The V3 domain of the HIV-1 gp120 envelope glycoprotein is critical for chemokine-mediated blockade of infection.
The ability of CD8 T cells derived from human immunodeficiency virus (HIV)-infected patients to produce soluble HIV-suppressive factor(s) (HIV-SF) has been suggested as an important mechanism of control of HIV infection in vivo. The C-C chemokines RANTES, MIP-1 alpha and MIP-1 beta were recently identified as the major components of the HIV-SF produced by both immortalized and primary patient CD8 T cells. Whereas they potently inhibit infection by primary and macrophage-tropic HIV-1 isolates, T-cell line-adapted viral strains tend to be insensitive to their suppressive effects. Consistent with this discrepancy, two distinct chemokine receptors, namely, CXCR4 (ref. 7) and CCR5 (ref. 8), were recently identified as potential co-receptors for T-cell line-adapted and macrophage-tropic HIV-1 isolates, respectively. Here, we demonstrate that the third hypervariable domain of the gp 120 envelope glycoprotein is a critical determinant of the susceptibility of HIV-1 to chemokines. Moreover, we show that RANTES, MIP-1 alpha and MIP-1 beta block the entry of HIV-1 into cells and that their antiviral activity is independent of pertussis toxin-sensitive signal transduction pathways mediated by chemokine receptors. The ability of the chemokines to block the early steps of HIV infection could be exploited to develop novel therapeutic approaches for AIDS.
Institute of Human Virology, University of Maryland Biotechnology Institute & School of Medicine, Baltimore, Maryland 21201, USA.
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D000595:Amino Acid Sequence; D002460:Cell Line; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D016655:HIV Core Protein p24 / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D037342:Pertussis Toxin; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D004279:DNA, Viral; D016655:HIV Core Protein p24; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin