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Antimicrobial Agents and Chemotherapy, July 2009, p. 3056-3064, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01502-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Cytotoxicological Analysis of a gp120 Binding Aptamer with Cross-Clade Human Immunodeficiency Virus Type 1 Entry Inhibition Properties: Comparison to Conventional Antiretrovirals {triangledown}

Walter Rangel Lopes de Campos,1 Dayaneethie Coopusamy,1 Lynn Morris,2 Bongani M. Mayosi,3 and Makobetsa Khati1*

CSIR Biosciences, P.O. Box 395, Pretoria 0001, South Africa,1 National Institute for Communicable Diseases, Private Bag X4, Sandringham 2131, South Africa,2 Department of Medicine, Groote Schuur Hospital and University of Cape Town, Observatory 7925, South Africa3

Received 10 November 2008/ Returned for modification 19 December 2008/ Accepted 2 April 2009

The long-term cumulative cytotoxicity of antiretrovirals (ARVs) is among the major causes of treatment failure in patients infected with human immunodeficiency virus (HIV) and patients with AIDS. This calls for the development of novel ARVs with less or no cytotoxicity. In the present study, we compared the cytotoxic effects of a cross-clade HIV type 1-neutralizing aptamer called B40 with those of a panel of nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and the entry inhibitor (EI) T20 in human cardiomyocytes and peripheral blood mononuclear cells. An initial screen in which cell death was used as the end-point measurement revealed that the B40 aptamer and T20 were the only test molecules that had insignificant (0.61 < P < 0.92) effects on the viability of both cell types at the maximum concentration used. PIs were the most toxic class (0.001 < P < 0.00001), followed by NNRTIs and NRTIs (0.1 < P < 0.00001). Further studies revealed that B40 and T20 did not interfere with the cellular activity of the cytochrome P450 3A4 enzyme (0.78 < P < 0.24) or monoamine oxidases A and B (0.83 < P < 0.56) when the activities of the enzymes were compared to those in untreated controls of both cell types. Mitochondrion-initiated cellular toxicity is closely associated with the use of ARVs. Therefore, we used real-time PCR to quantify the relative ratio of mitochondrial DNA to nuclear DNA as a marker of toxicity. The levels of mitochondrial DNA remained unchanged in cells exposed to the B40 aptamer compared to the levels in untreated control cells (0.5 > P > 0.06). These data support the development of B40 and related EI aptamers as new ARVs with no cytotoxicity at the estimated potential therapeutic dose.

* Corresponding author. Mailing address: CSIR Biosciences, P.O. Box 395, Pretoria 0001, South Africa. Phone: 27(12)8414770. Fax: 27(12)8313080. E-mail: Mkhati{at}csir.co.za

{triangledown} Published ahead of print on 13 April 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 3056-3064, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.01502-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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