The candidate has a strong background in epidemiology, and he has developed a research niche at Vanderbilt University studying the effect of nutrition on HIV treatment outcomes. He has published several original research studies in his field and enrolled in the Vanderbilt Masters of Science in Clinical Investigation program (2010-2012) to gain additional training in biostatistics and clinical trials. He is applyin for a K23 career development award to achieve his short-term goal of acquiring expertise in immunology and laboratory research skills. This will allow him to establish a strong foundation in translational research and therefore attain his long term goal of becoming an independent investigator studying the biological mechanisms that link HIV immunology, adipose tissue biology, and antiretroviral therapy (ART) complications. The introduction of effective combination ART for the treatment of HIV infection greatly reduced mortality from AIDS-related conditions, but this success has been tempered by higher rates of several cardiovascular and metabolic diseases more commonly associated with obesity or a sedentary lifestyle. Current evidence suggests both treated HIV infection and excess adipose tissue promote similar changes in immune activation that are implicated in the development of a range of chronic diseases, but at present there are few data on whether the effects of treated HIV and excess adiposity are synergistic or additive. The candidate will use a multifaceted approach to investigate the effects of excess adipose tissue and treated HIV on markers of innate immune activation that are well-established metabolic and cardiovascular disease risk factors, as well as markers of cellular immune activation implicated in reduced immune recovery, in a prospective cohort of HIV-infected adults on long-term ART representing a spectrum of adiposity from lean to obese and a control group of uninfected individuals. In addition to this clinical study, the candidate will conduct a series of translational experiments to investigate the mechanistic role of adipokines and other aspects of adipocyte biology in altering T cell function and promoting cellular immune activation. The goal of the this project is to identify target pathways directly relevant to the design of future, R01-supported intervention trials to improve HIV treatment outcomes by minimizing non-AIDS related co-morbidities as well as maximizing immune reconstitution. The outstanding environment at Vanderbilt University Medical Center is conducive to the candidate's development as a successful, independent translational investigator. He has access to a multidisciplinary group of mentors and the opportunity to collaborate with world leaders in the fields of infectious diseases, obesity, immunology, and cardiovascular disease research. He is supported by co-mentors with a proven record of guiding mentees to successful, productive research careers in academic medicine. Dr. Timothy Sterling is an internationally recognized HIV expert and the recipient of K24 funding from NIAID to mentor young investigators in translational research. Dr. Spyros Kalams is an accomplished immunologist and the Director of the Vanderbilt HIV Immunopathogenesis Core lab (where the candidate will receive hands-on, closely monitored training in laboratory research methods). Dr. David Harrison is a leading researcher in the field of vascular biology and hypertension, including the effects of activated T cells on vasoconstriction and sodium retention. In addition to state-of-the-art laboratory facilities and technical resources, the candidate has access to unique resources made possible by the Vanderbilt Clinical and Translational Science Award (CTSA), including the Clinical Research Center, the Vanderbilt Institute for Clinical and Translational Research, and the Clinical and Translational Scientist Development educational program. The university has invested in the candidate by supporting his research through the two-year Vanderbilt Physician Scientist Development Program, a highly competitive intramural funding mechanism that serves as a "bridge" to extramural funding (i.e. the K23 award mechanism). The management of chronic HIV infection and the obesity epidemic are two major 21st Century challenges for public health. The candidate's Research Plan will make a significant and transformative contribution to the HIV research field by identifying mechanisms and pathways linking adipose tissue to the inflammatory and immune processes implicated in the pathogenesis of cardiovascular and metabolic diseases and poor immune reconstitution. This award will allow the candidate to develop new skills in translational research, generate research findings with direct relevance to human health and the design of future R01-funded studies, and enable his successful transition to an independent and productive investigator. PROJECT NARRATIVE: The proportion of persons with HIV infection in the United States who are also overweight is rising. Excess adipose tissue may hinder the recovery of immune function on HIV treatment and further increase the risk of metabolic and cardiovascular diseases associated with long-term antiretroviral therapy. An improved understanding of the biological mechanisms linking adipose tissue, the immune system, and the negative effects of antiretroviral therapy will help design future interventions to improve HIV treatment outcomes and reduce health care expenditures.
The proportion of persons with HIV infection in the United States who are also overweight is rising. Excess adipose tissue may hinder the recovery of immune function on HIV treatment and further increase the risk of metabolic and cardiovascular diseases associated with long-term antiretroviral therapy. An improved understanding of the biological mechanisms linking adipose tissue, the immune system, and the negative effects of antiretroviral therapy will help design future interventions to improve HIV treatment outcomes and reduce health care expenditures.
|Koethe, J R; Jenkins, C A; Turner, M et al. (2015) Body mass index and the risk of incident noncommunicable diseases after starting antiretroviral therapy. HIV Med 16:67-72|
|Noto, Michael J; Koethe, John R; Miller, Geraldine et al. (2014) Detectable serum tobramycin levels in patients with renal dysfunction and recent placement of antibiotic-impregnated cement knee or hip spacers. Clin Infect Dis 58:1783-4|
|Koethe, John R; Marseille, Elliot; Giganti, Mark J et al. (2014) Estimating the cost-effectiveness of nutrition supplementation for malnourished, HIV-infected adults starting antiretroviral therapy in a resource-constrained setting. Cost Eff Resour Alloc 12:10|
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|Koethe, John R; Blevins, Meridith; Nyirenda, Christopher K et al. (2013) Serum Phosphate Predicts Early Mortality among Underweight Adults Starting ART in Zambia: A Novel Context for Refeeding Syndrome? J Nutr Metab 2013:545439|
|Koethe, John R; Dee, Kevin; Bian, Aihua et al. (2013) Circulating interleukin-6, soluble CD14, and other inflammation biomarker levels differ between obese and nonobese HIV-infected adults on antiretroviral therapy. AIDS Res Hum Retroviruses 29:1019-25|
|McDonald, Bethan; Moyo, Sikhulile; Gabaitiri, Lesego et al. (2013) Persistently elevated serum interleukin-6 predicts mortality among adults receiving combination antiretroviral therapy in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses 29:993-9|