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Antimicrobial Agents and Chemotherapy, October 2009, p. 4275-4282, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00397-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Natural Polymorphisms of Human Immunodeficiency Virus Type 1 Integrase and Inherent Susceptibilities to a Panel of Integrase Inhibitors{triangledown}

Andrea Low,1,{dagger} Nicole Prada,1,{dagger} Michael Topper,1,{dagger} Florin Vaida,2 Delivette Castor,1 Hiroshi Mohri,1 Daria Hazuda,3 Mark Muesing,1 and Martin Markowitz1*

Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, 455 First Avenue, New York, New York,1 University of California San Diego, San Diego, California,2 Merck Research Laboratories, West Point, Pennsylvania3

Received 25 March 2009/ Returned for modification 14 May 2009/ Accepted 27 July 2009

We evaluated the human immunodeficiency virus type 1 (HIV-1) integrase coding region of the pol gene for the presence of natural polymorphisms in patients during early infection (AHI) and with triple-class drug-resistant HIV-1 (MDR). We analyzed selected recombinant viruses containing patient-derived HIV-1 integrase for susceptibility to a panel of strand transfer integrase inhibitors (InSTI). A pretreatment sequence analysis of the integrase coding region was performed for 112 patients identified during acute or early infection and 15 patients with triple-class resistance. A phenotypic analysis was done on 10 recombinant viruses derived from nine patients against a panel of six diverse InSTI. Few of the polymorphisms associated with in vitro InSTI resistance were identified in the samples from newly infected individuals or those patients with MDR HIV-1. We identified polymorphisms V72I, L74I, T97A, V151I, M154I/L, E157Q, V165I, V201I, I203M, T206S, and S230N. V72I was the most common, seen in 63 (56.3%) of the AHI samples. E157Q was the only naturally occurring mutation thought to contribute to resistance to elvitegravir, raltegravir, and L-870,810. None of the patient-derived viruses demonstrated any significant decrease in susceptibility to the drugs tested. In summary, the integrase coding region contains as much natural variation as that seen in protease, but mutations associated with high-level resistance to existing InSTI are rarely, if ever, present in integrase naïve patients, especially those being used clinically. Most of the highly prevalent polymorphisms have little effect on InSTI susceptibility in the absence of specific primary mutations. Baseline testing for integrase susceptibility in InSTI-naïve patients is not currently warranted.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, an affiliate of the Rockefeller University, 455 First Avenue, 7th Floor, New York, NY 10016. Phone: (212) 448-5020. Fax: (212) 725-1126. E-mail: mmarkowitz{at}adarc.org

{triangledown} Published ahead of print on 3 August 2009.

{dagger} These authors contributed equally to the work described in this paper.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4275-4282, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00397-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Garrido, C., Geretti, A. M., Zahonero, N., Booth, C., Strang, A., Soriano, V., De Mendoza, C. (2010). Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection. J Antimicrob Chemother 65: 320-326 [Abstract] [Full Text]  


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