(provided by candidate): This proposal outlines a 5-year training program for the candidate to become an independent laboratory-based clinical investigator with research focus on intracellular metabolism of nucleoside analogs in relation to resistance and clinical toxicity. The candidate has completed residency training in Pediatrics and fellowship training in Infectious Diseases. The candidate's goal is to develop a command of virology and pharmacology by the integration of research studies on the cellular pharmacology of HIV reverse transcriptase inhibitors in relation to toxicity in different individuals with the aim of optimizing HIV therapeutic regimens both at the individual and population levels, and a structured curriculum to enhance scientific knowledge in these fields. Dr. Y.C Cheng a renowned cancer and viral pharmacologist will mentor the candidate's scientific development together with co-mentors and an advisory committee of accomplished clinical and scientific investigators with diverse and multidisciplinary backgrounds. The candidate's research objectives are to;i) determine host factors that affect the intracellular NRTI-triphosphate concentration, and ii) determine the contribution of the intracellular NRTI-triphosphate concentration to the development of observed clinical toxicities.
Specific aim 1 is to determine the effect of host factors on the metabolism of nucleoside analogs in human PBMCs.
In specific aim 2 the individual differences in phosphorylation of these nucleosides will be studied using state-of-the-art ELISA technique. The sensitivity of the ELISA will be assessed using HPLC as gold standard.
Specific aim 3 is to determine the association among intracellular triphosphate concentration, mitochondria! DNA concentration, and development of clinical or laboratory toxicity in HIV-infected individuals on NRTI-based regimens. The anticipated results from above studies will impact on optimization of HIV therapeutics and inform on the mechanisms of clinical toxicities associated with nucleoside analog usage. The novelty of the ELISA is to overcome, with respect to current HPLC methods, lack of sensitivity and the labor intensive nature. This will provide a quick and rapid technique for PK-PD studies to make it possible to screen large populations, and secondly, has a potential for therapeutic drug monitoring of HIV-1 patients and optimization of individual therapy especially in persons who are heavily treatment-experience with clinical toxicities.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Zhang, Hao
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Yale University
Schools of Medicine
New Haven
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Langs-Barlow, Allison; Selvaraj, Shanmugapriya; Ogbuagu, Onyema et al. (2015) Association of circulating cytochrome c with clinical manifestations of antiretroviral-induced toxicity. Mitochondrion 20:71-4
Selvaraj, S; Ghebremichael, M; Li, M et al. (2014) Antiretroviral therapy-induced mitochondrial toxicity: potential mechanisms beyond polymerase-? inhibition. Clin Pharmacol Ther 96:110-20
Barry, Oliver; Powell, Jonathan; Renner, Lorna et al. (2013) Effectiveness of first-line antiretroviral therapy and correlates of longitudinal changes in CD4 and viral load among HIV-infected children in Ghana. BMC Infect Dis 13:476
Paintsil, Elijah (2013) Update on recent guidelines for the management of urinary tract infections in children: the shifting paradigm. Curr Opin Pediatr 25:88-94
Haraguchi, Kazuhiro; Takeda, Shingo; Kubota, Yutaka et al. (2013) From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir. Curr Pharm Des 19:1880-97
Selvaraj, Shanmugapriya; Paintsil, Elijah (2013) Virologic and host risk factors for mother-to-child transmission of HIV. Curr HIV Res 11:93-101
Ghebremichael, Musie; Paintsil, Elijah (2011) High risk behaviors and sexually transmitted infections among men in Tanzania. AIDS Behav 15:1026-32
Paintsil, Elijah (2011) Resistance, resistance, go away: persistence of nevirapine-resistant HIV mutations in HIV-infected infants. AIDS 25:997-9
Kallem, Stacey; Renner, Lorna; Ghebremichael, Musie et al. (2011) Prevalence and pattern of disclosure of HIV status in HIV-infected children in Ghana. AIDS Behav 15:1121-7
Paintsil, Elijah; Dutschman, Ginger E; Hu, Rong et al. (2011) Determinants of individual variation in intracellular accumulation of anti-HIV nucleoside analog metabolites. Antimicrob Agents Chemother 55:895-903

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