GENETICALLY DIVERGENT STRAINS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-2 USE MULTIPLE CORECEPTORS FOR VIRAL ENTRY

Several members of the seven-transmembrane chemokine receptor family h ave been shown to serve, with CD4, as coreceptors for entry by human i mmunodeficiency virus type 1 (HIV-1). While coreceptor usage by HIV-I primary isolates has been studied by several groups, there is only lim ited information available concerning coreceptor usage by primary HIV- 2 isolates. In this study, we have analyzed coreceptor usage of 15 pri mary HIV-2 isolates, using lymphocytes from a donor with nonfunctional CCR5 (CCR5 -/-; homozygous 32-bp deletion). Based on the infections o f PBMCs, seven of these primary isolates had an absolute requirement f or CCR5 expression, whereas the remaining eight exhibited a broader co receptor usage. All CCR5-requiring isolates were non-syncytium inducin g, whereas isolates utilizing multiple coreceptors were syncytium indu cing. Blocking experiments using known ligands for chemokine receptors provided indirect evidence for additional coreceptor utilization by p rimary HIV-2 isolates. Analysis of GHOST4 cell lines expressing variou s chemokine receptors (CCR1, CCR2b, CCR3, CCR4, CCR5, CXCR4, BONZO, an d BOB) further defined specific coreceptor usage of primary HIV-2 isol ates. The receptors used included CXCR4, CCR1-5, and the recently desc ribed receptors BONZO and BOB. However, the efficiency at which the co receptors were utilized varied greatly among the various isolates. Ana lysis of V3 envelope sequences revealed no specific motif that correla ted with coreceptor usage. Our data demonstrate that primary HIV-2 iso lates are capable of using a broad range of coreceptors for productive infection in vitro. Additionally, our data suggest that expanded core ceptor usage by HIV-2 may correlate with disease progression.