HIV TYPE-I ENVELOPE DETERMINANTS FOR USE OF THE CCR2B, CCR3, STRL33, AND APJ CORECEPTORS

The envelope (Env) proteins of primate lentiviruses interact sequentia lly with CD4 and a coreceptor to infect cells. Changes in coreceptor u se strongly influence viral tropism and pathogenesis. We followed the evolution of coreceptor use in pig-tailed macaques that developed seve re CD4 T-cell loss during the derivation of a pathogenic simian HIV (S HIV) that contained the tar, rev, vpu, and env genes of the HXBc2 stra in of HIV-1 in a genetic background of SIVmac239. The Env from the par ental virus as well as one derived from the first macaque to develop A IDS exclusively used CXCR4 as a coreceptor, indicating that CXCR4 can function as a coreceptor in macaques even though it is rarely used by simian immunodeficiency viruses, One Env (Pnb5), obtained from a macro phage-tropic virus isolated from the cerebral spinal fluid, did not us e CCR5 or CXCR4. Instead, it used CCR2b and to a lesser extent CCR3, S TRL33, and APJ to infect cells. Chimeras between Pnb5 and the parental X4 Env indicated that the V3 loop is the major determinant of CXCR4 u se, with other regions of Env influencing the efficiency with which th is coreceptor was used. Tn contrast, the Pnb5 V1/2 and V3 regions in c ombination were both necessary and sufficient to confer full use of CC R2b, CCR3, STRL33, and APJ to the parental X4 Env protein. These resul ts are consistent with a single, conserved binding site in Env that in teracts with multiple coreceptors in conjunction with the V1/2 and V3 loops, and suggest that the V1/2 region plays a more important role in governing the use of CCR2b, CCR3, STRL33, and APJ than for CXCR4.