In a groundbreaking effort to redefine HIV care, scientists at the USF Health Institute for Translational Virology and Innovation are uncovering fresh strategies aimed at two of the most persistent challenges for people living with HIV: reducing long-term health complications and achieving a functional cure.
After decades of progress, HIV treatments such as antiretroviral therapy (ART), the current standard of care, have transformed HIV infection from a devastating terminal illness to a chronic condition, albeit one that requires lifelong adherence to medications. Now patients are experiencing the irony of that success: scientists are learning more about how HIV affects and contributes to other chronic illnesses and diseases of aging.
Even when the virus is well-controlled, people with HIV remain at higher risk for severe conditions, such as heart disease, neurological decline, certain cancers, and immune dysfunction. USF Health researchers say a major culprit may be hidden in plain sight: an abnormal, rapid overproduction of a molecule typically produced by the body to fight infections, called interferon-alpha (IFN-α), to toxic levels.
One of two key studies led by USF Health’s Dr. Robert C. Gallo and his French collaborators, including the late Dr. Danièle Zagury and Dr. Hélène LeBuanec, was published in Nature Communications Medicine two years ago. In this study, the researchers discovered that interferon-alpha (IFN-α) behaves paradoxically during HIV infection. While IFN-α usually helps control pathogens, in the case of HIV, it also activates the CCR5 gene, a co-receptor that HIV uses to enter immune cells. This activation increases the number of entry points for the virus, making it easier for it to spread. As HIV levels rise, the immune system produces even more IFN-α in response, which only amplifies the problem. This sets off a vicious cycle: more virus leads to more IFN-α, which causes further immune dysfunction. At high, toxic levels, IFN-α causes a wide variety of immune cell defects.
“ART transformed HIV from a death sentence into a chronic condition, but we now face new and very complex medical and quality-of-life challenges,” said Dr. Gallo, director of the USF Health Institute for Translational Virology and Innovation. Dr. Gallo also co-discovered HIV as the cause of AIDS and led the development of the HIV blood test. He also is widely recognized for his pioneering discoveries of interleukin-2, which made it possible to grow human T cells in the laboratory and enabled his and his colleagues’ discovery of the first human retroviruses, HTLV-1 and HTLV-2, as well as the development of modern cancer immunotherapies.
“Our research suggests that in trying to fight HIV, the body’s own immune defenses may contribute to long-term damage,” said Dr. Gallo, who is also the James P. Cullison Professor of Medicine in the Division of Infectious Disease at USF Health, director of the Microbial Oncology Program at Tampa General Hospital Cancer Institute, and chair of the scientific leadership board and co-founder of the Global Virus Network.
Dr. Gallo and his collaborators at the Institute, including Dr. Zach Porterfield, assistant professor; Dr. Yutaka Tagaya, assistant professor; and Dr. Hongshuo Song, associate professor, have spent years studying HIV pathogenesis. While IFN-α is part of the body’s natural response to viral infection, chronic elevation of this compound impairs immune function, even in patients whose viral load is undetectable through ART.
“We observed that even patients with stable CD4 counts and suppressed virus have widespread immune dysfunction,” said Dr. Porterfield, a virologist and immunologist whose lab is central to the Institute’s human tissue studies.
Dr. Gallo and his French colleagues’ previous research also revealed that a rare group of HIV-positive individuals called elite controllers, who naturally suppress the virus without medication, do not exhibit elevated IFN-α. People living with HIV who are treated with ART show a significant reduction in IFN-α levels once the virus is suppressed. This reduction leads to a partial restoration of immune function, though not complete normalization.
Using more sensitive detection methods, the researchers recently discovered that IFN-α levels in treated patients remain higher than usual, sufficient to cause ongoing, though less severe, immune cell dysfunction. The researchers now believe this lingering interferon-driven immune disruption is a major contributor to the chronic health complications seen in people with HIV, challenging the idea that these comorbidities are solely due to long-term exposure to ART drugs. This finding inspired a bold hypothesis: Could dampening IFN-α signaling in typical HIV-infected individuals mimic this elite controller phenotype?
The Institute is preparing preclinical studies that include using rare human tissue samples from longstanding patient cohorts in South Africa and Florida to answer that question. Their unique approach will use an antibody that lowers IFN-α levels by targeting its receptor, initially developed by National Institutes of Health (NIH) virologist Dr. Paolo Lusso. Dr. Lusso has already initiated preliminary studies at the NIH to begin evaluating the antibody’s effects in vivo.
As a virologist, Dr. Song will lead a series of virological and HIV-related assays. She was an author with Dr. Gallo on the Nature Communications Medicine paper that showed IFN-α contributes to chronic inflammation and immune exhaustion and increases the availability of CCR5, a key entry point HIV uses to infect cells. Her lab’s work will be essential to validating early findings and refining the intervention’s clinical potential.
“We’re using cutting-edge models that allow us to test how this antibody changes immune behavior in a living system,” said Dr. Song. “Our goal is to understand not only if the therapy works, but how it works, and whether it can realistically reduce the burden of HIV-related inflammation and immune damage.”
Dr. Tagaya will test the interferon antibody intervention strategy, while Dr. Porterfield will evaluate its effect using human tissue organoid models. In addition to leading tissue-based mechanistic studies, the Porterfield Lab coordinates clinical trial recruitment and human subject participation for the Institute.
Furthermore, the team will collaborate with Dr. Jay Rappaport at the Tulane National Biomedical Research Center to conduct parallel studies, complementing the other preclinical models. This multi-platform approach reflects a significant, institute-wide effort to advance foundational science and translational application.
“We’re developing two parallel strategies,” explained Dr. Tagaya. “One to explore a possible functional cure if the intervention is applied early, and another to reduce the burden of comorbidities in people with long-term infection who are aging with HIV.”
With an estimated 40 million people living with HIV globally, and more than half now over the age of 50, this work carries enormous clinical and economic implications. In the U.S. alone, the HIV drug market is valued at over $13 billion, with global markets estimated at $31.7 billion, not including the rising costs of managing related chronic illnesses.
“We’re not just looking to suppress the virus,” Dr. Gallo said. “We’re trying to restore immune health, extend quality of life, and potentially eliminate the need for daily medication. This is the next frontier in HIV care.”
The USF Health Institute for Translational Virology and Innovation interdisciplinary team is now laying the groundwork for Phase I/II clinical trials in collaboration with USF Health clinicians, the University of Miami, and community-based partners who care for over 15,000 people living with HIV. These trials aim to test whether targeting IFN-α signaling can alter the disease’s course, either by achieving medication-free remission or by easing the toll of aging with HIV.
As this next research phase unfolds, the team remains focused on a vision that could change millions of lives.
“We believe this work opens the door to something unprecedented,” Dr. Gallo said.