Mentored Scientist Award

In the United States, nearly a third of those diagnosed with HIV were diagnosed late, meaning that they were diagnosed with AIDS at the same time as or within one year of their HIV diagnosis. Late HIV diagnosis is associated with poor treatment outcomes and, in turn, less viral suppression, greater transmission of HIV to those who are not infected, and increased HIV-related morbidity and mortality. The United States’ goal of reducing HIV in part by increasing peoples’ awareness of their HIV status cannot be achieved without addressing late diagnosis.

Maternal and neonatal mortality and morbidity are persistently high in Uganda where there is also a generalized HIV epidemic. Ensuring early and appropriate antenatal care (ANC) allows for screening, treatment, and prevention of complications, while offering education and support to ensure healthy pregnancies and maternal and fetal outcomes. Few Ugandan women initiate antenatal care in the first trimester, as recommended. Timing of antenatal care initiation may vary by serostatus but there is little research on this.

Men in occupations that require high mobility, such as fishing, are particularly vulnerable to lapses in HIV prevention engagement. Kenya has been a leader in scaling up biomedical HIV prevention, including oral PrEP. However, in preliminary data from the Owete study, we found that uptake of HIV prevention, including daily oral PrEP, is low (3.8%) despite availability in government health facilities at no cost.

Immunocompromised individuals, including people living with HIV (PLWH), are more vulnerable to severe COVID-19 as compared to immunocompetent individuals. It remains unclear whether vaccines and previous infection stimulate equivalent immune defenses in PLWH, although HIV+ individuals have a higher rate of breakthrough infection than HIV- individuals post-vaccination. Recent studies have demonstrated that the quality and perhaps quantity of SARS-CoV-2 antibodies elicited by mRNA vaccines are diminished in ART-suppressed people living with HIV as compared to uninfected individuals.

Persons living with HIV (PLWH) are twice as likely to develop cardiovascular disease (CVD), and this excess risk persists despite viral suppression with antiretroviral therapy (ART). In the past 20 years, the global burden of CVD in PLWH has tripled, accounting for significant disease burden. Dyslipidemia is one mechanism by which HIV infection is associated with atherosclerotic CVD (ASCVD), partly due to side effects of ART.

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.