penciclovir and Acquired-Immunodeficiency-Syndrome

A heterogeneous herpes simplex virus type 2 (HSV-2) population was characterised from an AIDS patient with relapsing genital ulcer. The isolate had an unusual antiviral spectrum, showing resistance to penciclovir and susceptibility to acyclovir. Two viral populations were plaque purified, one resistant and the other susceptible to both antiviral drugs. The resistant clone was deficient in thymidine kinase (TK) activity and a nucleotide substitution, thymine for cytosine, at position 153 was identified in its TK gene. This mutation resulted in an amino acid change, arginine to tryptophan, in the ATP binding site. In the deficient mutant, a loss of virulence was observed in mice.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; Amino Acid Substitution; Animals; Antiviral Agents; Base Sequence; Chlorocebus aethiops; DNA, Viral; Drug Resistance, Viral; Female; Genes, Viral; Guanine; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Mice; Thymidine Kinase; Vero Cells; Virulence

Patients with AIDS often experience recurrent infections with varicella-zoster virus (VZV) requiring repeated or prolonged treatment with acyclovir (ACV), which may lead to the development of ACV resistance. The ACV resistance of isolates recovered from such patients is associated with diminished VZV thymidine kinase (TK) function. We determined the nucleotide sequences of the TK genes of 12 ACV-resistant VZV strains purified from nine patients with AIDS. Five VZV strains contained nucleotide deletions in their TK genes, introducing a premature termination codon which is expected to result in the production of a truncated protein. No detectable full-length TK protein could be immunoprecipitated from extracts of cells infected with these virus strains. These TK-deficient strains were cross resistant to the TK-dependent antiviral agents ACV, 9-(4-hydroxy-3-hydroxymethylbutyl-yl)guanine (penciclovir), and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil (BVaraU). The remaining seven strains each contained a nucleotide change that resulted in an amino acid substitution in the TK protein. These substitutions occurred throughout the TK protein, namely, in the ATP-binding site, the nucleoside-binding site, between the two binding sites, and at the carboxy terminus of the protein. We determined the effects of these mutations on the stability of TK protein expression in virus-infected cells and on the sensitivity of mutants to the TK-dependent antiviral agents ACV, BVaraU, and penciclovir.

Topics: Acquired Immunodeficiency Syndrome; Acyclovir; AIDS-Related Opportunistic Infections; Amino Acid Sequence; Antiviral Agents; Arabinofuranosyluracil; Base Sequence; Drug Resistance, Microbial; Genes, Viral; Genetic Variation; Guanine; Herpesviridae Infections; Herpesvirus 3, Human; Humans; Molecular Sequence Data; Mutagenesis; Precipitin Tests; Sequence Analysis; Sequence Homology, Amino Acid; Thymidine Kinase; Viral Plaque Assay