Increase of R5 HIV-1 infection and CCR5 expression in T cells treated with high concentrations of CXCR4 antagonists and SDF-1.

Abstract

The chemokine receptors CXCR4 and CCR5 are considered to be potential targets for the inhibition of HIV-1 replication. We found that the synthetic peptides T134 and T140 (see text for full names) inhibited X4 HIV-1 infection with selectivity and low toxicity because they acted as CXCR4 antagonists. However, high concentrations of T134, T140, and ALX40-4C (see text for full name) increased the expression of CCR5 and R5 HIV-1 infection, as did stromal cell-derived factor 1 (SDF-1). In contrast to CXCR4 antagonists and SDF-1, viral monocyte inflammatory protein (vMIP) II inhibited not only anti-CXCR4 monoclonal antibody (MAb) but also inhibited anti-CCR5 MAb binding to human peripheral blood mononuclear cells, and inhibited both X4 and R5 HIV-1 strains. T134, T140, ALX40-4C, and SDF-1 increased viral transcription in the treated cells. In addition, ALX40-4C and SDF-1 also increased nuclear transcription factor (NF)-kappaB. However, the mechanisms of action of T134 and T140 are different from those of clinically used anti-HIV drugs. Thus, synergistic activities were observed in the concomitant treatment with T134 and reverse transcriptase inhibitors or protease inhibitors. Our findings, presented here, are noteworthy in regard to the potential clinical use of these agents as drugs for the treatment of AIDS.

• Authors: K Gotoh, M Yoshimori, K Kanbara, H Tamamura, T Kanamoto, K Mochizuki, N Fujii, H Nakashima
• Journal: Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy (J Infect Chemother) Vol. 7 Issue 1 Pg. 28-36 (Mar 2001) ISSN: 1341-321X [Print] Netherlands
• PMID: 11406754 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antibodies, Monoclonal
• Benzylamines
• CD4 Antigens
• CXCL12 protein, human
• Chemokine CXCL12
• Chemokines
• Chemokines, CXC
• Cyclams
• Heterocyclic Compounds
• N-alpha-acetyl-nona-D-arginine amide acetate
• Oligopeptides
• Peptide Fragments
• Receptors, CCR5
• Receptors, CXCR4
• T134 peptide
• methionine stromal cell-derived factor-1beta
• vMIP-II
• Zidovudine
• Methionine
• T140 peptide
• plerixafor

Topics

• Animals
• Anti-HIV Agents (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Benzylamines
• CD4 Antigens (biosynthesis, genetics)
• CD4-Positive T-Lymphocytes (drug effects, metabolism, virology)
• COS Cells
• Chemokine CXCL12
• Chemokines (pharmacology)
• Chemokines, CXC (pharmacology)
• Chlorocebus aethiops
• Cyclams
• Drug Synergism
• Gene Expression Regulation (drug effects)
• HIV Long Terminal Repeat
• HIV-1 (physiology)
• Heterocyclic Compounds (pharmacology)
• Humans
• Methionine (analogs & derivatives, pharmacology)
• Oligopeptides (pharmacology)
• Peptide Fragments (pharmacology)
• Receptors, CCR5 (biosynthesis, genetics)
• Receptors, CXCR4 (antagonists & inhibitors)
• Transfection
• Tumor Cells, Cultured (drug effects, metabolism, virology)
• Virus Replication (drug effects)
• Zidovudine (pharmacology)