Profound anti-HIV-1 activity of DAPTA in monocytes/macrophages and inhibition of CCR5-mediated apoptosis in neuronal cells.
Monocytes/macrophages (M/M) are strategic reservoirs of HIV-1, spreading the virus to other cells and inducing apoptosis in T-lymphocytes, astrocytes and neurons. M/M are commonly infected by R5 HIV-1 strains, which use the chemokine receptor CCR5. D-Ala-peptide T-amide (DAPTA), or Peptide T, named for its high threonine content (ASTTTNYT), is a synthetic peptide comprised of eight amino acids (185-192) of the gp120 V2 region and functions as a viral entry inhibitor by targeting selectively CCR5. The anti-HIV-1 activity of DAPTA was evaluated in M/M infected with R5 HIV-1 strains. DAPTA at 10(-9) M inhibited HIV-1 replication in M/M by > 90%. PCR analysis of viral cDNA in M/M showed that DAPTA blocks HIV entry and in this way prevents HIV-1 infection. Moreover, DAPTA acts as a strong inhibitor and was more active than the non-peptidic CCR5 antagonist TAK-779 in inhibiting apoptosis (mediated by RS HIV-1 strains produced and released by infected M/M) on a neuroblastoma cell line. Our results suggest that antiviral compounds which interfere with receptor mechanisms such as CCR5 could be important, either alone or in combination with other antiretroviral treatments, in preventing HIV infection in the central nervous system and the consequential neuronal damage that leads to neuronal AIDS.
Department of Experimental Medicine and Biochemical Science, University of Rome Tor Vergata, Rome, Italy.
Michela
M
Pollicita
Michael R
MR
Ruff
Candace B
CB
Pert
Maria T
MT
Polianova
Dominique
D
Schols
Alessandro
A
Ranazzi
Carlo-Federico
CF
Perno
Stefano
S
Aquaro
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000187:drug effects / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D004279:DNA, Viral / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects* / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology / Q000821:virology; D015717:Peptide T / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000502:physiology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D004279:DNA, Viral; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1; D015717:Peptide T