Linked Life Data

12621451

Source:http://linkedlifedata.com/resource/pubmed/id/12621451

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2003-3-6
pubmed:abstractText
The central role of endoconvertases and HIV-1 protease (HIV-1 PR) in the processing of HIV proproteins makes the design of specific inhibitors important in anti-HIV gene therapy. Accordingly, we tested native alpha(1) antitrypsin (alpha(1)AT) delivered by a recombinant simian virus-40-based vector, SV(AT), as an inhibitor of HIV-1 proprotein maturation. Cell lines and primary human lymphocytes were transduced with SV(AT) without selection and detectable toxicity. Expression of alpha(1)AT was confirmed by Northern blotting, immunoprecipitation and immunostaining. SV(AT)-transduced cells showed no evidence of HIV-1-related cytopathic effects when challenged with high doses of HIV-1(NL4-3). As measured by HIV-1 p24 assay, SV(AT)-transduced cells were protected from HIV-1(NL4-3) at challenge dose of 40 000 TCID(50) (MOI = 0.04). In addition, peripheral blood lymphocytes treated with SV(AT) were protected from HIV doses challenge up to 40 000 TCID(50) (MOI = 0.04). By Western blot analyses, the delivered alpha(1)AT inhibited cellular processing of gp160 to gp120 and decreased HIV-1 virion gp120. SV(AT) inhibited processing of p55(Gag) as well. Furthermore, high levels of uncleaved p55(Gag) protein were detected in HIV virus particles recovered from SV(AT)-transduced cells lines and primary lymphocytes. Thus, delivering alpha(1)AT using SV(AT) to human lymphocytes strongly inhibits replication of HIV-1, most likely by inhibiting the activities both of the cellular serine proteases involved in processing gp160 and of the aspartyl protease, HIV-1 PR, which cleaves p55(Gag). alpha(1)AT delivered by SV(AT) may represent a novel and effective strategy for gene therapy to interfere with HIV replication, by blocking a stage in the virus replicative cycle that has until now been inaccessible to gene therapeutic intervention.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0969-7128
pubmed:author
pubmed:issnType
Print
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
467-77
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:12621451-Animals, pubmed-meshheading:12621451-COS Cells, pubmed-meshheading:12621451-Cells, Cultured, pubmed-meshheading:12621451-Gene Products, gag, pubmed-meshheading:12621451-Gene Therapy, pubmed-meshheading:12621451-Genetic Vectors, pubmed-meshheading:12621451-HIV Envelope Protein gp160, pubmed-meshheading:12621451-HIV Infections, pubmed-meshheading:12621451-Humans, pubmed-meshheading:12621451-Lymphocytes, pubmed-meshheading:12621451-Protein Precursors, pubmed-meshheading:12621451-Serine Proteinase Inhibitors, pubmed-meshheading:12621451-Simian virus 40, pubmed-meshheading:12621451-Transduction, Genetic, pubmed-meshheading:12621451-Virus Replication, pubmed-meshheading:12621451-alpha 1-Antitrypsin, pubmed-meshheading:12621451-gag Gene Products, Human Immunodeficiency Virus, pubmed-meshheading:12621451-pol Gene Products, Human Immunodeficiency Virus
pubmed:year
2003
pubmed:articleTitle
HIV-1 proprotein processing as a target for gene therapy.
pubmed:affiliation
Department of Pathology, Jefferson Medical College, Philadelphia, PA 19107, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.