Mentored Scientist Award

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.

Sexual minority (i.e., non-heterosexual) populations experience higher rates of mental health disorders and health related problems. Unique stressors such as discriminatory experiences, expectations of discrimination, internalization of social stigma, and concealment of sexual orientation, collectively termed “sexual minority stress”, are the primary explanatory model for these health disparities.

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.

The proposed study will test the effect of herbal extracts commonly used in Iran by various HIV and cellular based assays available at UCSF, and provide important information to develop effective and affordable anti-HIV latency therapies to those who have limited access to expensive modern medicine. Also, I will maintain the collaboration with Dr. Peterlin after completion of the proposed study during my sabbatical stay at UCSF, which will contribute to potential new discovery of cellular pathways to regulate HIV transcription and latency.

HIV-1 induced B cell dysfunction typically presents as a loss of memory B cells and attenuated antibody responses, paradoxically with concomitant increases in activated B cells and hypergammaglobulinaemia. While some loss of functionality could be due to the loss T cell help, T cell triggering of inhibitory signaling pathways has also been implicated. Of these pathways, members of the TNF-receptor superfamily and subsequent downstream signaling events appear to have a prominent impact on regulating B cell function.

Cardiovascular disease (CVD) is the leading cause of mortality in Latin America and the Caribbean (LAC), and has arisen as a major clinical and public health challenge in HIV. Social and economic vulnerability may potentiate increased CVD risk among PLHIV by reducing access to a healthy diet, increasing stress, and increasing maladaptive coping behaviors (e.g. alcohol consumption and smoking). In particular, research suggests food insecurity as a key structural barrier that may undermine CVD prevention efforts among PLHIV.