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Journal of Virology, September 2004, p. 10133-10148, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.10133-10148.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Independent Evolution of Human Immunodeficiency Virus (HIV) Drug Resistance Mutations in Diverse Areas of the Brain in HIV-Infected Patients, with and without Dementia, on Antiretroviral Treatment

Theresa K. Smit,1 Bruce J. Brew,2 Wallace Tourtellotte,3 Susan Morgello,4 Benjamin B. Gelman,5 and Nitin K. Saksena1*

Retroviral Genetics Laboratory, Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Westmead, Sydney,1 Centre for Immunology and Department of Neurology, St Vincent's Hospital, Darlinghurst Sydney, New South Wales, Australia,2 Neurology Research (127A), VA West Los Angeles Health Care Center, Los Angeles, California,3 Manhattan HIV Brain Bank, New York, New York,4 Department of Pathology, University of Texas Medical Branch, Galveston Texas5

Received 3 December 2003/ Accepted 26 April 2004

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

* Corresponding author. Mailing address: Retroviral Genetics Laboratory, Center for Virus Research, Westmead Millennium Institute, Darcy Rd., Westmead NSW 2145, Sydney, Australia. Phone: 612-98459119. Fax: 612-88243098. E-mail: nitin_saksena{at}wmi.usyd.edu.au.

Journal of Virology, September 2004, p. 10133-10148, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.10133-10148.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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