Disparate impact on CD4 T cell count by two distinct HIV-1 phylogenetic clusters from the same clade

HIV-1 evolved into various genetic subtypes and circulating recombinant forms (CRFs) in the global epidemic. The same subtype or CRF is usually considered to have similar phenotype. Being one of the world's major CRFs, CRF01_AE infection was reported to associate with higher prevalence of CXCR4 (X4) viruses and faster CD4 decline. However, the underlying mechanisms remain unclear. We identified eight phylogenetic clusters of CRF01_AE in China and hypothesized that they may have different phenotypes. In the National HIV Molecular Epidemiology Survey, we discovered that people infected by CRF01_AE cluster 4 had significantly lower CD4 counts (391 vs. 470, P < 0.0001) and higher prevalence of X4-using viruses (17.1% vs. 4.4%, P < 0.0001) compared with those infected by cluster 5. In an MSM cohort, X4-using viruses were only isolated from seroconvertors in cluster 4, which was associated with low a CD4 count within the first year of infection (141 vs. 440, P = 0.003). Using a coreceptor binding model, we identified unique V3 signatures in cluster 4 that favor CXCR4 use. We demonstrate that the HIV-1 phenotype and pathogenicity can be determined at the phylogenetic cluster level in the same subtype. Since its initial spread to humans from chimpanzees, estimated to be the first half of the 20th century, HIV-1 continues to undergo rapid evolution in larger and more diverse populations. The divergent phenotype evolution of two major CRF01_AE clusters highlights the importance of monitoring the genetic evolution and phenotypic shift of HIV-1 to provide early warning of the appearance of more pathogenic strains.