Scientists at Gladstone Institutes and UC San Francisco have created a detailed genetic map of how HIV interacts with human CD4+ T cells, the immune cells the virus primarily infects.
HIV has only a small number of genes, but it survives by exploiting human cellular machinery. Much HIV research has historically relied on immortalized cell lines, which are easier to study but do not fully represent the behavior of cells taken directly from human donors. The new work used primary human T cells, making the findings more relevant to real infection biology.
The team optimized CRISPR-based screening in these cells and tested human genes across the genome. In one approach, they disrupted genes to identify factors HIV needs. In another, they increased gene activity to find proteins that could defend cells against infection. The study identified hundreds of host proteins that either support or restrict HIV.
Two newly highlighted antiviral proteins, PI16 and PPID, stood out. PI16 appears to interfere with HIV fusion at the cell surface, potentially blocking entry. PPID acts after HIV enters the cell, reducing the virus’s ability to reach the nucleus and begin copying itself. In lab experiments, altering PPID made it much more effective at limiting infection.
The findings may point toward new treatment strategies and better models for studying HIV latency. Antiretroviral therapy can suppress HIV to undetectable levels, but hidden reservoirs allow the virus to return if treatment stops. A stronger understanding of host genes that help or block infection may give researchers new ways to target those reservoirs.