EXCLUSIVE AND PERSISTENT USE OF THE ENTRY CORECEPTOR CXCR4 BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 FROM A SUBJECT HOMOZYGOUS FOR CCR5 DELTA-32

Individuals who are homozygous for the 32-bp deletion in the gene codi ng for the chemokine receptor and major human immunodeficiency virus t ype 1 (HIV-1) coreceptor CCR5 (CCR5 -/-) lack functional cell surface CCR5 molecules and are relatively resistant to HIV-1 infection. HIV-1 infection in CCR5 -/- individuals, although rare, has been increasingl y documented. We now report that the viral quasispecies from one such individual throughout disease is homogenous, T cell line tropic, and p henotypically syncytium inducing (SI); exclusively uses CXCR4; and rep licates well in CCR5 -/- primary T cells. The recently discovered core ceptors BOB and Bonzo are not used. Although early and persistent SI v ariants have been described in longitudinal studies, this is the first demonstration of exclusive and persistent CXCR4 usage. With the cavea t that the earliest viruses available from this subject were from appr oximately 4 years following primary infection, these data suggest that HIV-1 infection can be mediated and persistently maintained by viruse s which exclusively utilize CXCR4. The lack of evolution toward the av ailable minor coreceptors in this subject underscores the dominant bio logical roles of the major coreceptors CCR5 and CXCR4. This and two si milar subjects (R. Biti, R. Ffrench, J. Young, B. Bennetts, G. Stewart , and T. Liang, Nat. Med. 3:252-253, 1997; I. Theodoreu, L. Meyer, M. Magierowska, C. Katlama, and C. Rouzioux, Lancet 349:1219-1220, 1997) showed relatively rapid CD4(+) T-cell declines despite average or low initial viral RNA load. Since viruses which use CXCR4 exclusively cann ot infect macrophages, these data have implications for the relative i nfection of the T cell compartment versus the macrophage compartment i n vivo and for the development of CCR5-based therapeutics.