Coreceptor usage and RANTES sensitivity of non-syncytium-inducing HIV-1 isolates obtained from patients with AIDS

Objectives: The biologic phenotype of HTV-1 primary isolates obtained from -50% of patients who progress to AIDS switches from non-syncytium-inducing (NSI) to syncytium-inducing (SI). We evaluated possible associations betwee n virus coreceptor usage, sensitivity to inhibition by beta-chemokines, and disease progression of patients who continue to yield NSI isolates after d eveloping AIDS. Study Design/Methods: Sequential virus isolates were analyzed for biologic phenotype using the MT-2 cell assay, for sensitivity to beta-chemokines usi ng RANTES inhibition, and for coreceptor usage using U87.CD4 and GHOST.CD4 cells expressing different chemokine/orphan receptors or donor peripheral b lood mononuclear cells (PBMC) defective in CCR5 expression. In addition, th e env V3 region was sequenced and the length of the V2 region determined. Results: All NSI isolates, regardless of patient status at time of isolatio n, were dependent on CCR5 expression for cell entry. Furthermore, there was no indication of broadened coreceptor usage of NSI isolates obtained from persons with late-stage AIDS. A majority of NSI isolates remained RANTES se nsitive; however, virus variants with reduced sensitivity were observed. Th e V2 lengths and the V3 sequences exhibited no or minor changes at analysis of sequential NSI isolates. Conclusions: Our data suggest that NSI isolates obtained from AIDS patients remain CCR5 dependent (ie, R5) and, in many cases, also remain sensitive t o RANTES inhibition. However, virus variants with decreased sensitivity to RANTES inhibition may evolve during disease progression, not only as a resu lt of a switch from NSI to SI but also in patients who develop AIDS while c ontinuing to maintain R5 isolates. GenBank Accession Numbers: AF199032-AF19 9043.