Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients.
Replication of HIV introduces errors into the genome which are responsible for conferring a growth advantage over wildtype virus when drugs such as zidovudine (ZDV) exert a selective pressure. The molecular basis for HIV-1 resistance to ZDV has been mapped to codons 41, 67, 70, 215 and 219 of the reverse transcriptase gene both in vitro and in clinical samples of blood. This study has investigated the relationship between the quantitative prevalence of ZDV resistance in multiple organs of the same individual. Proviral HIV-1 load was measured by quantitative-competitive PCR in 90 samples from organs of 11 patients dying with AIDS. Nine of these patients had been prescribed zidovudine. The distribution of wildtype and mutant sequences at the positions 41, 67, 70, 215 and 219 of the reverse transcriptase was assessed using a point mutation assay. The results showed that the highest proviral loads were predominately found in lymph node, spleen and lung and there was a significant association between viral load and resistance to ZDV (P=0.008). Inter-organ distribution of wildtype and mutant sequences at codons 41, 67, 70, 215 and 219 was frequently not uniform and in some patients differed markedly between the lymphoreticular system and other organs. These results demonstrate that treatment of HIV-1 infection with zidovudine does not exert uniform selective pressures in multiple organs. These findings have implications for the interpretation of resistance data and design of treatment strategies for HIV, arguing in particular that alterations in therapeutic regimens should consider the likelihood of different resistance patterns being present in multiple sites within the same individual.
Atkins
M
M
Division of Pathology and Communicable Diseases, Royal Free Hospital School of Medicine, London, UK.
Strappe
P
P
Kaye
S
S
Loveday
C
C
McLaughlin
J E
JE
Johnson
M A
MA
Tedder
R S
RS
Griffiths
P D
PD
Emery
V C
VC
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000473:pathology / Q000821:virology*; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000032:analysis; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011533:Proviruses / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019562:Viral Load; D015215:Zidovudine / Q000494:pharmacology*
D019380:Anti-HIV Agents; D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine