The binding subunit of pertussis toxin inhibits HIV replication in human macrophages and virus expression in chronically infected promonocytic U1 cells.
We have recently shown that the binding subunit of pertussis toxin (PTX-B) inhibits the entry and replication of macrophage-tropic (R5) HIV-1 strains in activated primary T lymphocytes. Furthermore, PTX-B suppressed the replication of T cell-tropic (X4) viruses at a postentry level in the same cells. In this study we demonstrate that PTX-B profoundly impairs entry and replication of the HIV-1(ADA) (R5), as well as of HIV pseudotyped with either murine leukemia virus or vesicular stomatitis virus envelopes, in primary monocyte-derived macrophages. In addition, PTX-B strongly inhibited X4 HIV-1 replication in U937 promonocytic cells and virus expression in the U937-derived chronically infected U1 cell line stimulated with cytokines such as TNF-alpha and IL-6. Of interest, TNF-alpha-mediated activation of the cellular transcription factor NF-kappaB was unaffected by PTX-B. Therefore, PTX-B may represent a novel and potent inhibitor of HIV-1 replication to be tested for efficacy in infected individuals. In support of this proposition, a genetically modified mutant of PTX (PT-9K/129G), which is safely administered for prevention of Bordetella pertussis infection, showed an in vitro anti-HIV profile superimposable to that of PTX-B.
Alfano
M
M
AIDS Immunopathogenesis Unit, Department of Biology and Technology, and Laboratory of Clinical Immunology, Division of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. massimo.alfano@hsr.it
Vallanti
G
G
Biswas
P
P
Bovolenta
C
C
Vicenzi
E
E
Mantelli
B
B
Pushkarsky
T
T
Rappuoli
R
R
Lazzarin
A
A
Bukrinsky
M
M
Poli
G
G
D000998:Antiviral Agents / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D017930:Genes, Reporter / Q000276:immunology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000821:virology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009052:Leukemia Virus, Murine / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000276:immunology* / Q000821:virology; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020298:U937 Cells; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics; D010566:Virulence Factors, Bordetella / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
D000998:Antiviral Agents; C028391:G protein, vesicular stomatitis virus; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; D010566:Virulence Factors, Bordetella; D008156:Luciferases; D037342:Pertussis Toxin