This proposal describes a 5 year career development and research plan to train the Candidate as an independent epidemiologic researcher with a focus on HIV neuropathogenesis and neurocognitive outcomes in HIV-infected children. The Candidate will answer key questions addressing the benefit of antiretroviral therapy (ART) on preservation and salvage of neurocognitive development, and the role of systemic monocyte activation as a potential mechanism of HIV-induced neurocognitive impairment. The training plan builds on the Candidate's research expertise in HIV pathogenesis, pediatric HIV and epidemiology, and will improve her understanding of HIV neuropathogenesis and its relation to cognitive development in children. The proposal provides a foundation with which the Candidate will develop an independent research program in pediatric HIV, with an emphasis on neuropathogenesis and neuroepidemiology. The mentoring plan integrates a highly productive collaboration between pediatric HIV researchers from the Kenya Research Program with institutional excellence in neurology and neuropsychology at the University of Washington. Additional expertise in neurocognitive assessments in Africa from the University of Minnesota will complement this mentoring plan. Research Plan - HIV compromises neurocognitive development in children and some neurocognitive deficits may persist despite ART. In particular, sustained immune activation, in spite of successful virological and immune response to treatment, may limit the benefit of ART. We will utilize existing and novel pediatric HIV cohorts to undertake new neurocognitive studies.
In Aim 1, we will determine the extent to which early ART started in infancy preserves long-term neurocognition and will identify prevalence, types and cofactors of neurocognitive deficits.
In Aim 2, we will determine prevalence and correlates of neurocognitive deficits in children diagnosed later in childhood who initiate ART and are followed thereafter.
In Aim 3, we will determine the relative influence of viral, immunologic and immune activation on neurocognitive outcomes in each group of HIV-infected and treated children. We hypothesize that early- and late-ART can salvage neurocognitive outcomes and that longer duration of systemic monocyte activation will correlate with severity of neurocognitive deficits. We anticipate that data from these studies will inform interventions to optimize neurocognitive outcomes in children with HIV. This training opportunity will result in the Candidate developing an independent translational research program focused on mechanisms and prevention of neurocognitive impairment in HIV-infected children.

Public Health Relevance

Sarah Benki-Nugent, MS, PhD is a Senior Fellow in the Division of Allergy and Infectious Diseases, Department of Medicine at the University of Washington. The proposed career development plan and research will provide the Candidate with mentored learning in HIV neuropathogenesis and neuropsychology while conducting research to determine the extent to which antiretroviral therapy can salvage neurocognitive abilities and to identify modifiable cofactors for residual neurocognitive deficits in African HIV-infected children. Findings from this research will form the basis of the Candidate's independent career focused on improvement of neurocognitive outcomes in HIV-infected African children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01NS080637-02
Application #
8514745
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Wong, May
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$169,822
Indirect Cost
$11,702
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Wamalwa, Dalton; Benki-Nugent, Sarah; Langat, Agnes et al. (2016) Treatment interruption after 2-year antiretroviral treatment initiated during acute/early HIV in infancy. AIDS 30:2303-13
Wagner, Anjuli; Slyker, Jennifer; Langat, Agnes et al. (2015) High mortality in HIV-infected children diagnosed in hospital underscores need for faster diagnostic turnaround time in prevention of mother-to-child transmission of HIV (PMTCT) programs. BMC Pediatr 15:10
Chohan, Bhavna H; Tapia, Kenneth; Benki-Nugent, Sarah et al. (2015) Nevirapine Resistance in Previously Nevirapine-Unexposed HIV-1-Infected Kenyan Infants Initiating Early Antiretroviral Therapy. AIDS Res Hum Retroviruses 31:783-91
Benki-Nugent, Sarah; Eshelman, Christal; Wamalwa, Dalton et al. (2015) Correlates of age at attainment of developmental milestones in HIV-infected infants receiving early antiretroviral therapy. Pediatr Infect Dis J 34:55-61
Slyker, Jennifer A; Casper, Corey; Tapia, Kenneth et al. (2014) Accelerated suppression of primary Epstein-Barr virus infection in HIV-infected infants initiating lopinavir/ritonavir-based versus nevirapine-based combination antiretroviral therapy. Clin Infect Dis 58:1333-7
Wamalwa, Dalton C; Lehman, Dara A; Benki-Nugent, Sarah et al. (2013) Long-term virologic response and genotypic resistance mutations in HIV-1 infected Kenyan children on combination antiretroviral therapy. J Acquir Immune Defic Syndr 62:267-74
Langat, Agnes; Benki-Nugent, Sarah; Wamalwa, Dalton et al. (2013) Lipid changes in Kenyan HIV-1-infected infants initiating highly active antiretroviral therapy by 1 year of age. Pediatr Infect Dis J 32:e298-304
Lehman, Dara A; Wamalwa, Dalton C; McCoy, Connor O et al. (2012) Low-frequency nevirapine resistance at multiple sites may predict treatment failure in infants on nevirapine-based treatment. J Acquir Immune Defic Syndr 60:225-33
McGrath, Christine J; Njoroge, Julia; John-Stewart, Grace C et al. (2012) Increased incidence of symptomatic peripheral neuropathy among adults receiving stavudine- versus zidovudine-based antiretroviral regimens in Kenya. J Neurovirol 18:200-4
Wamalwa, Dalton; Benki-Nugent, Sarah; Langat, Agnes et al. (2012) Survival benefit of early infant antiretroviral therapy is compromised when diagnosis is delayed. Pediatr Infect Dis J 31:729-31