Novel peptides based on HIV-1 gp120 sequence with homology to chemokines inhibit HIV infection in cell culture.
The sequential interaction of the envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) with CD4 and certain chemokine coreceptors initiates host cell entry of the virus. The appropriate chemokines have been shown to inhibit viral replication by blocking interaction of the gp120 envelope protein with the coreceptors. We considered the possibility that this interaction involves a motif of the gp120 that may be structurally homologous to the chemokines. In the amino acid sequences of most chemokines there is a Trp residue located at the beginning of the C-terminal α-helix, which is separated by six residues from the fourth Cys residue. The gp120 of all HIV-1 isolates have a similar motif, which includes the C-terminal part of a variable loop 3 (V3) and N-terminal part of a conserved region 3 (C3). Two synthetic peptides, derived from the relevant gp120 sequence inhibited HIV-1 replication in macrophages and T lymphocytes in sequence-dependent manner. The peptides also prevented binding of anti-CXCR4 antibodies to CXCR4, and inhibited the intracellular Ca(2+) influx in response to CXCL12/SDF-1α. Thus these peptides can be used to dissect gp120 interactions with chemokine receptors and could serve as leads for the design of new inhibitors of HIV-1.
Protein Chemistry Laboratory, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
Oleg
O
Chertov
Ning
N
Zhang
Xin
X
Chen
Joost J
JJ
Oppenheim
Jacek
J
Lubkowski
Connor
C
McGrath
Raymond C
RC
Sowder
Bruce J
BJ
Crise
Anatoli
A
Malyguine
Michele A
MA
Kutzler
Amber D
AD
Steele
Earl E
EE
Henderson
Thomas J
TJ
Rogers
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D008264:Macrophages / Q000821:virology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D018925:Chemokines; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D010455:Peptides; D019718:Receptors, CXCR4
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