CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes

The capacity of human immunodeficiency virus (HIV) and simian immunodeficie ncy virus (SIV) envelopes to transduce signals through chemokine coreceptor s on macrophages was examined by measuring the ability of recombinant envel ope proteins to mobilize intracellular calcium stores. Both HIV and SIV env elopes mobilized calcium via interactions with CCR5. The kinetics of these responses were similar to those observed when macrophages were treated with MIP-1 beta. Distinct differences in the capacity of envelopes to mediate c alcium mobilization were observed. Envelopes derived from viruses capable o f replicating in macrophages mobilized relatively high levels of calcium, w hile envelopes derived from viruses incapable of replicating in macrophages mobilized relatively low levels of calcium. The failure to efficiently mob ilize calcium was not restricted to envelopes derived from CXCR4-utilizing isolates but also included envelopes derived from CCR5-utilizing isolates t hat fail to replicate in macrophages. We characterized one CCR5-utilizing i solate, 92MW959, which entered macrophages but failed to replicate. A recom binant envelope derived from this virus mobilized low levels of calcium. Wh en macrophages were inoculated with 92MW959 in the presence of MIP-1 alpha, viral replication was observed, indicating that a CC chemokine mediated si gnal provided the necessary stimulus td allow the virus to complete its rep lication cycle. Although the role that envelope-CCR5 signal transduction pl ays in viral replication is not yet understood, it has been suggested that envelope-mediated signals facilitate early postfusion events in viral repli cation. The data presented here are consistent with this hypothesis and sug gest that the differential capacity of viral envelopes to signal through CC R5 may influence their ability to replicate in macrophages.