Chemokine receptor-directed agents as novel anti-HIV-1 therapies.
Historically, therapeutic benefit in the treatment of human immunodeficiency virus infection (HIV-1) infection has been best achieved by targeting viral proteins like HIV protease involved in viral replication rather than host cell proteins, like CD4, which facilitate the process of viral infection. Two discoveries in 1996 presented a novel opportunity to redress this issue: 1) the understanding that heptahelical G-protein coupled chemokine receptors on the surface of T cells and macrophages functioned together with CD4 to mediate viral entry, and 2) the observation that CD4 positive T cells from individuals homozygous for the CCR5 delta 32 null allele were resistant to infection by macrophage-tropic strains of the virus in vitro and in vivo. Since that time, data demonstrating that selective blockade of two chemokine receptors, CCR5 and CXCR4, by small molecule chemokine receptor antagonists or receptor-directed biologics could robustly inhibit the infection of human peripheral blood mononuclear cells (PBMCs) by macrophage-tropic and T-cell line tropic strains respectively in vitro has validated this potential approach to therapy. Early clinical trial data now also confirms that these types of agents will have anti-viral activity in some HIV-1 infected individuals; however to date, dose limiting off-target activities have prohibited a full test of their potential clinical value. It also remains to be seen how these types of agents will fare in synergy with existing HIV-1 targeted antivirals, or those currently in development.
Mills
Sander G
SG
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. sandy_mills@merck.com
DeMartino
Julie A
JA
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5 / Q000031:analogs & derivatives; D018925:Chemokines / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019713:Receptors, CCR5 / Q000276:immunology / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D000906:Antibodies; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D018925:Chemokines; D006576:Heterocyclic Compounds, 4 or More Rings; D009842:Oligopeptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine