My career objectives over the next five years are (1) to recruit and mentor young investigators interested in translational HIV research, (2) to further define the mechanisms and consequences of persistent inflammation during long-term antiretroviral therapy, and (3) to conduct pilot clinical trials aimed at reducing inflammation and/or size of the HIV reservoir during long-term therapy. These goals will be pursued in the context of a multidisciplinary research program aimed at translating basic research findings into the clinic ("translational research") while also collecting biologic specimens from well characterized cohorts for focused laboratory based research (often referred to as "reverse translation"). Specifically, l will conduct a series of studies aimed at determining the complex relationship that exists between HIV persistence (during therapy), chronic inflammation and end-organ function. I will also oversee the conduct of a series of studies aimed at reducing inflammation and/or size of the reservoirs. This work will be funded by a series of grants, including a recently funded U19 whose overall objectives are to investigate the impact chronic inflammation has on HIV persistence during effective therapy. I am seeking to recompete an existing K24. Prior to receiving this K24 grant, I devoted approximately 50% of total effort to clinical care and administrative/teaching responsibilities. The K24 allowed me to focus on mentoring a series of research fellows and junior investigators, many of whom are now independent investigators. If successful, I will continue to devote approximately 25% of my effort to mentoring junior investigators in the conduct of cohort development, translational research and clinical research. Public health implications: Most HIV infected adults with access to antiretroviral therapy are able to achieve and maintain durable viral suppression with modern antiretroviral drug regimens. Despite effective suppression of HIV replication, many if not most patients exhibit persistent immune dysfunction, which in turn may cause end-organ disease. Also, it is now widely accepted that current therapies are not curative, meaning all HIV infected individuals in need of treatment will have to remain on therapy for many decades. This has significant costs and health implications for those infected with HIV. Efforts aimed at reducing chronic inflammation and/or curing HIV will therefore have long-term benefits for both the global epidemic.
A more thorough understanding of the role of persistent inflammation and immune dysfunction in causing HIV persistence and/or disease in antiretroviral-treated adults could lead to fundamental changes in the management of this disease. Insights into the impact of inflammation on end-organ disease may even have implications for the understanding and management of other chronic inflammatory conditions. Efforts aimed at curing HIV infection could also prove lead to the prevention of HIV transmission on a global level.
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|Scherzer, Rebecca; Gandhi, Monica; Estrella, Michelle M et al. (2014) A chronic kidney disease risk score to determine tenofovir safety in a prospective cohort of HIV-positive male veterans. AIDS 28:1289-95|
|Hunt, Peter W; Sinclair, Elizabeth; Rodriguez, Benigno et al. (2014) Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 210:1228-38|
|Lee, Sulggi A; Sinclair, Elizabeth; Jain, Vivek et al. (2014) Low proportions of CD28- CD8+ T cells expressing CD57 can be reversed by early ART initiation and predict mortality in treated HIV infection. J Infect Dis 210:374-82|
|Spivak, Adam M; Andrade, Adriana; Eisele, Evelyn et al. (2014) A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis 58:883-90|
|Siewe, Basile; Wallace, Jennillee; Rygielski, Sonya et al. (2014) Regulatory B cells inhibit cytotoxic T lymphocyte (CTL) activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs. PLoS One 9:e92934|
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|Borges, Álvaro H; Weitz, Jeffrey I; Collins, Gary et al. (2014) Markers of inflammation and activation of coagulation are associated with anaemia in antiretroviral-treated HIV disease. AIDS 28:1791-6|
|Serrano-Villar, Sergio; Sainz, Talia; Lee, Sulggi A et al. (2014) HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog 10:e1004078|
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