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Title

Variable sensitivity of CCR5-tropic human immunodeficiency virus type 1 isolates to inhibition by RANTES analogs

Authors
Torre, V S
Marozsan, A J
Albright, J L
Collins, K R
Quiñones-Mateu, M E
Arts, E J
Published in Journal of Virology. 2000, vol. 74, no. 10, p. 4868-76
Abstract Aminooxypentane (AOP)-RANTES efficiently and specifically blocks entry of non-syncytium-inducing (NSI), CCR5-tropic (R5) human immunodeficiency virus type 1 (HIV-1) into host cells. Inhibition appears to be mediated by increased intracellular retention of the CCR5 coreceptor- AOP-RANTES complex and/or competitive binding of AOP-RANTES with NSI R5 HIV-1 isolates for CCR5. Although AOP-RANTES and other beta-chemokine analogs are potent inhibitors, the extreme heterogeneity of the HIV-1 envelope glycoproteins (gp120 and gp41) and variable coreceptor usage may affect the susceptibility of variant HIV-1 strains to these drugs. Using the same peripheral blood mononuclear cells (PBMC) with all isolates, we observed a significant variation in AOP-RANTES inhibition of 13 primary NSI R5 isolates; 50% inhibitory concentrations (IC(50)) ranged from 0.04 nM with HIV-1(A-92RW009) to 1.3 nM with HIV-1(B-BaL). Experiments performed on the same isolate (HIV-1(B-BaL)) with PBMC from different donors revealed no isolate-specific variation in AOP-RANTES IC(50) values but did show a considerable difference in virus replication efficiency. Exclusive entry via the CCR5 coreceptor by these NSI R5 isolates suggests that variable inhibition by AOP-RANTES is not due to alternative coreceptor usage but rather differential CCR5 binding. Analysis of the envelope V3 loop sequence linked a threonine or arginine at position 319 (numbering based on the HXB2 genome) with AOP-RANTES resistance. With the exception of one isolate, A319 was associated with increased sensitivity to AOP-RANTES inhibition. Distribution of AOP-RANTES IC(50) values with these isolates has promoted ongoing screens for new CCR5 agonists that show broad inhibition of HIV-1 variants.
Keywords Amino Acid SequenceAnti-HIV Agents/pharmacologyCell LineChemokine CCL5/analogs & derivatives/pharmacologyDrug ResistanceMicrobialGiant Cells/physiologyHIV Envelope Protein gp120/geneticsHIV Envelope Protein gp160/geneticsHIV Infections/virologyHIV-1/drug effects/genetics/isolation & purification/physiologyHumansInhibitory Concentration 50LeukocytesMononuclear/virologyMolecular Sequence DataPeptide Fragments/geneticsReceptorsCCR5/metabolism
Identifiers
PMID: 10775626
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Research group HIV (835)
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TORRE, V S et al. Variable sensitivity of CCR5-tropic human immunodeficiency virus type 1 isolates to inhibition by RANTES analogs. In: Journal of Virology, 2000, vol. 74, n° 10, p. 4868-76. https://archive-ouverte.unige.ch/unige:26085

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Deposited on : 2013-01-31

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