Like all viruses, human immunodeficiency virus (HIV) has spent millions of years evolving ways to slip past the body’s defenses. At the heart of this evolutionary battle lies a fundamental question: which human proteins help HIV replicate inside our cells, and which ones try to stop it? In a study published April 20, 2026, in Cell, Researchers at the Quantitative Biosciences Institute (QBI), University of California, San Francisco (UCSF) and Gladstone Institutes, Ujjwal Rathore and Eli Dugan, working in the labs of Alexander Marson and Nevan J. Krogan, reported the most comprehensive catalog of these interactions ever assembled in primary human immune cells, opening exciting new doors for HIV drug discovery.

To do this, the team used two complementary CRISPR-based approaches, one that shuts genes off and one that turns them on, to scan the entire human genome for proteins that influence HIV infection in CD4+ T cells, the primary immune cells HIV targets. Conducted directly in T cells isolated from human blood donors, the screens identified hundreds of proteins that either help HIV replicate or actively fight it off. Among the most striking discoveries was a previously unrecognized antiviral protein called PPID, which physically grabs the HIV capsid and limits its entry into the cell nucleus.

The two screening approaches proved highly complementary. The gene knockout screen was effective at identifying proteins the virus depends on to infect cells. The gene activation screen proved especially powerful at uncovering natural antiviral defenses — proteins that cells could deploy to fight back against HIV, many of which had been invisible to previous studies because they are at insufficient levels under normal conditions.

“For the first time, we have a genome-wide view of HIV-host interactions in the cells that actually matter,” said Ujjwal Rathore, Ph.D., M.S., co-first and co-corresponding author. “This isn't just a snapshot. It's a resource the whole field can build on to ask better questions about HIV biology and to find new therapeutic strategies we haven't been able to pursue before."

Of particular interest was PPID, a protein previously linked only to general cellular housekeeping. PPID belongs to the same protein family as CypA, a factor that HIV co-opts to help itself replicate. PPID uses a similar strategy to bind the HIV capsid — but instead of helping the virus, it traps the viral core and prevents it from reaching the nucleus. By engineering a chimeric protein that fused CypA with PPID’s antiviral domain, the team was even able to convert CypA from a helper of the virus into a blocker of it.

“Understanding exactly how PPID blocks HIV gives us a molecular blueprint, showing which parts of the capsid matter and how this restriction works. That kind of mechanistic insight can help guide future antiviral strategies,” stated Nevan J. Krogan, Ph.D., director of QBI, and senior investigator at Gladstone Institutes

Together, the data represent the most complete functional map of HIV-host interactions in primary human T cells ever generated, a resource the researchers say will serve the field for years to come. The research was made possible through support from the NIH/NIAID and the HIV Accessory & Regulatory Complexes (HARC) Center, a multi-institution collaboration led by Dr. Krogan that brings together leading HIV researchers across UCSF, the Gladstone Institutes, and beyond to accelerate the path toward a cure.

“Antiretroviral therapy has been transformative, but it is not a cure,” says Alex Marson, M.D., Ph.D, director of the Gladstone-UCSF Institute of Genomic Immunology and a principal investigator in the HARC Center. “A deeper understanding of how HIV operates inside human immune cells will be essential for developing better strategies to control or eliminate the virus. That is what this work helps provide.”

This research was supported by the National Institutes of Health (NIH) and the NIH/NIAID HIV Accessory & Regulatory Complexes (HARC) Center, a multi-institution collaboration uniting investigators at UCSF, the Gladstone Institutes, Fred Hutchinson Cancer Center, Stanford University, and the National Cancer Institute. Additional support was provided by the Howard Hughes Medical Institute, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, the Simons Foundation, the Arc Institute, the amfAR Mathilde Krim Fellowship, the California HIV/AIDS Research Program, and Gilead Sciences.