HIV/HCV-related health disparities in Baltimore: from community to lab bench

HIV and hepatitis C virus (HCV) are two important chronic viral pathogens that cause serious global morbidity and mortality and disproportionately affect people of racial, gender, and socioeconomic minorities. Because they often share routes of transmission, co-occurrence of HCV and HIV infections is common. In the US, approximately a quarter of HIV-positive patients are coinfected with HCV, leading to severe comorbidities. Baltimore City has one of the highest rates of HIV infection in the US, and HCV infection is increasingly common, particularly among specific high-risk populations. As an Urban Research University situated at the center of the concurrent HIV and HCV epidemics in Baltimore, Morgan State University is obligated to be an integral part of the efforts to tackle these problems.

We propose a multi-pronged approach to study HIV-HCV co-infection, with epidemiologic, clinical, and basic science components. The two aims of this project are to:

• Aim 1. Determine factors associated with HCV infection among HIV-infected men: a cohort study. Under the hypothesis that the characteristics of HCV/HIV coinfection might be unique in Baltimore, my group has established a retrospective cohort of 1985 HIV-infected men receiving HIV primary care at a large multisite community health center in Metropolitan Baltimore. A large database with >85 variables has been built and quality-verified based on these patients. A study on the incident HCV and associated risk factors has been completed and published1. The important findings include: (1) a resurgence of incident HCV was detected among HIV-infected men who have sex with men (MSM) since 2010; and (2) the re-emerging HCV epidemic was associated with epidemics of polydrug use and sexually transmitted infections (STIs). Analysis of existing data collected through this effort will lead to more discoveries and publishable findings. We will analyze the following: a. Trends and risk factors of prevalent HCV, cascade of care and treatment uptake for chronic HCV, and factors associated with spontaneous HCV clearance among the HIV-infected men; b. Association between recreational drug/polydrug use and acquisition of HCV and various anogenital STIs in high-risk groups of the HIVinfected men, especially the MSM; c. Trends, prevalence, and risk factors of HCV, STIs, and polydrug use among certain underrepresented minorities, such as African Americans, transgender women, and residents of selected zip codes. By completing this aim, we estimate that at least 6-10 research articles will be published. The studies and findings will also lay the groundwork for expanding and establishing new study populations to address different aspects of HCV infections among HIV-infected individuals.

• Aim 2. Study the roles for monocytes/macrophages (MO/Mφ) in HIVinduced chronic immune activation and as cellular reservoirs for HIV persistence and reactivation with and without HCV coinfection. A major barrier to reducing HIV-related health disparities is the lack of a cure due to HIV latency in cellular reservoirs. In addition, HIV-induced chronic immune activation is evident even when the virus is effectively suppressed. However, the cellular source of the immune mediators, including cytokines and soluble cell surface receptors, remains unclear. We hypothesize that MO/Mφ could serve as cellular reservoirs for HIV persistence and sustain chronic immune activation through viral relapse and/or secretion of virally modified exosomes. In this aim, we will use a unique model system of long-term culture (>100 days) of primary human MO/Mφ established in my lab to study the following: a. Expression of activation markers and cytokines/chemokines in MO/Mφ derived from HIV-monoinfected or HCV/HIV-coinfected patients at various points before and after initiation or switching of antiretroviral therapies, either directly ex vivo or after in vitro culture; b. Cellular and molecular requirements and mechanisms for HIV latency/persistence as well as spontaneous and induced viral reactivation in MO/Mφ obtained from HIV-monoinfected or HIV/HCV-coinfected patients ex vivo or in an in vitro infection model; c. Effects of virally modified exosomes derived from HIV-infected MO/Mφ on modulating cellular activation and HIV replication in infected and bystander CD4+ T cells and MO/Mφ.