BACKGROUNDSusceptibility to HIV-1 infection varies between individuals, but the biological determinants of acquisition risk remain poorly defined.METHODSWe conducted a case-control study nested within a high-risk cohort in Kenya. We compared the plasma extracellular RNA collected before HIV-1 acquisition with that from matched uninfected individuals acting as controls to identify immunological processes linked to infection risk.RESULTSIndividuals who later acquired HIV-1 exhibited upregulation of immune processes that facilitate viral infection, including T cell suppression and type II IFN and Th2 immune responses. In contrast, processes associated with antiviral defence and tissue repair, such as neutrophil and NK cell responses, type I IFN responses, wound healing, and angiogenesis, were downregulated.CONCLUSIONThese findings highlight dampened antiviral immunity prior to exposure as a correlate of increased risk for subsequent HIV-1 acquisition.FUNDINGThis work was supported by a Wellcome Trust Award (209289/Z/17/Z) and the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) through the Developing Excellence in Leadership, Training and Science in Africa (DELTAS Africa) programme (Del-22-007), which is supported by the Science for Africa Foundation; Wellcome Trust; the UK Foreign, Commonwealth & Development Office; the European Union; and the Ragon Institute of Mass General, MIT, and Harvard. The Bill & Melinda Gates Foundation, Gilead Sciences Inc., and Aidsfonds provided additional support. The US President's Emergency Plan for AIDS Relief (PEPFAR) supported the cohort study through the US Agency for International Development (USAID).