Viral entry through CXCR4 is a pathogenic factor and therapeutic target inhuman immunodeficiency virus type 1 disease

The chemokine receptors CCR5 and CXCR4 function as the principal coreceptor s for human immunodeficiency virus type 1 (HIV-1). Coreceptor function has also been demonstrated for a variety of related receptors in vitro. The rel ative contributions of CCR5, CXCR4, and other putative coreceptors to HIV-1 disease in vivo have yet to be defined. In this study, we used sequential primary isolates and recombinant strains of HIV-1 to demonstrate that CXCR4 -using (X4) viruses emerging in association with disease progression are hi ghly pathogenic in ex vivo lymphoid tissues compared to CXCR4-independent v iruses. Furthermore, synthetic receptor antagonists that specifically block CXCR4-mediated entry dramatically suppressed the depletion of CD4(+) T cel ls by recombinant and clinically derived X4 HIV-1 isolates. Moreover, in vi tro specificity for the additional coreceptors CCR3, CCR8, BOB, and Bonzo d id not augment cytopathicity or diminish sensitivity toward CXCR4 antagonis ts in lymphoid tissues. These data provide strong evidence to support the c oncept that adaptation to CXCR4 specificity in vivo accelerates HIV-1 disea se progression. Thus, therapeutic intervention targeting the interaction of HIV-1 gp120 with CXCR4 may be highly valuable for suppressing the pathogen ic effects of late-stage viruses.