Macrophage (M)-tropic strains of HIV-1 are the predominant strains replicating in vivo at the time of seroconversion and during the asymptomatic stages of HIV infection. In approximately 40% of HIV-infected individuals, T cell (T)-tropic HIV strains emerge as the predominant species during the course of HIV infection; this "shift" to T-tropic strain dominance is associated with rapid CD4+ T-cell decline and rapid disease progression. The purpose of this study was to investigate whether the ligands of the beta-chemokine receptor CCR5 (MIP-1- alpha, MIP-1-beta and RANTES), which block the entry/replication of macrophage (M)-tropic HIV strains in vitro by interfering with the ability of M-tropic HIV to utilize CCR5 as an entry co- receptor, influence the replication of T cell line (T)-tropic HIV strains. Treatment of CD4+ T cells from certain HIV- infected subjects with Beta-chemokines in vitro was found to enhance the emergence or replication of endogenous T-tropic HIV quasispecies. Furthermore, the infection efficiency of low inocula of T-tropic HIV in CD4+ T cells from uninfected donors in vitro was dramatically increased by treatment of cells with numerous beta-chemokines, including MCP-1, which is not a CCR5 ligand. RANTES was demonstrated to enhance the entry of T- tropic HIV strains into CD4+ T cells and this effect was dependent on Gi protein-coupled signal transduction; in contrast, its antagonist, amino-oxypentane (AOP)-RANTES, inhibited M-tropic entry but did not increase T-tropic HIV entry. Enhancement of T-tropic HIV entry by beta-chemokines was associated with increased colocalization of CD4 and the T-tropic coreceptor CXCR4, although this was not associated with elevated expression of CXCR4 on CD4+ T cells. These observations suggest that beta-chemokines may play a role in the shift from predominantly M-tropic to T-tropic HIV strain replication in vivo and that the administration of beta-chemokines to HIV- infected subjects for the purpose of limiting the replication and spread of HIV should be approached with caution as such treatment may result in the accelerated emergence of T-tropic HIV strains.
NIH ExPorter
NIH ExPorter