Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine.
We attempted to determine whether HIV-1 developed resistance to (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection during therapy with 3TC. Genotypic analysis of HIV-1 strains isolated from 6 patients receiving 3TC revealed that as early as 2 months of therapy, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met184-->Val) in the reverse transcriptase-coding region of the pol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with Ile by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution were profoundly less susceptible to 3TC (1800- to 5500-fold decreased sensitivity) as compared to pretherapy virus strains. These strains were also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14-fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient. Our data suggest that reversal of such beneficial changes is associated with the Met184-->Val substitution of the pol gene of HIV-1. The data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection, but only transiently.
Kavlick
M F
MF
Experimental Retrovirology Section, National Cancer Institute, Bethesda, MD 20892, USA.
Shirasaka
T
T
Kojima
E
E
Pluda
J M
JM
Hui
F
F
Yarchoan
R
R
Mitsuya
H
H
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count / Q000187:drug effects; D004352:Drug Resistance, Microbial; D005838:Genotype; D016655:HIV Core Protein p24 / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D016655:HIV Core Protein p24; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D016047:Zalcitabine