HIV virus eradication is a complex health challenge due to its long-lived persistence and how it hides in latently infected cells that escape the body’s immune system. Effective HIV treatments have decreased the likelihood of someone developing AIDS, while helping individuals live long and healthy lives without transmission to sexual partners. But for individuals with long-standing HIV infection, conditions such as cardiovascular disease, certain cancers, and HIV-associated neurocognitive disorders are more common. In 2019, the U.S. Department of Health and Human Services (HHS) launched the Ending the HIV Epidemic in the U.S. (EHE) initiative to end the HIV epidemic within 10 years. The UNC Institute for Global Health & Infectious Diseases is home to one of the 19 NIH Centers for AIDS Research (CFARs) where high quality AIDS research projects are underway. Following is a broad look at some of our work in HIV research.
Searching for a cure
Nancy Archin, PhD, is using single cell and spatial transcriptomics to better define the sources of persistent and latent HIV infection in gut tissues of both men and women. This includes assessing whether sex differences contribute to HIV persistence in tissues, determining whether combination latency reversal agents can target this reservoir better than single drugs, and testing whether novel approaches to enhance the immune effector function capacity of natural killer (NK) cells and CD8 T lymphocytes can eliminate cells containing virus emerging from latency.
Victor Garcia, PhD, has made seminal contributions to the understanding of HIV pathogenesis central to our ability to eventually eradicate the virus. Before Dr. Garcia, no one had successfully tested a latency reversal molecule in animals with human cells that showed a reduction in HIV in peripheral blood or in resting CD4 T-cells.He also pioneered the development of a humanized mouse model which has a fully functioning human immune system that can be infected with HIV in the same manner as humans. It is now widely used to address key questions of HIV infection, transmission, prevention, and more recently, persistence and cure. Now, the biomedical researcher and his team is focused on developing and implementing an effective ultra-long-acting antiviral delivery system to combat the spread of HIV, funded by a $1.9 million award from the Bill & Melinda Gates Foundation.
David Margolis, MD, is defining the role of epigenetic factors in the restriction of HIV expression which has led to diverse, multidisciplinary collaborations and translational clinical studies resulting in discovery and high-impact work. He directs the UNC HIV Cure Center and is the principal investigator for CARE (Collaboratory of AIDS Researchers for Eradication), an NIH-funded U19 research organization that seeks to develop the tools to bring an HIV cure from the bench to the clinic, and leads a new effort with the AIDS Clinical Trials Group to build more recruitment and access a bigger population.
The search for new weapons
To increase the choices for prevention treatment, the IGHID’s Global HIV Prevention and Treatment Clinical Trials Unit continues to pursue safe and effective long-acting alternative agents for HIV pre-exposure prophylaxis (PrEP). Joe Eron, MD, Mina Hosseinipour, MD, and David Wohl, MD, lead the CTU, bringing together a diverse team of scientists working with some of the world’s most severely affected populations in Chapel Hill, Greensboro, Vietnam and Malawi, to conduct leading trials through NIAID feeder networks. They include the ACTG (AIDS Clinical Trials Group), of which Joe Eron, MD, is the vice chair (co-PI), the HVTN (HIV Vaccine Trials Network), HPTN (HIV Prevention Trials Network), of which Myron Cohen, MD, is co-PI, and the IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) Network.
Recently, the North Carolina and Vietnam sites participated in HPTN 083, enrolling high-risk MSM (men who have sex with men). This was the first study to compare the two-month injectable Cabotegravir with an oral treatment to prevent HIV. The Malawi site participated in the landmark HPTN 084 study, co-chaired by Mina Hosseinipour, MD, which focused on high-risk women. Both studies contributed to the FDA’s approval of long-acting Cabotegravir (Cabenuva) in Dec. 2021.
Addressing the pressing clinical care issues of patients
Characterizing changes in the needs of people living with HIV, as therapeutics and care evolve, is especially needed right now as PWH are living longer and healthier lives. Challenges engaging with care early following infection and consistently accessing care are not new among PWH. However, preventing and managing comorbidities, is increasingly challenging for PWH who may experience these at younger ages alongside HIV. The UNC CFAR HIV Clinical Cohort Study, led by Joe Eron, MD, and Sonia Napravnik PhD, has been leveraging large clinical data to address pressing questions in the care of PWH for over two decades, also in collaboration with the CFAR Network of Integrated Clinical Systems and the North American AIDS Cohort Collaboration on Research and Design.
Reducing the impact of chronic health conditions
Even when the disease is well controlled, HIV and treatment can affect other parts of the body, such as the brain and the heart. People living with HIV are significantly more likely to develop cardiovascular disease and have an increased risk of dementia than people without HIV. Ada Adimora, MD, MPH, and Michelle Floris-Moore, MD, MS, co-lead a team of researchers in the Schools of Medicine, Pharmacy, and Public Health, working with the Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS), to evaluate disparities in care, the effects of HIV on comorbid conditions, such as cardiovascular and neurologic disease, and novel epidemiologic methods.
Age-associated cognitive decline
The once life-threatening brain complications associated with HIV infection are now uncommon due to highly effective ART. Yet, up to 50% still experience neurological disorders, and age-associated cognitive decline is exacerbated in people living with HIV. The continued high prevalence of HIV-Associated Neurocognitive Disorder in people living with AIDS suggests the persistence of HIV infected cells in the brain. Using an innovative animal model, Angela Wahl, PhD, is studying the role of microglia in HIV latency and persistence in the brain, to answer questions that haven’t been possible before. This investigative team includes Archin, Guochun Jiang, PhD, assistant professor of biochemistry and biophysics, and Corbin Jones, PhD, professor of biology and genetics, along with other collaborators.
HIV and its treatment can also cause brain deficits in attention, language, motor skills, memory, and other cognitive functions that significantly affect a person’s quality of life. People who have HIV-Associated Neurocognitive Disorder may also experience depression or psychological distress. Bradley Gaynes, MD, MPH, is working to address mental health needs in low- and middle-income countries. In Hanoi, Vietnam, he’s testing in a pilot randomized trial whether a problem-solving psychotherapy called Friendship Bench, adapted to meet the needs of an HIV positive, methadone-maintenance clinic population with common mental disorders in Vietnam can be delivered with fidelity by both professional counsellors and peer counselors. With Brian Pence, PhD, he’s developing a critical mass of both research and training in low- and middle-income countries to build the Department of Psychiatry’s Division of Global Health, a joint collaboration with the Department of Epidemiology in the School of Public Health, called HEADS-UP. The two are also adapting and testing another version of Friendship Bench in a group of adolescent Malawians with HIV and depression.
Chronic inflammation and cancer
HIV appears to cause chronic inflammation throughout the body, which may be associated with conditions such as lymphoma and type 2 diabetes. Researchers are working to better understand inflammation, even in people receiving ART to manage HIV. Yuri Fedoriw, MD, LabCorp Distinguished Professor; Co-Director of the Project-Malawi Cancer Program; and Global Cancer Pathology Director, IGHID, is working with a research team in Sub-Saharan Africa and the U.S. to improve diagnosis and care for patients with lymphoma, particularly lymphoma arising in the setting of HIV infection. The team is enrolling newly diagnosed lymphoma patients in Malawi and South Africa for an observational cohort study, and working to characterize the tumor-microenvironment in the most common aggressive B-cell lymphoma worldwide. They also plan to expand their efforts to other common lymphoma subtypes, including Classic Hodgkin Lymphoma.
Jennifer Tang, MD, MSCR, associate professor of obstetrics and gynecology, and UNC Global Women’s Health is working closely with Lameck Chinula, MD, and Friday Saidi, MBBS, MMed, to assess completion and performance of a novel invasive cervical cancer (ICC) screen-and-treat algorithm among HIV-positive women in Lilongwe, Malawi. The Lineberger Comprehensive Cancer Center 1905 has enrolled 1,250 Malawian women, half of whom are living with HIV. Participants were all offered cervical cancer screening by self-collection of cervicovaginal samples for HPV testing. Participants who were positive for HPV, and 10% of those who were HPV-negative, were offered same-day colposcopy, cervical biopsy, and thermocoagulation treatment for the HPV, if they were eligible. Participants found to have high-grade cervical dysplasia (CIN2/3) on biopsy are followed up 6 months after treatment for repeat colposcopy and cervical biopsy, to ensure that they have been adequately treated.
Testing and diagnosis
Many senior adults have been living with HIV for years; others are recently infected or diagnosed. According to the Centers for Disease Control and Prevention (CDC), in 2018, 35% of people aged 50 and older already had a late-stage infection of AIDS when they received a diagnosis. It is important for people aged 50+ to know their HIV status so they can begin treatment. Ann M. Dennis, MD, MS, is evaluating HIV transmission networks in North and South Carolina, to develop and implement a partner services intervention that uses a social network strategy to increase testing and linkage to HIV care or prevention.
Christopher Hurt, MD, is assistant professor of medicine and principal investigator of the NC HIV Training & Education Center (NCHTEC), which supports capacity-building and training of HIV professionals, and is part of the Southeast Regional Network of AIDS Education and Training Centers funded through the Ryan White HIV/AIDS Program (HRSA U1OHA30535). Since the current grant cycle began in 2019, Hurt has directed the expansion of the Center’s training opportunities to better engage medical case managers, social workers, and other non-prescribers. Committed professionals are essential to HIV service delivery but are often overlooked for training opportunities. NCHTEC has also coordinated a series of trainings on how structural and institutional racism impact HIV service delivery. In recognition of recent successes, the NCHTEC team was awarded supplemental discretionary funding for the 2022-23 fiscal year. These funds will be used to help HIV professionals learn more about the federal Ending the HIV Epidemic (EHE) initiative and how it impacts their work – now and in the future. The team also plans to expand clinician-focused trainings and support for local health departments, and their implementation of PrEP services, statewide.