21060108

Source:http://linkedlifedata.com/resource/pubmed/id/21060108

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Predicate	Object
rdf:type	pubmed:Citation
lifeskim:mentions	umls-concept:C0019704, umls-concept:C0020792, umls-concept:C0178719, umls-concept:C0205322, umls-concept:C0376601, umls-concept:C0441655, umls-concept:C1880022
pubmed:issue	1
pubmed:dateCreated	2010-12-24
pubmed:abstractText	Pharmacokinetic and pharmacodynamic considerations significantly impact infectious disease treatment options. One aspect of pharmacodynamics is the postantibiotic effect, classically defined as delayed bacterial growth after antibiotic removal. The same principle can apply to antiviral drugs. For example, significant delays in human immunodeficiency virus type 1 (HIV-1) replication can be observed after nucleoside/nucleotide reverse transcriptase inhibitor (N/NtRTI) removal from culture medium, because these prodrugs must be anabolized into active, phosphorylated forms once internalized into cells. A relatively new class of anti-HIV-1 drugs is the integrase strand transfer inhibitors (INSTIs), and the INSTIs raltegravir (RAL) and elvitegravir (EVG) were tested here alongside positive N/NtRTI controls tenofovir disoproxil fumarate (TDF) and azidothymidine (AZT), as well as the nonnucleoside reverse transcriptase inhibitor negative control nevirapine (NVP), to assess potential postantiviral effects. Transformed and primary CD4-positive cells pretreated with INSTIs significantly resisted subsequent challenge by HIV-1, revealing the following hierarchy of persistent intracellular drug strength: TDF > EVG ? AZT > RAL > NVP. A modified time-of-addition assay was moreover developed to assess residual drug activity levels. Approximately 0.8% of RAL and 2% of initial EVG and TDF 1-h pulse drug levels persisted during the acute phase of HIV-1 infection. EVG furthermore displayed significant virucidal activity. Although there is no reason to suspect obligate intracellular modification, this study nevertheless defines significant intracellular persistence of prototype INSTIs. Ongoing second-generation formulations should therefore consider the potential for significant postantiviral effects among this drug class. Combined intracellular persistence and virucidal activities suggest potential pre-exposure prophylaxis applications for EVG.
pubmed:grant	http://linkedlifedata.com/resource/pubmed/grant/AI052014, http://linkedlifedata.com/resource/pubmed/grant/P30AI060354, http://linkedlifedata.com/resource/pubmed/grant/R01 AI052014-09
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pubmed:language	eng
pubmed:journal	http://linkedlifedata.com/resource/pubmed/journal/0315061
pubmed:citationSubset	IM
pubmed:chemical	http://linkedlifedata.com/resource/pubmed/chemical/Adenine, http://linkedlifedata.com/resource/pubmed/chemical/Anti-HIV Agents, http://linkedlifedata.com/resource/pubmed/chemical/Integrase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/JTK 303, http://linkedlifedata.com/resource/pubmed/chemical/MK 0518, http://linkedlifedata.com/resource/pubmed/chemical/Phosphonic Acids, http://linkedlifedata.com/resource/pubmed/chemical/Pyrrolidinones, http://linkedlifedata.com/resource/pubmed/chemical/Quinolones, http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine, http://linkedlifedata.com/resource/pubmed/chemical/tenofovir disoproxil
pubmed:status	MEDLINE
pubmed:month	Jan
pubmed:issn	1098-6596
pubmed:author	pubmed-author:EngelmanAlanA, pubmed-author:HaimHillelH, pubmed-author:KohYasuhiroY
pubmed:issnType	Electronic
pubmed:volume	55
pubmed:owner	NLM
pubmed:authorsComplete	Y
pubmed:pagination	42-9
pubmed:dateRevised	2011-8-1
pubmed:meshHeading	pubmed-meshheading:21060108-Adenine, pubmed-meshheading:21060108-Anti-HIV Agents, pubmed-meshheading:21060108-Cell Line, pubmed-meshheading:21060108-HIV-1, pubmed-meshheading:21060108-HeLa Cells, pubmed-meshheading:21060108-Humans, pubmed-meshheading:21060108-Integrase Inhibitors, pubmed-meshheading:21060108-Phosphonic Acids, pubmed-meshheading:21060108-Pyrrolidinones, pubmed-meshheading:21060108-Quinolones, pubmed-meshheading:21060108-Zidovudine
pubmed:year	2011
pubmed:articleTitle	Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity.
pubmed:affiliation	Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Division of AIDS, Harvard Medical School, Boston, MA 02115, USA.
pubmed:publicationType	Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural