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

We demonstrated previously that CD45 RA(+) CD4(+) T cells are infected prim arily 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 evo lution of tropism for CD45RA(+) and CD45RO(+) CD4(+) cells, coreceptor usag e, and molecular phylogeny of coexisting NSI and SI HIV-1 clones that were isolated from four patients in the period spanning SI conversion. NSI varia nts were CCR5-restricted and could be isolated throughout infection from CD 45RO(+) CD4(+) cells. SI variants seemed to evolve in CD45RO(+) CD4(+) cell s, but, in time, SI HIV-1 infection of CD45RA(+) CD4(+) cells equaled infec tion of CD45RO(+) CD4(+) cells. In parallel with this shift, SI HIV-1 varia nts first used both coreceptors CCR5 and CXCR4, but eventually lost the abi lity to use CCR5. Phylogenetically, NSI and SI HIV-1 populations diverged o ver time. We observed a differential expression of HIV-1 coreceptors within CD45RA(+) and CD45RO(+) cells, which allowed us to isolate virus from puri fied 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 ex pression of HIV-1 coreceptors provides distinct cellular niches for NSI and SI HIV-1, contributing to their coexistence and independent evolutionary p athways.