Paracrine signals from HIV-1-infected immune cells reprogram cervical cancer pathways

Persistent infection with high-risk human papillomavirus (HR-HPV) is the primary cause of cervical cancer. Co-infection with HIV-1 increases the risk of cervical cancer progression 6-fold, despite adherence to antiretroviral therapy (ART). While chronic HIV-1 infection is known to cause inflammation, the paracrine effects of HIV-1-infected immune cells on cervical signaling remain unclear. We performed transcriptomics on cervical swabs from Kenyan women stratified by HIV-1 and cancer status, which revealed HIV-1 infection drove cancer-like gene expression in non-cancerous cervical cells. In parallel, global abundance proteomics and phosphoproteomics of cervical cancer cells exposed to HIV-1-infected human primary CD4⁺ T cell secretomes revealed altered MAPK, PI3K-AKT, cell cycle, and beta-catenin pathways. Concordantly, IRS1 was upregulated in both patient cervical samples and cultured cells. Our findings suggest HIV-1 dysregulates cervical cell signaling via paracrine mechanisms to phenocopy <i>PIK3CA</i>-activating mutations through IRS1-PI3K-AKT pathway activation. Our findings highlight IRS1 and the PI3K pathway as a potential therapeutic target for cervical cancer in women living with HIV-1.