Transient increases in inflammatory cytokines and chemokines are predictive of subsequent HIV-1 infection

Background Current HIV prevention strategies focus on targeting ‘at-risk’ individuals with sexual health education and HIV prevention medications such as PrEP. Despite these efforts, ~1.3 million new infections occur globally each year. We therefore asked whether it is possible to further stratify ‘at-risk’ individuals into high- and low-risk categories, enabling more targeted intervention toward those most vulnerable. Methods To explore this, we screened plasma samples from HIV-negative partners in serodiscordant couples in Zambia and Rwanda for hallmark inflammatory cytokines. We compared cytokine levels between individuals who remained uninfected and those who later seroconverted (pre-infected). Results Analysis of plasma from 501 uninfected individuals and 91 pre-infected individuals identified several significantly elevated cytokines in pre-infected individuals with IL-7, ITAC, and IL-8 being the most significantTo assess whether these elevations were transient or chronic, we analyzed earlier pre-infection samples collected up to 18 months before estimated date of infection (EDI) in Zambia and up to 7 months pre-EDI in Rwanda. In Zambia, IL-7, ITAC, and IL-8 were significantly lower at the earlier time point, suggesting a transient increase prior to infection. No difference was observed in Rwanda, likely due to the shorter sampling interval, supporting the idea that these elevations occur within a limited window of time.To determine whether these diagnostic cytokines were elevated following infection, we analyzed longitudinal samples from pre-infection, early acute post-infection (0–3 months), and early-chronic post-infection (6–9 months). Identified biomarkers IL-7, IL-8 and ITAC showed a consistent decline following infection, with the most pronounced drop immediately following infection. Mixed-effects modelling quantified cytokine-specific longitudinal changes across pre-early and early-late post-infection intervals, confirming the univariable analyses. Discussion Overall, we identified key plasma biomarkers that may help distinguish individuals at elevated risk of HIV acquisition which could inform more targeted prevention strategies.