Infectivity and replication capacity of drug-resistant human immunodeficiency virus type 1 variants isolated during primary infection.
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.
Simon
Viviana
V
Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, 7th Floor, New York, NY 10016, USA. vsimon@adarc.org
Padte
Neal
N
Murray
Deya
D
Vanderhoeven
Jeroen
J
Wrin
Terri
T
Parkin
Neil
N
Di Mascio
Michele
M
Markowitz
Martin
M
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D024921:Drug Resistance, Multiple, Viral; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015683:Gene Products, gag / Q000502:physiology; D015750:Genes, gag; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D014779:Virus Replication
D019380:Anti-HIV Agents; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease