Mentored Scientist Award

Inducible T-cell kinase (ITK) belongs to the Tec family of tyrosine kinases, and is expressed in mast cells and T lymphocytes. ITK functions downstream of the T-cell receptor (TCR) and regulates T-cell development, activation and differentiation. The role of ITK signaling in HIV persistence is yet unknown. In this proposal we aim to determine the impact of ITK on?HIV latency reversal and infected cell proliferation in primary CD4+?T cells and cell lines. In addition, we propose to investigate mechanisms regulating establishment of latency by regulating activation status of CD4+T cells.

There is a high prevalence of unhealthy alcohol use (UAU) in sub-Saharan Africa, especially among persons living with HIV (PWH). Persons with UAU are at greater risk of HIV acquisition, while PWH with UAU are more likely to not know their HIV status, not be engaged in care, and experience poor outcomes. UAU also portends to a substantially higher risk of tuberculosis (TB) disease, regardless of HIV status.

 Young men who have sex with men (YMSM) are disproportionally affected by HIV in the United States, accounting for nearly half of new HIV diagnoses among MSM. Pre-exposure prophylaxis (PrEP) has demonstrated high levels of efficacy for HIV prevention; however, uptake has been suboptimal with uptake barriers including cost; stigma; not wanting to take a daily pill; and difficulty locating providers. New PrEP options are now available for YMSM and have the potential to address many of barriers to PrEP uptake, especially non-daily options which are preferred by many YMSM.

Tuberculosis (TB) remains a major cause of morbidity and mortality for people living with HIV (PWH) worldwide, particularly in low-income settings. HIV and TB are both associated with increased rates of obstructive lung disease (OLD), with post-TB lung disease being an increasingly recognized entity associated with both pulmonary dysfunction and persistent respiratory symptoms. Sex-based differences have been found in TB prevalence, with men demonstrating higher rates of TB in multinational studies. However, whether there are sex-based differences in post-TB OLD among PWH is unknown.

Most HIV-infected patients who stop taking antiretroviral drugs experience rapid viral rebound and suffer in the longer term from the presence of more virus in blood and lower CD4+ T cell counts. HIV-1 infection generally increases T-cell metabolism, which means that cells are more active, which promotes successful viral integration and replication. Our preliminary data show that although therapeutic T cell vaccination can effectively generate cytotoxic T cells that kill HIV-infected cells, in most cases this antiviral activity is insufficient to limit viral replication.

Reduction of persistent HIV-infected cells in reservoir tissues is essential towards HIV cure. It is difficult to measure tissue penetration of therapeutics (antiretrovirals, ARVs, and curative agents) in many of these sites (e.g. brain, cardiac, lung tissue) due to the inability to sample these tissues in living people. Leveraging postmortem tissue banked at UCSF from deceased people with HIV (PWH), we will determine ARV penetration in these tissue reservoir sites, and determine if there is a link between ARV exposure to size the viral reservoir in each tissue.

Combination antiretroviral therapy (cART) for the treatment of HIV infection has been a tremendous medical success, which continues to make strides.1 cART has dramatically reduced morbidity and mortality associated with HIV infection, allowing those that are infected to live for years without progressing to AIDS. cART does not clear the infection, however, and infected people must remain on treatment indefinitely. There have been several instances of HIV cure or remission.

Although significant strides have been made in controlling viral pathogenicity via. Anti-Retroviral Therapy (ART), a major barrier to curing HIV-1 infection is the transcriptionally silent, latent proviral reservoir that resides within HIV infected individuals. These stable yet extremely rare (~1 in 1 million cells) viral reservoirs are primarily thought to be harbored in quiescent, homeo-statically proliferating, resting memory CD4+ T-cells.

Progress towards ending the HIV epidemic among Black American women, particularly among those living in the American south, is severely delayed. Data from international studies suggest that mobile and migrant women may be an especially vulnerable and underserved group within an already marginalized population. Yet, to date, the HIV implications of migration and mobility among Black American women have yet to be explored, despite evidence of an historic internal migration of Black Americans to southern urban centers.

Primary health care clinics in South Africa were confronting substantial population burdens of HIV and non-communicable disease (NCD) with limited resources even prior to the Covid-19 pandemic. Care outcomes and implementation of new programs vary between clinics in the same settings; qualitative research suggests that clinic factors such as leadership may play a key role in optimizing primary care.