Drs. Lieberman, Collman, and Co-Authors Link RSAD2/Viperin Gene with Certain Chronically HIV-Infected Cells
Philadelphia, PA, Oct. 03, 2024 and researchers at the Perelman School of Medicine's Center for AIDS Research and center director Ronald G. Collman, M.D. - have identified the RSAD2/Viperin gene as a potential HIV treatment target within certain HIV reservoir cells. Their The results were published in the paper, "HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages," in the Journal of Virology.
HIV does not have a cure because there is no known method - yet - for eliminating the virus from the body once infected. Although HIV can be managed with antiretroviral therapy (ART), the virus persists in infected cells throughout the body, called "HIV reservoirs." Reservoirs not only serve as the main barrier in HIV cure research, which focuses in large part on strategies to destroy these HIV reservoirs, but also contribute to chronic inflammation and comorbidities in people living with HIV.
A certain type of immune cell - myeloid cells, including macrophages and microglia - often serves as an HIV reservoir because, unlike other cells infected with HIV, these cells tend not to be killed by HIV's viral replication. Due to their comparative longevity as reservoirs and prevalence within the nervous system, HIV-infected macrophages often cause neurocognitive complications in people with HIV that develop even despite antiretroviral treatment (ART).
Lieberman and Collman, joined forces to research the genetics of macrophages that might play a role in maintaining the HIV reservoir status quo. Their investigation revealed a surprising candidate in the gene RSAD2/Viperin - which usually fights viruses. In HIV-infected macrophages, RSAD2/Viperin expression was quite high compared both with controls and HIV-infected CD4+ T cells (the other major type of cell that can become a viral reservoir of HIV).
RSAD2/Viperin is a gene associated with interferon response, and typically, both the gene itself and the interferons that trigger its activation have antiviral effects. However, certain interferons have been found to play paradoxical roles in chronic HIV by enabling the virus' persistence, and upon finding RSAD2/Viperin's elevated expression in reservoir macrophages, the researchers hypothesized that the gene must be abetting HIV's continued presence within these cells.
To test this, the research team used the siRNA method to target and reduce RSAD2/Viperin's expression in macrophages infected with HIV. Once they reduced the gene's expression, several measures of HIV's presence and activity fell, including viral transcripts, p24 protein production, and multinucleated giant cells (another indicator of active viral activity). Reduced RSAD2/Viperin also altered histone modification of HIV genomes - that is, the control of HIV's latency by chromatin and epigenetic factors. These findings suggest a novel role for RSAD2/Viperin in regulating chromatin that otherwise might suppress HIV replication during latency.
"Looking closely at RSAD2/Viperin in these HIV-infected MDMs, we've identified yet another paradox of HIV infection," said Lieberman, program leader, Genome Regulation and Cell Signaling Program,Ellen and Ronald Caplan Cancer."Our data show that while, yes, this is an antiviral gene that can come to the body's defense against the virus at first, it also seems to maintain HIV's ability to persist as a chronic infection. That makes RSAD2/Viperin a compelling candidate for further research and possible targeting of HIV reservoirs - which is critical to future cure research."
"We've come to understand yet another facet of chronic HIV infection's complexity," agreed Collman. "We're hopeful that these findings will be helpful as the field continues to pursue possible therapeutic interventions that would eliminate the viral reservoir in the search for an HIV cure, or reduce negative consequences of infection that can persist even despite effective therapy, such as neurocognitive decline."
Co-authors: Urvi Zankharia, Fang Lu, Olga Vladimirova, Bhanu Chandra Karisetty, Jayamanna Wikramasinghe, Andrew Kossenkov, and Paul M. Lieberman of The Wistar Institute; and Yanjie Yi and Ronald G. Collman of The Perelman School of Medicine at The University of Pennsylvania.
Work supported by: NIH grants R6133-133696, P30AI045008, and P30CA010815.
Publication information: "HIV-induced RSAD2/Viperin supports sustained infection of monocyte-derived macrophages," from Journal of Virology.
ABOUT THE WISTAR INSTITUTE
The Wistar Institute is the nation's first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world's most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org.
ABOUT PENN MEDICINE
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn's Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation's first medical school.
The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of "firsts" in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.
The University of Pennsylvania Health System's patient care facilities stretch from the Susquehanna River in Pennsylvania to the New Jersey shore. These include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Lancaster General Health, Penn Medicine Princeton Health, and Pennsylvania Hospital-the nation's first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is an $11.1 billion enterprise powered by more than 49,000 talented faculty and staff.
