Envelope glycoproteins from human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus can use human CCR5 as a coreceptor for viral entry and make direct CD4-dependent interactions with this chemokine receptor.
Several members of the chemokine receptor family have recently been identified as coreceptors, with CD4, for entry of human immunodeficiency virus type 1 (HIV-1) into target cells. In this report, we show that the envelope glycoproteins of several strains of HIV-2 and simian immunodeficiency virus (SIV) employ the same chemokine receptors for infection. Envelope glycoproteins from HIV-2 use CCR5 or CXCR4, while those from several strains of SIV use CCR5. Our data indicate also that some viral envelopes can use more than one coreceptor for entry and suggest that some of these coreceptors remain to be identified. To further understand how different envelope molecules use CCR5 as an entry cofactor, we show that soluble purified envelope glycoproteins (SU component) from CCR5-tropic HIV-1, HIV-2, and SIV can compete for binding of iodinated chemokine to CCR5. The competition is dependent on binding of the SU glycoprotein to cell surface CD4 and implies a direct interaction between envelope glycoproteins and CCR5. This interaction is specific since it is not observed with SU glycoprotein from a CXCR4-tropic virus or with a chemokine receptor that is not competent for viral entry (CCR1). For HIV-1, the interaction can be inhibited by antibodies specific for the V3 loop of SU. Soluble CD4 was found to potentiate binding of the HIV-2 ST and SIVmac239 envelope glycoproteins to CCR5, suggesting that a CD4-induced conformational change in SU is required for subsequent binding to CCR5. These data suggest a common fundamental mechanism by which structurally diverse HIV-1, HIV-2, and SIV envelope glycoproteins interact with CD4 and CCR5 to mediate viral entry.
Hill
C M
CM
Skirball Institute of BioMolecular Medicine, New York, New York 10016, USA.
Deng
H
H
Unutmaz
D
D
Kewalramani
V N
VN
Bastiani
L
L
Gorny
M K
MK
Zolla-Pazner
S
S
Littman
D R
DR
D016475:3T3 Cells; D000818:Animals; D000906:Antibodies / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism*; D002461:Cell Line, Transformed; D054407:Chemokine CCL4; D004331:Drosophila melanogaster; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology; D019713:Receptors, CCR5; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015704:CD4 Antigens; D054407:Chemokine CCL4; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D015728:Receptors, HIV; C078684:simian immunodeficiency virus gp130