Basic amino acid residues in the V3 loop of simian immunodeficiency virus envelope alter viral coreceptor tropism and infectivity but do not allow efficient utilization of CXCR4 as entry cofactor

In contrast to human immunodeficiency viruses type 1 and type 2 (HIV-1 and HIV-2, respectively), simian immunodeficiency virus (SIVmac) rarely uses CX CR4 () for efficient entry into target cells. Basic amino acid residues in the V3 loop of HIV Env allow efficient coreceptor utilization of X4. Theref ore, we investigated if similar changes in the SIVmac Env protein also medi ate a coreceptor switch from CCR5 (R5) to X4. Functional analysis revealed that none of eight SIVmac variants, containing V3 regions with an overall c harge between +4 and +10, efficiently utilized X4 as entry cofactor Nonethe less, these alterations had differential effects on SIV coreceptor tropism and on Env expression levels. A single amino acid substitution of L328R, lo cated near the tip of the V3 loop, resulted in grossly reduced Env expressi on levels and impaired viral infectivity. Notably, additional basic residue s restored efficient Env expression and virion incorporation but not infect ivity In comparison to the L328R mutation, changes of P334K and D337K had l ittle disruptive effects on SIVmac entry and replication. Interestingly, mu tation of L320K and P321R disrupted coreceptor usage of GPR15 but not R5. T hese changes also impaired SIVmac replication in peripheral blood mononucle ar cells (PBMC) derived from a Delta 32/Delta 32 donor but not in R5-expres sing human or simian PBMC. Our results show that positively charged amino a cid residues in the V3 loop affect SIVmac coreceptor tropism and infectivit y but do not allow efficient utilization of X4. (C) 2001 Academic Press.