Mentored Scientist Award

Food insecurity, which refers to having limited or uncertain availability of nutritionally adequate and safe food, and violence are prevalent among women in the United States, and disproportionately affect HIV-positive women. Both food insecurity and violence are associated with negative health behaviors and outcomes including HIV risk behaviors, chronic diseases, poor mental health, and reduced engagement in HIV care and treatment. Evidence suggests that food insecurity is associated with increased risk for intimate partner violence (IPV).

HIV-infected individuals on antiretroviral therapy have higher than expected rates of cardiovascular disease (CVD) than uninfected individuals, and HIV-induced chronic inflammation is believed to be directly and causally associated with the accelerated atherosclerosis development. Prior studies have revealed that chronic inflammatory states, such as atherosclerosis, show significantly increased levels of circulating endothelium-derived extracellular vesicles (EVs), which are preferentially taken up by monocytes and lead to monocyte activation.

Dr. Joshua Vásquez, MD, Assistant Professor in the Division of Experimental Medicine and the Division of Pulmonary and Critical Care Medicine at UCSF who is establishing himself as a clinician-scientist in HIV immunology. This award will provide him with preliminary data and support to apply for future funding for projects aimed at: (1) characterizing the pulmonary reservoir of HIV and (2) to determining whether defects in alveolar macrophages are associated with HIV-related chronic obstructive pulmonary disease and persist, despite antiretroviral therapy.

Populations in sub-Saharan Africa are the most mobile in the world: up to 80% of households have at least one migrant member. Mobility is a risk factor for HIV transmission, but its impact on medication adherence for persons living with HIV (PLHIV) remains poorly understood. We will leverage the ongoing study Understanding Mobility and Risk in SEARCH Communities (RO1MH104132), which has followed over 1100 PLHIV from 12 East African communities since 2016, to study this association.

The poor cytotoxicity of CD8+ T cells against cells harboring reactivated HIV which have a low expression of viral antigens presents a profound barrier to the success of HIV cure strategies. Discovering new pathways that safely enhance the function of cytotoxic T-lymphocytes (CTLs) has immense potential for harnessing CTLs for the ‘shock and kill’ approach. While in a quiescent state, HIV-infected resting CD4+ T cells do not express sufficient HIV antigens and, thus, are not targeted by CTLs.

Considerable progress in the recognition, diagnosis, and treatment of HIV has led to a significant increase in the life expectancy of this population. With this change, however, HIV+ individuals are at higher risk of developing certain co-morbidities including cardiovascular disease (CVD). HIV infection has emerged as an independent risk factor for left ventricular diastolic dysfunction (DD), predisposing these individuals to chronic illnesses including atrial fibrillation, pulmonary hypertension, and heart failure with preserved ejection fraction (HFpEF).

In many countries with high HIV prevalence, there exists extensive stigma and discrimination against sexual minorities. In South Africa, national HIV prevention programs have largely failed to tailor HIV testing services to these marginalized, key populations, including Men who have Sex with Men (MSM). As a result, MSM have some of the highest HIV prevalence estimates in the country (33.9%) and are not testing at rates commensurate with their risk.

Pneumonia is the leading cause of death amongst HIV positive persons in Uganda and other resource limited countries. Antimicrobial resistance is rising at an alarming rate throughout the world and complicating the treatment of both pneumonia and tuberculosis. Understanding region-specific microbial causes of pneumonia and their drug resistance attributes is critical for developing successful empiric therapeutic algorithms.

The recent recognition that a host innate antiviral immune response mediates up to 95% of CD4 T-cell (CD4) death during HIV infection has markedly changed our understanding of HIV pathogenesis. Abortively infected resting CD4 are swept up into a fiery, highly inflammatory programmed cell death termed pyroptosis. In sharp contrast to resting lymphoid tissue CD4, circulating blood CD4 are highly resistant to pyroptosis.

Rhesus CMV-vectored SIV (RhCMV/SIV) vaccines have been shown to provide protection against infection in ~50% of adult macaques. Circulating CTL frequency in individual animals was shown to be correlated with protection in only some groups and at selected pre-infection time points, suggesting the possibility that gut-resident CTL are more important. We will test if gut-resident, Mamu-E-restricted, SIV-specific T cell responses elicited by the RhCMV/SIV vaccine will alter the composition of the earliest expanding virus population, due to restriction of viral replication in T cells.