In 2003, IAVI (formerly the International AIDS Vaccine Initiative) identified several gaps in HIV epidemiology and vaccine research. IAVI launched cohort studies to better understand at-risk populations, their suitability for clinical trial participation and their unmet needs for preventive services and products. Our goals included (i) improving our understanding of HIV incidence and volunteer retention among ‘key populations’ of at-risk persons suitable for participation in large-scale HIV prevention trials; (ii) identifying and addressing unmet needs for health care, counselling and prevention among these key populations; (iii) understanding host–virus interactions both shortly after virus acquisition and longer term; (iv) generating data and reagents from recently transmitted HIV to support new vaccine product discovery; and (v) understanding clinical outcomes of HIV disease in the African context to define clinical trial endpoints where antiretroviral therapy (ART) was not (yet) widely available, while building the clinical, laboratory and quality systems to support future trials. To this end, starting in 2004, IAVI established partnerships with nine experienced clinical research centres in east and southern Africa to enrol suitable volunteers (Figure 1). This manuscript includes data from two broad protocols that followed persons at risk of HIV acquisition (1) ‘A prospective, open cohort, observational feasibility study to determine HIV incidence in preparation for future preventive HIV vaccine clinical trials’ (IAVI Protocol B) and (2) ‘Heterosexual transmission of HIV in Africa’ [Emory Heterosexual Transmission (HT) study]. Between 2005 and 2009, varying by research centre, through to December 2011, they served as the source populations for a third cohort study on the natural history of HIV infection, ‘A prospective, observational, multi-center study to evaluate laboratory, clinical, immunologic and viral markers of disease progression in recently HIV-infected volunteers’ (IAVI Protocol C). Table 1 summarizes the start and stop dates for each site and each cohort. As part of participating in each respective cohort study, clinical and laboratory teams were trained in good clinical practices and good clinical laboratory practices, laboratories were accredited, and all assays were standardized and conducted under an external quality control programme.1 Study teams met annually, typically in Africa, to share experiences and results and for additional training.