Richard T. D’Aquila, MD, has worked on improving therapy for human immunodeficiency virus (HIV) infection for more than 25 years. Director of the Northwestern HIV Translational Research Center and The Howard Taylor Ricketts Professor of Medicine, D’Aquila now works to cure the infection.
“Despite many advances in antiretroviral medications, they still must be taken for life because HIV persists as a latent provirus throughout therapy and its transcription returns to high levels in the blood within weeks of stopping the medications,” he said. “Recently, one patient was able to stop medications for many years without virus rebounding from its long-lived ‘latent reservoir’ in blood resting memory T lymphocytes. This ‘functional cure’ followed heroic interventions and proved that cures are possible.”
D’Aquila received his medical degree from Albert Einstein College and completed his residency in internal medicine at the University of Pennsylvania Hospitals. He completed a fellowship in infectious disease and postdoctoral fellowship in molecular virology at Yale University School of Medicine.
What is the ultimate goal of your research?
Ending the HIV epidemic. I would like to contribute to curing more than one infected person—ideally all 35 million infected now—with a less-than-lifelong therapy. I would also like to help develop a practical, universally-available biomedical intervention that prevents new infections.
Tell us about your current research.
My research aims to leverage newly recognized host defenses, called ‘intrinsic immune’ factors, against HIV for a feasible and scalable approach to a cure, as well as more effective biomedical prevention.
These cellular defensive proteins were identified as a result of studying several HIV gene products that are essential for virus replication. This revealed that HIV encodes proteins that degrade or neutralize these cellular intrinsic immune factors. In the absence of viral proteins that antagonize the cellular factors, HIV cannot replicate. The growing number of intrinsic immune defenses are distinct from innate and adaptive immunity—although important interactions between the systems that enhance protection from pathogens are emerging.
The family of APOBEC3 proteins is studied in our laboratory. They block reverse transcription and integration, and have other anti-HIV mechanisms that operate both in virions and in target cells.
Early after HIV infects a cell, HIV-1’s virion infectivity factor (Vif) is highly expressed and recruits the cell’s APOBEC3s to a cullin-RING ubiquitin ligase complex that poly-ubiquinates them, leading to their degradation in the proteosome.
Our work has shown that HIV reactivated from resting memory cells can be rendered non-infectious by boosting APOBEC3 levels in primary cells. The goal is to add to prior efforts to enhance adaptive immunity by using these intrinsic and innate defenses to render non-infectious all reactivated virions purged from the latent reservoir by future ‘latency reversing agents’ now entering clinical trials.
Several projects are underway to: (a) prove the concept that APOBEC3 proteins can be boosted enough to retain antiviral activity despite Vif by testing currently available biologicals in early phase clinical trials; (b) screen for, and rationally design, small molecules that stabilize and boost APOBEC3 levels in the cell and/or interfere with Vif-mediated degradation; (c) test the hypothesis that improving APOBEC3 activity (and/or avoiding its degradation by HIV Vif) during the first hours to weeks after HIV exposure will either prevent infection or render the infection non-pathogenic.
How does your research advance medical science and knowledge?
Earlier in my career, I was privileged to contribute to moving the key concept of combinations of antiretrovirals from the laboratory into the clinic, improving antiretroviral medications through clinical trials, and advancing antiretroviral resistance testing into standard of care that personalizes therapy. My current research is not only aimed at contributing to the “end-game” against HIV, but will improve understanding of the biology of other infections and malignancies.
How did you become interested in HIV/AIDS research?
AIDS was first identified during my senior residency. By the time I had gained molecular virology skills from fellowship training, the viral etiology, now called HIV, was identified. At a time when clinical care of AIDS patients could only prepare the patient and family for an eventual, often rapid death, I was fortunate to be involved in early antiretroviral drug development efforts in the laboratory and clinical trials. This translational focus hooked me for life.
Who makes up your research team?
The laboratory team is new and growing. It now includes Chisu Song, PhD, and Harry Taylor, PhD, both research assistant professors at Feinberg. Chisu studies the molecular virology of APOBEC3 and other intrinsic immune factors, specializing in characterizing proteins and nucleic acids in virions. Harry is a cell biologist focused on characterizing virus-cell interactions, especially those that contribute to premature senescence in HIV-infected persons despite antiretroviral therapy. I have extensive and growing collaborations with molecular virologists, clinical HIV researchers, structural biologists, and high throughput screening laboratories in Chicago and across the globe.
What do you enjoy about teaching and mentoring young scientists in the lab?
My best days are those when I can spend a couple of hours brainstorming with young laboratory or clinical scientists about new ideas that spark new projects. This can involve mentoring committee meetings, laboratory group meetings, or frequent one-on-one meetings (often arising spontaneously over a coffee break). If both laboratory and clinical scientists interact to learn from each other and help each other to design a new ‘translational’ project, that’s a very special day. I also cherish when someone in the group (not always me) introduces a concept from a different field that provides a fresh perspective and sparks new insights into old problems.