CORECEPTOR USAGE OF PRIMARY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES VARIES ACCORDING TO BIOLOGICAL PHENOTYPE

The biological phenotype of primary human immunodeficiency-virus type 1 (HIV-1) isolates varies according to the severity of the HIV infecti on, Here H-e show that the two previously described groups of rapid/hi gh, syncytium-inducing (SI) and slow/flow, non-syncytium-inducing (NSI ) isolates are distinguished by their ability to utilize different che mokine receptors for entry into target cells. Recent studies hare iden tified the C-X-C chemokine receptor CSCR4 (also named fusin or Lestr) and the C-C chemokine receptor CCR5 as the principal entry cofactors f or T-cell-line tropic and non-T-cell line-tropic HIV-1, respectively, Using U87.CD4 glioma cell lines, stably expressing the chemokine recep tor CCR1, CCR2b, CCR3, CCR5, or CXCR4, we have tested chemokine recept or specificity for a panel of genetically diverse envelope glycoprotei n genes cloned from primary HIV-1 isolates and have found that recepto r usage was closely associated with the biological phenotype of the vi rus isolate but not the genetic subtype, We have also analyzed a panel of 36 well-characterized primary HIV-1 isolates for syncytium inducti on and replication in the same series of cell lines, Infection by slow /low viruses was restricted to cells expressing CCR5, whereas rapid/hi gh viruses could use a variety of chemokine receptors, In addition to the regular use of CXCR4, many rapid/high viruses used CCR5 and some a lso used CCR3 and CCR2b, Progressive HIV-1 infection is characterized by the emergence of viruses resistant to inhibition by beta-chemokines , which corresponded to changes in coreceptor usage, The broadening of the host range may even enable the use of uncharacterized coreceptors . in that two isolates from immunodeficient patients infected the pare ntal U87.CD4 cell line larking any engineered coreceptor, Tyro primary isolates with multiple coreceptor usage were shown to consist of mixe d populations, one with a narrow host range using CCR5 only and the ot her with a broad host range using CCR3, CCR5, or CXCR4, similar to the original population, The results show that all 36 primary HIV-1 isola tes induce syncytia, provided that target cells carry the particular c oreceptor required by the virus.