A study published in iScience has uncovered a potential biological explanation for why women living with HIV face a significantly higher risk of developing cervical cancer, even when their HIV infection is well controlled with antiretroviral therapy. The study, “Paracrine Signals from HIV-1-Infected Immune Cells Reprogram Cervical Cancer Pathways,” was led by first author Charles Olwal of the University of Ghana and senior authors Nevan Krogan (QBI UCSF), Peter Kojo Quashie (University of Ghana), Yaw Bediako (Yemaachi Biotech), and Mehdi Bouhaddou (UCLA), bringing together researchers from eight institutions across Ghana, Kenya, and the United States.

Cervical cancer is primarily caused by persistent infection with high-risk strains of human papillomavirus (HPV). However, women living with HIV are approximately six times more likely to develop invasive cervical cancer than women without HIV. Until now, scientists have not fully understood why this elevated risk persists, particularly among individuals receiving effective HIV treatment. To investigate, researchers analyzed cervical samples from Kenyan women with and without HIV, spanning a range of disease stages from healthy cervical tissue to invasive cervical cancer. They also conducted laboratory experiments exposing cervical cells to molecules released by HIV-infected immune cells.

The findings revealed something unexpected: cervical tissue from women living with HIV—but without signs of cancer—already displayed gene activity patterns resembling those seen in cervical cancer patients. This suggests that HIV infection may induce a cancer-like molecular state in HPV-infected cervical tissue before precancerous lesions or invasive cancer develop.

Because HIV does not directly infect cervical epithelial cells, the team looked for indirect mechanisms. Their experiments showed that immune cells infected with HIV release signaling molecules that can alter the behavior of nearby cervical cells. These molecular messages activated several biological pathways known to drive cancer development, including pathways involved in cell growth, cell division, and survival.

One pathway stood out in particular: the PI3K-AKT signaling pathway, one of the most frequently altered pathways across many human cancers. The researchers observed activation of this pathway both in patient samples and in cervical cells exposed to secretions from HIV-infected immune cells. The study also identified IRS1, a key regulator of PI3K-AKT signaling, as consistently elevated across multiple experiments. This suggests that HIV-associated inflammation and immune-cell communication may activate cancer-promoting signals without requiring direct infection of cervical tissue. Importantly, all HIV-positive participants in the study were receiving antiretroviral therapy and had suppressed viral loads. This indicates that even well-controlled HIV infection may continue to influence the surrounding tissue environment through persistent immune signaling.

The findings offer a new framework for understanding how HIV contributes to cervical cancer progression. Rather than acting solely through immune suppression, HIV may actively reshape the molecular landscape of cervical tissue, creating conditions that make cancer development more likely. Beyond advancing our understanding of HIV-associated cancers, the research highlights potential therapeutic targets. The authors suggest that components of the PI3K-AKT pathway—and particularly IRS1—could be explored as future intervention points for preventing or slowing cervical cancer progression in women living with HIV. The work is especially relevant for sub-Saharan Africa, where both HIV and cervical cancer remain major public health challenges. By uncovering the molecular links between the two diseases, the study provides a foundation for developing more targeted strategies to reduce cancer risk in vulnerable populations.