This is an application for a K23 award for Dr. Theodore Ruel, an assistant professor in pediatric infectious diseases at the University of California, San Francisco, who is establishing himself as an independent investigator in patient-based translational research of pediatric HIV in Africa. This K23 award will provide Dr. Ruel with the support necessary to accomplish the following goals: (1) to gain skills in the biostatistical analyses of longitudinal data;(2) to receive training in the design and operation of international clinical research;(3) to develop collaborations with leading HIV laboratory scientists (3) to perform research investigating factors in disease progression in HIV-infected African children;and (4) to generate data that will form the basis of an R01 application. Dr. Ruel has assembled a mentoring team to be lead by Dr. Diane Havlir, an accomplished international researcher of the pathogenesis and treatment of HIV, and to include four co-mentors: Dr. Edwin Charlebois, a biostatistician and HIV epidemiologist;Dr. Moses Kamya, a clinical researcher of HIV in Africa;Dr. Joseph K. Wong, an HIV molecular virologist;and Dr. Diane Wara, a pediatric HIV immunologist. Africa bears the greatest burden of the HIV epidemic in children worldwide and there is a great need for more information about endemic strains of HIV to guide management strategies. Mounting data from adults suggest that HIV subtype D strains have increased CXCR4 tropism and lead to more rapid disease progression compared to Subtype A, but there has been limited study in children, who have distinct developing immune physiology. Leveraging the resources of a longitudinal cohort of 300 HIV-infected Ugandan children, Dr. Ruel will test the central hypothesis that HIV Subtype D and D-envelope containing recombinant strains of HIV cause accelerated disease progression compared to HIV Subtype A strains in African children, and investigate several theories about the mechanism and predicted consequences. Specifically, he will compare, by HIV subtype, the rates of disease progression (Aim 1), the prevalence and evolution of CXCR4 tropism (Aim 2), and the levels of proviral HIV DNA in naove and memory lymphocytes (Aim 3). He will also begin to investigate the impact of these factors on CD4 recovery following the initiation of therapy (Aim 4). At the completion of this award, Dr. Ruel will be well positioned to develop an R01 application based on novel data about the pathogenesis of non-subtype B strains of HIV in HIV-infected African children.
Africa is host to an estimated 2 million HIV-infected children, yet there is limited knowledge about the non- subtype B strains of HIV that infect them. The data generated from the proposed research will provide new insight into several factors of disease progression in this population. This information has the potential to inform the development of optimal treatment guidelines that can target those at the greatest need for early therapy, while sparing those who can wait the risks of drug toxicity and the development of resistant virus.
|Koss, Catherine A; Natureeba, Paul; Nyafwono, Dorcas et al. (2016) Brief Report: Food Insufficiency Is Associated With Lack of Sustained Viral Suppression Among HIV-Infected Pregnant and Breastfeeding Ugandan Women. J Acquir Immune Defic Syndr 71:310-5|
|Achan, Jane; Kakuru, Abel; Ikilezi, Gloria et al. (2016) Growth Recovery Among HIV-infected Children Randomized to Lopinavir/Ritonavir or NNRTI-based Antiretroviral Therapy. Pediatr Infect Dis J 35:1329-1332|
|Bartelink, Imke H; Savic, Rada M; Dorsey, Grant et al. (2015) The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J 34:e63-70|
|Koss, Catherine A; Natureeba, Paul; Mwesigwa, Julia et al. (2015) Hair concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and breastfeeding Ugandan women. AIDS 29:825-30|
|Sears, David; Mpimbaza, Arthur; Kigozi, Ruth et al. (2015) Quality of inpatient pediatric case management for four leading causes of child mortality at six government-run Ugandan hospitals. PLoS One 10:e0127192|
|Cohan, Deborah; Natureeba, Paul; Koss, Catherine A et al. (2015) Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women. AIDS 29:183-91|
|Kakuru, Abel; Achan, Jane; Muhindo, Mary K et al. (2014) Artemisinin-based combination therapies are efficacious and safe for treatment of uncomplicated malaria in HIV-infected Ugandan children. Clin Infect Dis 59:446-53|
|Ruel, Theodore D; Kakuru, Abel; Ikilezi, Gloria et al. (2014) Virologic and immunologic outcomes of HIV-infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase inhibitor therapy. J Acquir Immune Defic Syndr 65:535-41|
|Jenster, Meike; Bonifacio, Sonia L; Ruel, Theodore et al. (2014) Maternal or neonatal infection: association with neonatal encephalopathy outcomes. Pediatr Res 76:93-9|
|Koss, Catherine A; Natureeba, Paul; Plenty, Albert et al. (2014) Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy. J Acquir Immune Defic Syndr 67:128-35|
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