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Journal of Virology, July 2003, p. 7736-7745, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.7736-7745.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Infectivity and Replication Capacity of Drug-Resistant Human Immunodeficiency Virus Type 1 Variants Isolated during Primary Infection

Viviana Simon,1* Neal Padte,1 Deya Murray,1 Jeroen Vanderhoeven,1 Terri Wrin,2 Neil Parkin,2 Michele Di Mascio,3,{dagger} and Martin Markowitz1

Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York,1 ViroLogic Inc., South San Francisco, California,2 Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico3

Received 21 January 2003/ Accepted 16 April 2003

It is believed that replication capacity is an important determinant of human immunodeficiency virus type 1 (HIV-1) pathogenicity and transmissibility. To explore this, we conducted a comprehensive analysis of the replication properties of nine drug-resistant and nine drug-susceptible viral isolates derived from patients with primary HIV-1 infection. Viral isolates were tested for single-cycle infectivity in the GHOST cell line. The infectivity of isolates carrying resistance-associated mutations was significantly higher than that of drug-susceptible isolates. Additionally, the growth kinetics of these isolates were determined in CD4+ T lymphocytes. Drug-resistant isolates replicated as well as drug-susceptible viruses. Insertion of the resistance-conferring regions into an NL4-3-based molecular background resulted in chimeras that displayed a modest but significant reduction in replication capacity compared to the drug-susceptible chimeric viruses. Of note, two multidrug-resistant isolates and one protease inhibitor-resistant isolate displayed higher rates of infectivity and growth kinetics than the other drug-resistant or drug-susceptible isolates. These distinct replicative features, however, were not seen in the corresponding chimeras, indicating that changes within the C-terminal region of Gag as well as within the protease and reverse transcriptase genes contribute to but are not sufficient for the level of compensatory adaptation observed. These findings suggest that some drug-resistant viruses isolated during primary infection possess unique adaptive changes that allow for both high viral replication capacity and resistance to one or more classes of antiretroviral drugs. Further studies are needed to elucidate the precise regions that are essential for these characteristics.

* Corresponding author. Mailing address: Aaron Diamond AIDS Research Center, 455 First Ave., 7th Floor, New York, NY 10016. Phone: (212) 448-5128. Fax: (212) 725-1126. E-mail: vsimon{at}adarc.org.

{dagger} Present address: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Journal of Virology, July 2003, p. 7736-7745, Vol. 77, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.14.7736-7745.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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