Kevin R. Robertson - US grants

This is an application with three specific aims. In the first specific aim the Principal Investigator will assess quantitative viral load in plasma and CSF over time, and derive estimates of cumulative viral load. These will be correlated with measures of CNS dysfunction. In the second specific aim, the Investigator will use an assay of neurotoxicity based on cultured cells and relate the cytotoxicity of CSF from HIV seropositive individuals to viral load. In the third specific aim, the relationship between cytotoxicity and neurological disease will be measured.

Nigeria has the second highest HIV burden and one of the highest rates of perinatal HIV transmission globally. HIV adversely affects the brain across the age spectrum (NeuroAIDS), causing a variety of derangements including neurocognitive, neurodevelopmental and neuropsychiatric disorders. These disorders worsen quality of life and drive poor adherence to antiretroviral treatment (ART), thereby increasing the risk of ART failure, morbidity, mortality, and HIV spread. Because relevant research has been neglected, there is no evidence- base to inform clinical practice locally and progress in the field has been limited. We have isolated the omissions in research infrastructure stunting emergence of a versatile NeuroAIDS research team and limiting NeuroAIDS research productivity despite over 20 years of dementia and related research at the University of Ibadan. We propose to capitalize on collaborations between diverse committed scientists and institutions, to address these omissions and develop sustainable NeuroAIDS research capacity at the University of Ibadan. Trainees in the proposed Multidisciplinary NeuroAIDS Research Training to Improve HIV Outcomes in Nigeria will acquire skills to address themes such as: i) impact of neurocognitive, neurodevelopmental and neuropsychiatric disorders on adherence, ART success, survival, and HIV spread across the age spectrum; ii) understanding the roles of aging, malnutrition and prevalent infections that may involve the central nervous system such as malaria and tuberculosis; and iii) discovering sustainable diagnostic, prevention and treatment strategies. Acquired skills will be relevant and broadly applicable to the NeuroAIDS field. Using structured mentoring, we will: 1) train and mentor neurologists/psychiatrists to have neuropsychological and neurodevelopmental expertise for NeuroAIDS research; 2) develop clinical research skills and provide didactic training to multidisciplinary investigators manifesting high potential to conduct NeuroAIDS research; 3) conduct short- and medium-term training practicums plus long-term mentoring to develop critical NeuroAIDS research skills in neuropharmacology, neuropsychological data analyses and grant writing; 4) conduct NeuroAIDS research symposia for researchers and intensive skills workshops for research support staff; and 5) establish a multidisciplinary NeuroAIDS research collaborative as an institutionally committed umbrella for sustainable multidisciplinary NeuroAIDS research. We will prepare a cadre of skilled, multidisciplinary researchers and outstanding research support staff, ensuring emergence of broad and integrative NeuroAIDS research expertise at the University of Ibadan. Trained scientists will contribute to discovery of sustainable solutions to NeuroAIDS, which will stimulate local health authorities to allocate more clinical and research resources to NeuroAIDS. A solid platform will emerge to support the next-level of grant applications such as the NIH Brain Disorders in Developing World: Research Across the Lifespan. Aggregated expertise will feed into University of Ibadan's long-term goal of developing a PhD Program in Neurosciences. !

Nigeria has a high burden of HIV-related brain disorders (NeuroAIDS), including mental health disorders and neurocognitive or neurological impairment. Over the last 4 years, the Multidisciplinary NeuroAIDS Research Training to Improve HIV Outcomes in Nigeria (D43TW009608-03) has developed three NeuroAIDS research cores with 10 investigators, two observational studies, and trained research support staff, including 3 psychometricians at the University of Ibadan (UI). Reviewing our progress with our Nigerian partners, we have identified residual gaps, which we propose to address by doubling the number of investigators and psychometricians through the Expanded Multidisciplinary NeuroAIDS Research Training to Improve HIV Outcomes in Nigeria. In the Mental Health Core, we will: 1) add implementation science by providing PhD training to a physician who excelled in the Northwestern University Master of Science in Clinical Investigation (MSCI) program, and 2) provide focused didactics and mentored research for 3 clinical psychologists/mental health nurses, thus expand UI's community of NeuroAIDS researchers to include these disciplines that are currently unrepresented but are key components of Nigeria's mental healthcare system. In the Translational and Clinical Sciences Core, we will provide intensive laboratory training for a pharmacology PhD candidate, postdoctoral training to a virologist, MSCI to a neurology/infectious diseases physician, and specialty clinical research training to a radiologist, all with integrated mentored research. In the Neuropsychological Infrastructure Core, we will provide postdoctoral neuropsychology fellowships for psychiatrists or neurologists to produce two experts who will train new psychometricians, as well as lead already-trained psychometricians and biostatisticians to create transformative capacity for neuropsychological assessment and analytics locally. Over half of each trainee's time will be in UI. The aggregated capacity of the cores will build into a research program equipped to lead in: 1) Mental Health Research- e.g., depression, stigma, disclosure, quality of life and, substance abuse; and 2) Translational and Clinical Research- e.g. understanding the biologic basis and optimal treatment of HAND; and unraveling the contribution of CNS compartmentalization, ART toxicity, drug resistance, cerebrovascular diseases, genomics, and co-infections to NeuroAIDS. The program will be distinguished by neuropsychological assessment expertise and locally standardized assessment instruments with appropriate norms to provide reliable and valid measurement of neurobehavioral consequences of HIV and its treatments in Nigeria. Training will be expanded further, knowledge disseminated, and ideas cross- fertilized through forums that we created in UI, including a monthly NeuroAIDS Collaboratory and a biannual NeuroAIDS Week with about 150 attendees/year. Manuscript writing and grantsmanship mentoring will prepare the trainees to become funded independent investigators. In 5 years, UI's multidisciplinary researchers will shoulder NeuroAIDS research in Nigeria with extramural funding, impacting the whole of Africa.