The basis for variation in disease progression rates among individuals infected with HIV-1 is not well understood, but appears to be related to aberrant T cell activation levels, which are likely determined by features of the invading pathogen, the infected host, and their interaction. Recent findings have suggested that features of the viral lifecycle are important correlates of clinical progression (in addition to plasma HIV-1 RNA level). For example, patients bearing a virus of low pol replication capacity have elevated CD4+ T cell counts, despite substantial levels of viral replication, suggesting that these variants have lowered in vivo virulence. In addition, other highly variable features of the viral genome, such as ENV and GAG, may determine virulence through T cell activation modulation. And lastly, host determinants, such as HLA type, have been associated with variation in disease progression and may confer their protective (or deleterious) effect via modulation of T cell activation level. To investigate the basis for variation in disease progression rates in individuals with HIV-1, I will conduct cross-sectional and longitudinal analyses using data from two ongoing cohorts of recently infected individuals and chronically infected individuals who will be assayed for HLA type, viral genotype (ENV, GAG, POL), viral pol replication capacity, and T cell activation measurements. I will determine host HLA Class I and II genetic predictors of variation in immune activation response to HIV-1 infection (Aim 1), viral genetic determinants of immune activation in HIV-1 infection (Aim 2), and if viruses of low pol RC are associated with lower T cell activation (Aim 3). By identifying important modulators of activation, we can determine targets for intervention to lower T cell activation levels. To achieve these aims, I have assembled a mentoring committee of internationally recognized scientists with strong track records in clinical investigation, immunopathogenesis, and biostatistics research. These mentors span several relevant disciplines, including clinical research methods (Drs. Hecht and Havlir), bioinformatics (Dr. Segal), immunogenetics (Dr. Oksenberg) and immunopathogenesis (Drs. McCune and Nixon). Their mentorship will help me achieve my goal of developing an independent career in quantitatively oriented translational research, focusing on determination of key elements of HIV-1 pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AI066917-01
Application #
7004326
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Mckaig, Rosemary G
Project Start
2005-07-01
Project End
2010-05-31
Budget Start
2005-07-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$121,330
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ooms, Marcel; Brayton, Bonnie; Letko, Michael et al. (2013) HIV-1 Vif adaptation to human APOBEC3H haplotypes. Cell Host Microbe 14:411-21
Ndhlovu, Lishomwa C; Lopez-Verg├Ęs, Sandra; Barbour, Jason D et al. (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119:3734-43
Crawford, Timothy Q; Ndhlovu, Lishomwa C; Tan, Alice et al. (2011) HIV-1 infection abrogates CD8+ T cell mitogen-activated protein kinase signaling responses. J Virol 85:12343-50
Gourraud, P A; Karaouni, A; Woo, J M et al. (2011) APOBEC3H haplotypes and HIV-1 pro-viral vif DNA sequence diversity in early untreated human immunodeficiency virus-1 infection. Hum Immunol 72:207-12
Favre, David; Mold, Jeff; Hunt, Peter W et al. (2010) Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2:32ra36
Ndhlovu, Lishomwa C; Leal, Fabio E; Eccles-James, Ijeoma G et al. (2010) A novel human CD4+ T-cell inducer subset with potent immunostimulatory properties. Eur J Immunol 40:134-41
Long, Brian R; Erickson, Ann E; Chapman, Joan M et al. (2010) Increased number and function of natural killer cells in human immunodeficiency virus 1-positive subjects co-infected with herpes simplex virus 2. Immunology 129:186-96
Ndhlovu, Lishomwa C; Sinclair, Elizabeth; Epling, Lorrie et al. (2010) IL-2 immunotherapy to recently HIV-1 infected adults maintains the numbers of IL-17 expressing CD4+ T (T(H)17) cells in the periphery. J Clin Immunol 30:681-92
Barbour, Jason D; Ndhlovu, Lishomwa C; Xuan Tan, Qi et al. (2009) High CD8+ T cell activation marks a less differentiated HIV-1 specific CD8+ T cell response that is not altered by suppression of viral replication. PLoS One 4:e4408
Favre, David; Lederer, Sharon; Kanwar, Bittoo et al. (2009) Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 5:e1000295

Showing the most recent 10 out of 17 publications