the development of novel HIV therapies and vaccines, and is highly relevant for public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058740-09
Application #
8317645
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Mckaig, Rosemary G
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$529,116
Indirect Cost
$109,183
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Verma, Shefali S; Frase, Alex T; Verma, Anurag et al. (2016) PHENOME-WIDE INTERACTION STUDY (PheWIS) IN AIDS CLINICAL TRIALS GROUP DATA (ACTG). Pac Symp Biocomput 21:57-68
Moore, Carrie B; Verma, Anurag; Pendergrass, Sarah et al. (2015) Phenome-wide Association Study Relating Pretreatment Laboratory Parameters With Human Genetic Variants in AIDS Clinical Trials Group Protocols. Open Forum Infect Dis 2:ofu113
Wanga, Valentine; Venuto, Charles; Morse, Gene D et al. (2015) Genomewide association study of tenofovir pharmacokinetics and creatinine clearance in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics 25:450-61
Lehmann, David S; Ribaudo, Heather J; Daar, Eric S et al. (2015) Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols. Pharmacogenet Genomics 25:51-9
Vardhanabhuti, Saran; Ribaudo, Heather J; Landovitz, Raphael J et al. (2015) Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia. Open Forum Infect Dis 2:ofv085
Stapleton, Jack T; Xiang, Jinhua; McLinden, James H et al. (2014) A novel T cell evasion mechanism in persistent RNA virus infection. Trans Am Clin Climatol Assoc 125:14-24; discussion 24-6
Chivero, Ernest T; Bhattarai, Nirjal; Rydze, Robert T et al. (2014) Human pegivirus RNA is found in multiple blood mononuclear cells in vivo and serum-derived viral RNA-containing particles are infectious in vitro. J Gen Virol 95:1307-19
Johnson, Daniel H; Venuto, Charles; Ritchie, Marylyn D et al. (2014) Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics 24:195-203
Haas, David W; Kwara, Awewura; Richardson, Danielle M et al. (2014) Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. J Antimicrob Chemother 69:2175-82
Siewe, Basile; Wallace, Jennillee; Rygielski, Sonya et al. (2014) Regulatory B cells inhibit cytotoxic T lymphocyte (CTL) activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs. PLoS One 9:e92934

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