Co-receptor usage in distinct phylogenetic clusters of HIV-1 CRF01_AE is associated with differential immune reconstitution after antiretroviral therapy

ABSTRACT HIV-1 CRF01_AE cluster 4 is the predominant strain among men who have sex with men (MSM) in China and comprises two lineages, clusters 4a and 4b. We aimed to compare immune reconstitution after antiretroviral therapy (ART) between individuals infected with clusters 4a and 4b and to explore virological determinants underlying cluster-specific differences. We conducted a multicenter cohort study in Jiangsu Province, China, enrolling 604 cluster 4-infected patients with sustained viral suppression after 24 weeks of ART. We used generalized additive mixed models to characterize CD4 + T-cell recovery, logistic regression to identify factors associated with immunological non-response (INR), and Cox regression models to evaluate determinants of the CD4 + T-cell normalization. HIV-1 co-receptor tropism was inferred using Geno2pheno. We included 604 patients (391 cluster 4a, 213 cluster 4b). Patients with cluster 4a exhibited a significantly slower recovery rate than those with cluster 4b ( β : −9.88 cells/μL/year; interaction term P = 0.006). Relative to cluster 4b, cluster 4a infection was associated with a higher risk of INR (adjusted OR: 1.61, 95% CI: [1.05, 2.48]) and a lower probability of CD4 + T-cell normalization (adjusted HR: 0.64, 95%CI: [0.49, 0.84]). Cluster 4a displayed a higher prevalence of CXCR4 tropism, driven by amino acid combinations at key V3 loop positions. Clusters 4a and 4b showed distinct patterns of immune reconstitution after ART. Cluster 4a infection was associated with poorer immune reconstitution, potentially related to its higher prevalence of CXCR4 tropism. Given the expanding prevalence of cluster 4 among MSM, monitoring its genetic evolution and virulence is crucial. IMPORTANCE The differential impact of HIV-1 CRF01_AE clusters 4a and 4b on immune reconstitution after antiretroviral therapy (ART) remains unclear, particularly among men who have sex with men in China. Our study reveals that cluster 4a infection is associated with slower immune recovery and poorer clinical outcomes compared to cluster 4b, likely be related to its higher tendency for CXCR4 tropism. These findings highlight the need for vigilant monitoring of viral evolution and tailored management strategies for patients infected with distinct HIV-1 lineages.