Baseline immune transcriptional states predict future HIV-1 acquisition in individuals at risk of sexual infection

Natural resistance to HIV-1 acquisition in highly exposed seronegative (HESN) individuals suggests the existence of pre-existing host states associated with reduced susceptibility. However, the baseline molecular determinants of susceptibility remain poorly understood. We analyzed peripheral blood mononuclear cell transcriptomes by RNA sequencing in 104 HIV-1-seronegative men who have sex with men (MSM) at high risk of sexual exposure, including 65 HESN and 39 who subsequently seroconverted. Differential expression, functional enrichment, and spatial genomic clustering analyses were integrated with Elastic Net regularized logistic regression. HESN individuals showed enrichment of sensory receptor (p.adj = 2 × 10⁻¹⁶) and cell-adhesion pathways (p.adj = 9 × 10⁻³), together with non-random genomic clustering (p.adj = 1 × 10⁻⁴) of differentially expressed genes (DEGs) at immune-related loci, including TCR, IGH, KIR, and MHC/HLA regions. In contrast, future seroconverters exhibited increased mRNA metabolism (p.adj = 1.5 × 10⁻¹⁴), immune activation (p.adj = 0.01), and type I interferon signaling (p.adj = 0.02). A 14-gene risk score showed an out-of-fold area under the curve (AUC) of 0.888. Cross-cohort transportability was evaluated in an independent ectocervical RNA-seq data set. Applied without refitting, the signature showed moderate discrimination between long-term HESN and HIV-negative women at high risk of acquisition (AUC = 0.689). The out-of-fold molecular risk score was also associated with time to HIV-1 seroconversion in MSM (log-rank, P = 7.1 × 10⁻¹¹; score × time interaction, P = 0.0086). These findings identify distinct pre-infection transcriptional states associated with HIV-1 acquisition and support partially transportable transcriptional architecture across blood and genital mucosal compartments. IMPORTANCE Modeling the baseline transcriptome enables prediction of future HIV-1 acquisition and identifies a transcriptional score associated with time to seroconversion. These findings raise new hypotheses about the biological and genetic mechanisms underlying the HESN phenotype.