Despite significant progress in the interruption of HIV-1 transmission from an infected mother to her infant in developed countries, it is estimated that daily 1,600 infants are infected perinatally worldwide. Thus, understanding the risk factors associated with other-to-infant transmission remains critically important for the development of improved strategies for the prevention of vertical transmission. Moreover, although therapy has improved significantly for HIV-1 infected children, many challenges remain for the optimization of treatment. In the initial 4 years of funding, my laboratory has made several important observations that have helped to elucidate the pathogenesis of HIV-1 vertical transmission and disease progression in children. Our findings strongly suggest that certain HIV-1 phenotypes and genotypes combined with host chemokine receptor and chemokine genotypes are critical for determining the risk for infection and subsequent disease progression. In this revised, competitive renewal application, we propose to build on these initial findings by focusing on the impact of host genotype on perinatal transmission and disease progression.
The specific aims of this proposal are: 1. To determine the association of chemokine receptor and chemokine genotypes on HIV-1 perinatal and postpartum (breast milk) transmission in two cohorts of children from Sub-Saharan Africa; 2. To identify chemokine receptor and chemokine genotypes that impact on HIV-1 related disease progression in children; and 3. To identify host chemokine receptor and chemokine genotypes that impact on development of HIV-1 related neurocognitive impairment in children. The findings of this research will provide an improved understanding of the pathogenesis of HIV-1 infection of children and perinatal transmission, and help to develop improved treatment/prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039004-10
Application #
6855120
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Sharma, Usha K
Project Start
1995-09-30
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
10
Fiscal Year
2005
Total Cost
$304,000
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Rawat, Pratima; Spector, Stephen A (2017) Development and characterization of a human microglia cell model of HIV-1 infection. J Neurovirol 23:33-46
Spector, Stephen A; Rappaport, Jay (2017) HIV cure strategists: ignore the central nervous system at your patients' peril. AIDS 31:167-168
Saitoh, Akihiko; Capparelli, Edmund; Aweeka, Francesca et al. (2010) CYP2C19 genetic variants affect nelfinavir pharmacokinetics and virologic response in HIV-1-infected children receiving highly active antiretroviral therapy. J Acquir Immune Defic Syndr 54:285-9
Spector, Stephen A; Zhou, Dejiang (2008) Autophagy: an overlooked mechanism of HIV-1 pathogenesis and neuroAIDS? Autophagy 4:704-6
Zhou, Dejiang; Spector, Stephen A (2008) Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS 22:695-9
Singh, Kumud K; Hughes, Michael D; Chen, Jie et al. (2008) Associations of chemokine receptor polymorphisms With HIV-1 mother-to-child transmission in sub-Saharan Africa: possible modulation of genetic effects by antiretrovirals. J Acquir Immune Defic Syndr 49:259-65
Saitoh, Akihiko; Haas, Richard H; Naviaux, Robert K et al. (2008) Impact of nucleoside reverse transcriptase inhibitors on mitochondrial DNA and RNA in human skeletal muscle cells. Antimicrob Agents Chemother 52:2825-30
Saitoh, Akihiko; Sarles, Elizabeth; Capparelli, Edmund et al. (2007) CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children. AIDS 21:2191-9
Saitoh, Akihiko; Fletcher, Courtney V; Brundage, Richard et al. (2007) Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic Syndr 45:280-5
Saitoh, Akihiko; Singh, Kumud K; Sandall, Sharsti et al. (2006) Association of CD4+ T-lymphocyte counts and new thymic emigrants in HIV-infected children during successful highly active antiretroviral therapy. J Allergy Clin Immunol 117:909-15

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