Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5).
Peptide T, which is derived from the V2 region of HIV-1, inhibits replication of R5 and dual-tropic (R5/X4) HIV-1 strains in monocyte-derived macrophages (MDMs), microglia, and primary CD4(+)T cells. Little to no inhibition by peptide T was observed with lab adapted X4 viruses such as IIIB, MN, or NL4-3 propagated in CD4(+) T cells or in the MAGI entry assay. The more clinically relevant R5/X4 early passage patient isolates were inhibited via either the X4 or R5 chemokine receptors, although inhibition was greater with R5 compared to X4 receptors. Virus inhibition ranged from 60 to 99%, depending on the assay, receptor target, viral isolate and amount of added virus. Peak inhibitory effects were detected at concentrations from 10(-12) to 10(-9) M. Peptide T acted to block viral entry as it inhibited in the MAGI cell assay and blocked infection in the luciferase reporter assay using HIV virions pseudotyped with ADA envelope. These results using early passage virus grown in primary cells, together with two different entry reporter assays, show that peptide T selectively inhibits HIV replication using chemokine receptor CCR5 compared to CXC4, explaining past inconsistencies of in vitro antiviral effects.
Ruff
M R
MR
Department of Physiology and Biophysics, Basic Science Building, Room 215, Georgetown University School of Medicine, 3900 Reservoir Road, NW, Washington, DC 20007, USA. ruffm@georgetown.edu
Melendez-Guerrero
L M
LM
Yang
Q E
QE
Ho
W Z
WZ
Mikovits
J W
JW
Pert
C B
CB
Ruscetti
F A
FA
D000911:Antibodies, Monoclonal / Q000276:immunology; D000998:Antiviral Agents / Q000378:metabolism; D001681:Biological Assay; D002478:Cells, Cultured; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005333:Fetus; D005434:Flow Cytometry; D017930:Genes, Reporter; D016655:HIV Core Protein p24 / Q000276:immunology; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D017628:Microglia / Q000166:cytology / Q000378:metabolism / Q000821:virology; D015717:Peptide T / Q000276:immunology / Q000502:physiology*; D019713:Receptors, CCR5 / Q000502:physiology*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D018925:Chemokines; D016655:HIV Core Protein p24; D019713:Receptors, CCR5; D015717:Peptide T; D008156:Luciferases