The CCR5 and CXCR4 coreceptors are both used by human immunodeficiency virus type 1 primary isolates from subtype C

Abstract

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses with different coreceptor usage profiles were isolated from 29 South African patients with advanced AIDS. All 24 R5 isolates were inhibited by the CCR5-specific agents, PRO 140 and RANTES, while the two X4 viruses and the three R5X4 viruses were sensitive to the CXCR4-specific inhibitor, AMD3100. The five X4 or R5X4 viruses were all able to replicate in peripheral blood mononuclear cells that did not express CCR5. When tested using coreceptor-transfected cell lines, one R5 virus was also able to use CXCR6, and another R5X4 virus could use CCR3, BOB/GPR15, and CXCR6. The R5X4 and X4 viruses contained more-diverse V3 loop sequences, with a higher overall positive charge, than the R5 viruses. Hence, some HIV-1 subtype C viruses are able to use CCR5, CXCR4, or both CXCR4 and CCR5 for entry, and they are sensitive to specific inhibitors of entry via these coreceptors. These observations are relevant to understanding the rapid spread of HIV-1 subtype C in the developing world and to the design of intervention and treatment strategies.

FIG. 1.

Predicted V3 amino acid sequence of 16 South African HIV-1 subtype C isolates (12 R5 isolates and 5 R5X4 or X4 isolates) compared to an HIV-1 subtype C consensus sequence. The overall positive charge, number of amino acids, and biotype of each isolate are shown on the right. Dashes indicate concurrence, and a period indicates a deletion or lack of an insertion. Changed amino acids are indicated. Positions 11 and 25 (associated with changes in biological phenotype), the tip of the V3 loop, and the region with insertions are highlighted in grey.