Several fundamental virologic issues represent important hurdles for the development of effective prevention and treatment strategies for pediatric HIV infection. Questions include: (1) Are certain viral phenotypes or genotypes more likely to be transmitted from an infected mother to her infant? (2) Does viral load during pregnancy correlate with maternal-fetal transmission? (3) What are the optimal methods to quantitate virologic load in infants and children to monitor disease progression and antiretroviral therapy? (4) What is the role of antiretroviral resistance in drug failure and disease progression? The research proposed will develop dependable, standardized and biologically meaningful assays of virus replication to assess disease risk and effective interventions.
The Specific Aims of the research are: (1) To identify and validate phenotypic and genotypic markers correlating with disease progression and antiviral resistance. For these studies maternal-infant transmission will be correlated with phenotypic properties including syncytia induction, growth rate and cell tropism. The genotypes associated with these phenotypic variations will also be correlated with HIV transmission. (2) To quantitate HIV virus load by optimization of assays of infectivity and viral DNA and RNA. These methods will be applied for quantitation of specific components of the peripheral blood including plasma, CD4+ lymphocytes, monocyte/macrophages and dendritic cells, and correlated with the development of viral resistance. (3) Develop improved methodologies to screen for antiretroviral resistance by phenotypic and genotypic assays, and apply these assays to children receiving treatment as part of ACTG protocols. The research proposed will identify virologic markers for monitoring HIV infection of pregnant women and children, and will provide new approaches to treatment and prevention of HIV infection.

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University of California San Diego
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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
Saitoh, Akihiko; Foca, Marc; Viani, Rolando M et al. (2008) Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics 121:e513-21
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
Hitti, Jane; Andersen, Janet; McComsey, Grace et al. (2007) Protease inhibitor-based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol 196:331.e1-7
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
Singh, K K; Spector, S A (2007) Fidelity of whole-genome amplification of blood spot DNA for HLA typing and SNP analyses. Clin Genet 72:156-9
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
Seage 3rd, George R; Buchacz, Kate; Weinberg, Geoffrey A et al. (2006) The Pediatric AIDS Severity Score (PASS): a multidimensional AIDS-severity adjustment for pediatric HIV infection. J Acquir Immune Defic Syndr 43:603-10
Patel, Kunjal; Weinberg, Geoffrey A; Buchacz, Kate et al. (2006) Simple Pediatric AIDS Severity Score (PASS): a pediatric severity score for resource-limited settings. J Acquir Immune Defic Syndr 43:611-7
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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