Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat

Silvia Ghezzi, Douglas M. Noonan, Maria Grazia Aluigi, Giuliana Vallanti, Manuela Cota, Roberto Benelli, Monica Morini, Jacqueline D. Reeves, Elisa Vicenzi, Guido Poli, Adriana Albini

Research output: Contribution to journalArticle

Abstract

Certain chemokines inhibit HIV replication through binding to cell surface receptors which also act as viral coreceptors. Based on our previous observations that HIV-1 Tat can interact with α- and β-chemokine receptors, we investigated the potential effect of extracellular Tat (ecTat) on infection and replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 strains in primary activated peripheral blood mononuclear cells (PBMC) of uninfected donors. Receptor desensitization and binding competition studies were used to determine chemokine receptor binding by ecTat. Standard HIV replication assays based on reverse transcriptase (RT) activity determination in culture supernatants of PBMC and real time PCR for HIV-1 gag DNA were used to determine potential effects on early (entry or RT) steps of infection. ecTat bound to CXCR4 expressing monocytes and mitogen-activated PBMC, and competed with the natural ligand of CXCR4, SDF-1α (stromal cell-derived factor-1α) in calcium mobilization assays. EcTat inhibited replication of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at concentrations close to those of SDF-1α, whereas it only modestly interfered with R5 HIV-1 (BaL) replication in PBMC. Both SDF-1α and ecTat inhibited accumulation of X4 HIV-1 gag DNA, indicating interference with viral entry and/or RT. Our data show the surprising and counter-intuitive observation that ecTat selectively represses X4 HIV replication. This could favour spreading of R5 viruses, a condition observed in vivo immediately after transmission and in the early asymptomatic phase of infection. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)992-996
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume270
Issue number3
DOIs
Publication statusPublished - Apr 21 2000

Fingerprint

HIV Infections
HIV-1
Blood
Chemokine CXCL12
Blood Cells
RNA-Directed DNA Polymerase
Chemokine Receptors
HIV
Assays
Viral Interference
DNA
Cell Surface Receptors
Asymptomatic Infections
Viruses
Mitogens
Chemokines
Infection
Real-Time Polymerase Chain Reaction
Monocytes
Ligands

Keywords

  • Acute infection
  • Chemokines
  • CXCR4
  • Entry
  • HIV-1
  • HIV-1 Tat protein
  • Infection
  • Pathogenesis
  • Tat
  • Virus-cell interactions

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat. / Ghezzi, Silvia; Noonan, Douglas M.; Aluigi, Maria Grazia; Vallanti, Giuliana; Cota, Manuela; Benelli, Roberto; Morini, Monica; Reeves, Jacqueline D.; Vicenzi, Elisa; Poli, Guido; Albini, Adriana.

In: Biochemical and Biophysical Research Communications, Vol. 270, No. 3, 21.04.2000, p. 992-996.

Research output: Contribution to journalArticle

Ghezzi, Silvia ; Noonan, Douglas M. ; Aluigi, Maria Grazia ; Vallanti, Giuliana ; Cota, Manuela ; Benelli, Roberto ; Morini, Monica ; Reeves, Jacqueline D. ; Vicenzi, Elisa ; Poli, Guido ; Albini, Adriana. / Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat. In: Biochemical and Biophysical Research Communications. 2000 ; Vol. 270, No. 3. pp. 992-996.
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AB - Certain chemokines inhibit HIV replication through binding to cell surface receptors which also act as viral coreceptors. Based on our previous observations that HIV-1 Tat can interact with α- and β-chemokine receptors, we investigated the potential effect of extracellular Tat (ecTat) on infection and replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 strains in primary activated peripheral blood mononuclear cells (PBMC) of uninfected donors. Receptor desensitization and binding competition studies were used to determine chemokine receptor binding by ecTat. Standard HIV replication assays based on reverse transcriptase (RT) activity determination in culture supernatants of PBMC and real time PCR for HIV-1 gag DNA were used to determine potential effects on early (entry or RT) steps of infection. ecTat bound to CXCR4 expressing monocytes and mitogen-activated PBMC, and competed with the natural ligand of CXCR4, SDF-1α (stromal cell-derived factor-1α) in calcium mobilization assays. EcTat inhibited replication of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at concentrations close to those of SDF-1α, whereas it only modestly interfered with R5 HIV-1 (BaL) replication in PBMC. Both SDF-1α and ecTat inhibited accumulation of X4 HIV-1 gag DNA, indicating interference with viral entry and/or RT. Our data show the surprising and counter-intuitive observation that ecTat selectively represses X4 HIV replication. This could favour spreading of R5 viruses, a condition observed in vivo immediately after transmission and in the early asymptomatic phase of infection. (C) 2000 Academic Press.

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