Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine.
The association between human immunodeficiency virus type I (HIV-1) RNA load changes and the emergence of resistant virus variants was investigated in 24 HIV-1-infected asymptomatic persons during 2 years of treatment with zidovudine by sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L), and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first month, followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modeling suggests that this resurgence is caused by host-parasite dynamics, and thus reflects infection of the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of treatment, the RNA load returned to baseline values, which was associated with the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite the relative loss of RNA load suppression, selection toward mutations at RT codons 215 and 41 continued. Identical patterns were observed in the mathematical model. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance.
de Jong
M D
MD
Antiviral Therapy Laboratory, Department of Virology, National AIDS Therapy Evaluation Centre, University of Amsterdam, The Netherlands.
Veenstra
J
J
Stilianakis
N I
NI
Schuurman
R
R
Lange
J M
JM
de Boer
R J
RJ
Boucher
C A
CA
D001483:Base Sequence; D018791:CD4 Lymphocyte Count; D017931:DNA Primers; D014644:Genetic Variation; D054303:HIV Reverse Transcriptase; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018451:Homosexuality, Male; D006790:Host-Parasite Interactions; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000096:biosynthesis / Q000097:blood*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000627:therapeutic use*
D017931:DNA Primers; D012367:RNA, Viral; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase