Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cellsReport as inadecuate




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Molecular and Cellular Therapies

, 2:1

HIV pathogenesis and Treatment

Abstract

BackgroundHIV eradication strategies are now being evaluated in vitro and in vivo. A cornerstone of such approaches is maximal suppression of viral replication with combination antiretroviral therapy ART. Since many antiretroviral agents have off target effects, and different classes target different components of the viral life cycle, we questioned whether different classes of ART might differentially affect the survival and persistence of productively HIV-infected CD4 T cells.

MethodsIn vitro infections of primary CD4 T cells using clinical isolates of HIV-1 that were either protease inhibitor susceptible HIV PI-S, or resistant HIV PI-R were treated with nothing, lopinavir, efavirenz or raltegravir. Cell viability, apoptosis, and the proportion of surviving cells that were P24 positive was assessed by flow cytometry.

ResultsIn HIV PI-S infected primary cultures, all three antiretroviral agents decreased viral replication, and reduced the total number of cells that were undergoing apoptosis P < 0.01 similarly. Similarly, in the HIV PI-R infected cultures, both efavirenz and raltegravir reduced viral replication and reduced apoptosis compared to untreated control P < 0.01, while lopinavir did not, suggesting that HIV replication drives T cell apoptosis, which was confirmed by association by linear regression P < 0.0001 . However since HIV protease has been suggested to directly induce apoptosis of infected CD4 T cells, and HIV PI are intrinsically antiapoptotic, we evaluated apoptosis in productively infected HIV P24+ cells. More HIV p24 positive cells were apoptotic in the Efavirenz or raltegravir treated cultures than the lopinavir treated cultures P = 0.0008 for HIV PI-R and P = 0.06 for the HIV PI-S, indicating that drug class impacts survival of productively infected CD4 T cells.

ConclusionsInhibiting HIV replication with a PI, NNRTI or INSTI reduces total HIV-induced T cell apoptosis. However, blocking HIV replication with PI but not with NNRTI or INSTI promotes survival of productively HIV-infected cells. Thus, selection of antiretroviral agents may impact the success of HIV eradication strategies.

AbbreviationsAIDSAcquired immunodeficiency syndrome

ANOVAAnalysis of variance

cARTCombination antiretroviral therapy

ELISAEnzyme linked immunosorbent assay

HIVHuman immunodeficiency virus

INSTIIntegrase strand transfer inhibitor

IUInternational Unit

NIHNational Institutes of Health

NRTINucleoside reverse transcriptase inhibitor

NNRTINon-nucleoside reverse transcriptase inhibitor

PBSPhosphase buffered saline

PEPhycoerythrin

PIProtease inhibitor

PI-RProtease inhibitor resistant

PI-SProtease inhibitor susceptible

SAHASuberoylanilide hydroxamic acid

TCMCentral memory T cells

TUNELTerminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling.

Electronic supplementary materialThe online version of this article doi:10.1186-2052-8426-2-1 contains supplementary material, which is available to authorized users.

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Author: Nathan W Cummins - Amy M Sainski - Sekar Natesampillai - Gary D Bren - Andrew D Badley

Source: https://link.springer.com/







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