T-tropic human immunodeficiency virus type 1 (HIV-1)-derived V3 loop peptides directly bind to CXCR-4 and inhibit T-tropic HIV-1 infection.
Certain types of chemokine receptors have been identified as coreceptors for HIV-1 infection. The process of viral entry is initiated by the interaction between an envelope protein gp120 of HIV-1, CD4, and one of the relevant coreceptors. To understand the precise mechanism of the Env-mediated fusion and entry of HIV-1, we examined whether the V3 region of gp120 of T-cell line tropic (T-tropic) virus directly interacts with the coreceptor, CXCR-4, by using five synthetic V3 peptides: two cyclized V3 peptides (V3-BH10 and V3-ELI) which correspond to the V3 regions of the T-tropic HIV-1 IIIB and HIV-1 ELI strains, respectively, a linear V3 peptide (CTR36) corresponding to that of HIV-1 IIIB strain; and cyclized V3 peptides corresponding to that of the macrophage-tropic (M-tropic) HIV-1 ADA strain (V3-ADA) or the dualtropic HIV-1 89.6 strain (V3-89. 6). FACScan analysis with a CXCR-4(+) human B-cell line, JY, showed that V3-BH10, V3-ELI, and V3-89.6 but not CTR36 or V3-ADA blocked the binding of IVR7, an anti-CXCR-4 monoclonal antibody (MAb), to CXCR-4 with different magnitudes in a dose-dependent manner, while none of the V3 peptides influenced binding of an anti-CD19 MAb at all. Next, the effects of the V3 peptides on SDF-1beta-induced transient increases in intracellular Ca2+ were investigated. Three V3 peptides (V3-BH10, V3-ELI, and V3-89.6) prevented Ca2+ mobilization. Furthermore, the three peptides inhibited infection by T-tropic HIV-1 in a dose-dependent manner as revealed by an MTT assay and a reverse transcriptase assay, while the other peptides had no effects. These results present direct evidence that the V3 loop of gp120 of T-tropic HIV-1 can interact with its coreceptor CXCR-4 independently of the V1/V2 regions of gp120 or cellular CD4.
Sakaida
H
H
Laboratory of Virus Immunology, Research Center for Acquired Immunodeficiency Syndrome, Institute for Virus Research, Kyoto University, Kyoto 606, Japan.
Hori
T
T
Yonezawa
A
A
Sato
A
A
Isaka
Y
Y
Yoshie
O
O
Hattori
T
T
Uchiyama
T
T
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D015658:HIV Infections / Q000209:etiology / Q000517:prevention & control* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013601:T-Lymphocytes / Q000821:virology*
D000911:Antibodies, Monoclonal; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019718:Receptors, CXCR4; D054303:HIV Reverse Transcriptase; D002118:Calcium