MSCR Scholar Explores Sex Differences to Optimize HIV Treatment
Cecile Lahiri, MD, MSc, assistant professor, Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, received an NIH K23 award for her work on defining antiretroviral pharmacology within HIV reservoirs of males and females, including peripheral blood nuclear cells and the gut. She is also a co-investigator for the Emory Women’s HIV Interagency Study (WHIS), a cohort designed to investigate the impact of HIV-1 infection of women in the United States.
As a former ACTSI KL2 Mentored Clinical and Translational Research scholar, her research studies integrated pharmacokinetic-viral dynamic modeling to investigate the effect of antiretroviral drugs in reservoir compartments of HIV-infected individuals.
Globally, women account for nearly half of all people living with HIV, concentrated especially in low- and middle-income countries. Unfortunately, women’s underrepresentation in HIV clinical studies leads to gaps in knowledge of the virus’ proliferation across sexes. Evaluation of sex-specific biological differences and their respective responses to pharmacologic agents can inform physicians how to treat HIV-positive women safely and efficiently. This will lead to optimal HIV eradication strategies.
HIV is a special type of retrovirus containing RNA (ribonucleic acid). By replicating backwards, they allow for easy mutation of DNA. The immune system typically defends the body against illness using guards in the blood called CD4+ cells (T cells) to recognize any intruders and destroy them. Viral load tests the health status and effectiveness of the antiretroviral therapy (ART). While no cure exists, ART can drastically reduce morbidity and mortality rates of HIV-positive individuals. This keeps the virus from multiplying and destroying the host’s immune system. The goal of treatment is to decrease one’s viral loads, ideally to an undetectable level.
One looming issue with HIV is that the treatment cannot eliminate the cells harboring this detrimental DNA. These HIV reservoirs, like peripheral blood mononuclear cells or rectal tissue, present a major barrier to an HIV cure and are not routinely measured by clinical lab tests. While ART is able to deplete the reservoirs over time, it does so slowly. So slowly, in fact, that it would take 60-80 years to achieve complete eradication. While HIV RNA may be undetectable in blood plasma, it may still be active and multiplying in these sites, integrating its genetic material into the DNA of a host cell. These cells are located throughout numerous organ systems, including the brain, lymphoid tissue, bone marrow, and genital tract. These pools trigger a consistent inflammatory response. Even at a low level, this chronic inflammation affects the way cells and tissues replicate, speeding up the aging process. This process, premature senescence, is the reason patients with long-term HIV infection are at an increased risk for cancer, heart disease, bone frailty, and neurocognitive disorders. These come 10 to 15 years earlier than what would be expected in the general population. One of the reasons that HIV-1 eludes eradication may be due to limited antiretroviral penetration into reservoir sites.
We have a very poor understanding of sex differences within HIV reservoirs. While women have up to 40% lower HIV loads and higher CD4+ T-cell counts than men do, progression to AIDS is faster in women. Much like the rates of infection for other diseases, women also experience increased levels of generalized immune activation and experience the consequences of elevated inflammatory activity more frequently than men. These marked physiological differences between men and women (hormonal, metabolic, immunologic, etc.) make it conceivable that the location and amounts of HIV RNA (especially in the case of HIV reservoirs) may be different across the two and that the sexes may respond differently to HIV medications.
Lahiri evaluates the impact of sex discrepancies in HIV treatment and cure. Using the HIV medication dolutegravir, she investigates how the drug gets into the different parts of the body. By comparing the viral loads in blood plasma, special blood cells, and rectal tissue, investigators will be able to learn how fast dolutegravir lowers viral loads between sites and the differences in how it behaves in males versus females. She expects that optimal drug doses needed to suppress HIV will be higher in peripheral blood mononuclear cells, including the primary players of the human immune – lymphocytes and monocytes, as well as rectal tissue reservoirs compared to blood plasma, and will be different between sexes.
”I plan to prioritize the exploration of sex differences by leveraging the extensive research infrastructure, including the clinical core for the Center for Aids Research (CFAR), the Atlanta Clinical & Translational Science Institute (ACTSI), and the motivated cohort of the Atlanta Women’s Interagency HIV Study (WIHS),” said Lahiri.
Her ACTSI-supported Master of Science in Clinical Research (MSCR) foundation, as well as clinical and translational research, uniquely positions her for an independent career in the application of clinical pharmacology within HIV cure strategies.
The goal of the ACTSI KL2 Scholars Program is to support career development for junior faculty (MD, PhD, or MD/PhD) from a wide variety of disciplines at the ACTSI institutions – Emory University, Morehouse School of Medicine (MSM), and Georgia Institute of Technology (Georgia Tech) – to become independent, established, and ethical clinical and/or translational research investigators. The ACTSI-supported Emory Master of Science in Clinical Research (MSCR) degree program, from the Laney Graduate School at Emory, provides didactic and mentored clinical and translational research training. The degree is designed for participants who hold a doctorate or equivalent degree (such as physicians and PhD-level scientists) or predoctoral trainees enrolled in a dual degree program (MD/MSCR and PhD/MSCR tracks) and have demonstrated a commitment to a career in clinical investigation.
The ACTSI is a city-wide partnership between Emory, MSM, and Georgia Tech and is one of a national consortium striving to improve the way biomedical research is conducted across the country. The consortium, funded through the National Center for Advancing Translational Sciences as one of the National Institutes of Health’s Clinical and Translational Science Awards, shares a common vision to translate laboratory discoveries into treatments for patients, engage communities in clinical research efforts, and train the next generation of clinical investigators.