Mentored Scientist Award

Untreated HIV infection is distinguished by two major clinical hallmarks: progressive depletion of CD4 T cells, and chronic inflammation. We now know that resting “bystander” CD4 T cells in lymphoid tissue undergo a process of abortive HIV infection where incomplete reverse transcripts are formed and detected by the host DNA sensor, interferon gamma-inducible protein 16 (IFI16). This activation of IFI16 causes the assembly of an inflammasome, which cleaves caspase-1 and causes pyroptosis in the CD4 T cell.

Pre-exposure prophylaxis (PrEP) with once-daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)
prevents acquisition of HIV infection [1-4]. Although well tolerated, [5, 6] cases of nephrotoxicity have occurred
during TDF use, especially in HIV-infected individuals. [7-23] Such cases have resolved in most [7, 22, 24-26] but
not all [15, 19, 23, 27] persons after drug discontinuation, and may involve proximal tubular dysfunction [7-13, 16,
17, 19-22, 24, 26, 28], Fanconi syndrome, [16, 24, 25], or glomerular dysfunction.[7, 10, 11, 14, 15, 21-23, 26, 27].

Gastrointestinal (GI) tract tissues harbor a large pool of cells latently infected with HIV. However, their exact identity and the mechanisms of latency are unknown. Transforming growth factor (TGF)-β has several functions in gut homeostasis, including the formation and maintenance of tissue-resident memory (TRM) CD8 T cells. Signaling by TGF-β induces expression of CD103, an αE integrin that binds to epithelial E-cadherin. CD4 TRMs also exist, but only a small proportion express CD103, and the role of TGF-β in their formation, function, and maintenance is unknown.

In the United States, Latinos are disproportionately impacted by HIV and have high rates of substance use and depression. Untreated substance use and depression often co-occur and are driving poor engagement in HIV care and impeding efforts to eliminate health disparities and the reduction of new infections. This Mentored Scientist Award will support the conduct of original research in the area of substance use and depression fromthe CFAR Network of Integrated Clinical Systems (CNICS) cohort of HIV+ Latinos.

In the initial days to weeks after infection with HIV, viral RNA enters the central nervous system (CNS) and is thought to form reservoirs in brain tissue that, in the long term, contribute to HIV-associated neurocognitive disorder (HAND) in up to 50% of patients. As patients are usually diagnosed with HIV well after CNS reservoirs have formed, patients with acute HIV (e.g.

Tuberculosis (TB) is the leading cause of death among adults living with HIV in sub-Saharan Africa. Recent randomized clinical trial data has shown that earlier ART initiation (within two weeks for CD4 <50/µl and within two months for CD4 >50/µl) reduces mortality by 40 to 50%. There is a large gap, however, in the translation of this evidence into real world practice.

Malaria remains one of the most formidable infectious diseases worldwide, particularly in sub-Saharan Africa, where it overlaps with the HIV epidemic. For many people in highly endemic areas, malaria parasitemia is asymptomatic, however, parasitemia provides a reservoir of parasites that drives malaria transmission.

Antiretroviral (ARV) therapy has greatly reduced HIV-related mortality, but treated patients still display excess mortality compared to HIV-negative individuals. This mortality is mostly driven by "non-AIDS defining conditions" such as cardiovascular and hepatic disease as well as non-AIDS related malignancies.

Malaria during pregnancy commonly leads to placental malaria, with adherence of parasite-infected erythrocytes in the placenta, and high risk of adverse maternal and fetal outcomes. Risk factors for placental malaria are not well understood. Moreover, there is an urgent need to identify optimal methods of diagnosing placental malaria.