Differential coreceptor expression allows for independent evolution of non–syncytium-inducing and syncytium-inducing HIV-1

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Abstract
We demonstrated previously that CD45RA+ CD4+ T cells are infected primarily by syncytium-inducing (SI) HIV-1 variants, whereas CD45RO+ CD4+ T cells harbor both non-SI (NSI) and SI HIV-1 variants. Here, we studied evolution of tropism for CD45RA+ and CD45RO+ CD4+ cells, coreceptor usage, and molecular phylogeny of coexisting NSI and SI HIV-1 clones that were isolated from four patients in the period spanning SI conversion. NSI variants were CCR5-restricted and could be isolated throughout infection from CD45RO+ CD4+ cells. SI variants seemed to evolve in CD45RO+ CD4+ cells, but, in time, SI HIV-1 infection of CD45RA+ CD4+ cells equaled infection of CD45RO+ CD4+ cells. In parallel with this shift, SI HIV-1 variants first used both coreceptors CCR5 and CXCR4, but eventually lost the ability to use CCR5. Phylogenetically, NSI and SI HIV-1 populations diverged over time. We observed a differential expression of HIV-1 coreceptors within CD45RA+ and CD45RO+ cells, which allowed us to isolate virus from purified CCR5+ CXCR4– and CCR5– CXCR4+ CD4+ cells. The CCR5+ subset was exclusively infected by CCR5-dependent HIV-1 clones, whereas SI clones were preferentially isolated from the CXCR4+ subset. The differential expression of HIV-1 coreceptors provides distinct cellular niches for NSI and SI HIV-1, contributing to their coexistence and independent evolutionary pathways.