Individual Contributions of Mutant Protease and Reverse Transcriptase to Viral Infectivity, Replication, and Protein Maturation of Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1

doi:10.1128/JVI.75.7.3291-3300.2001

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Journal of Virology, April 2001, p. 3291-3300, Vol. 75, No. 7
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.7.3291-3300.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Individual Contributions of Mutant Protease and Reverse Transcriptase to Viral Infectivity, Replication, and Protein Maturation of Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1

Gabriela Bleiber,¹ Miguel Munoz,² Angela Ciuffi,² Pascal Meylan,¹^,² and Amalio Telenti¹^,²^,^*

Division of Infectious Diseases¹ and Institute of Microbiology,² Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

Received 31 July 2000/Accepted 5 January 2001

Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease (PR) and reverse transcriptase (RT) inhibitorsmay display impaired infectivity and replication capacity. Theindividual contributions of mutated HIV-1 PR and RT to infectivity,replication, RT activity, and protein maturation (herein referredto as "fitness") in recombinant viruses were investigated by separatelycloning PR, RT, and PR-RT cassettes from drug-resistant mutantviral isolates into the wild-type NL4-3 background. Both mutantPR and RT contributed to measurable deficits in fitness of viralconstructs. In peripheral blood mononuclear cells, replicationrates (means ± standard deviations) of RT recombinants were 72.5%± 27.3% and replication rates of PR recombinants were 60.5% ±33.6% of the rates of NL4-3. PR mutant deficits were enhancedin CEM T cells, with relative replication rates of PR recombinantsdecreasing to 15.8% ± 23.5% of NL4-3 replication rates. Cloningof the cognate RT improved fitness of some PR mutant clones. Fora multidrug-resistant virus transmitted through sexual contact,RT constructs displayed a marked infectivity and replication deficitand diminished packaging of Pol proteins (RT content in virionsdiminished by 56.3% ± 10.7%, and integrase content diminishedby 23.3% ± 18.4%), a novel mechanism for a decreased-fitness phenotype.Despite the identified impairment of recombinant clones, fitnessof two of the three drug-resistant isolates was comparable tothat of wild-type, susceptible viruses, suggestive of extensivecompensation by genomic regions away from PR and RT. Only limitedreversion of mutated positions to wild-type amino acids was observedfor the native isolates over 100 viral replication cycles in theabsence of drug selective pressure. These data underscore thecomplex relationship between PR and RT adaptive changes and viralevolution in antiretroviral drug-resistant HIV-1.

^* Corresponding author. Mailing address: Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne,Switzerland. Phone: 41 21 314 0550. Fax: 41 21 314 1008. E-mail:amalio.telenti{at}chuv.hospvd.ch.

Journal of Virology, April 2001, p. 3291-3300, Vol. 75, No. 7
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.7.3291-3300.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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