Rapid CD4 cell loss is caused by specific CRF01_AE cluster with V3 signatures favoring CXCR4 usage

Abstract

1HIV-1 evolved into various genetic subtypes and circulating recombinant forms (CRFs) 3 2 in the global epidemic, with the same subtype or CRF usually having similar phenotype. 3Being one of the world's major CRFs, CRF01_AE infection was reported to associate 3 4 with higher prevalence of CXCR4 (X4) viruses and faster CD4 decline. However, the 3 5 underlying mechanisms remain unclear. We identified eight phylogenetic clusters of 3 6 CRF01_AE in China and hypothesized that they may have different phenotypes. In the 3 7 national HIV molecular epidemiology survey, we discovered that people infected by 3 8 CRF01_AE cluster 4 had significantly lower CD4 count (391 vs. 470, p < 0.0001) and 3 9higher prevalence of predicted X4-using viruses (17.1% vs. 4.4%, p < 0.0001) 4 0 compared to those infected by cluster 5. In a MSM cohort, X4-using viruses were only 4 1 isolated from sero-convertors infected by cluster 4, which associated with rapid CD4 4 2 loss within the first year of infection (141 vs. 440, p = 0.01). Using co-receptor binding 4 3 model, we identified unique V3 signatures in cluster 4 that favor CXCR4 usage. We 4 4