Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients

Abstract

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.

Histopathological detection of owl's eye inclusions is still specific for cytomegalovirus in the era of human herpesviruses 6 and 7

“…Nine patients had been prescribed zidovudine during their illness but all died before protease inhibitor drugs became available. 19 …”

The growth and the control of human immunodeficiency virus in the lung: implications for highly active antiretroviral therapy

“…HIV exposure to the widely used zidovudine leads to a distinct pattern of mutations in the RT gene, leading to resistance. The frequency and pattern of these mutations, specifically at codons 41, 67, 70, 215 and 219, varies between HIV isolated from different organs [66]. The most comprehensive study to date focused on the mutation pattern seen in various organs isolated from post-mortem tissue [66].…”

“…The frequency and pattern of these mutations, specifically at codons 41, 67, 70, 215 and 219, varies between HIV isolated from different organs [66]. The most comprehensive study to date focused on the mutation pattern seen in various organs isolated from post-mortem tissue [66]. The report determined that the mutation pattern of proviral DNA reverse transcriptase in response to zidovudine in the lung is distinct from that seen in peripheral blood.…”

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses

“…Most of these specimens were obtained during active pulmonary disease, when increased immune activation and viral replication would be expected. High concentrations of HIV-1 in the lung compared to other organs collected during autopsy [25], and different drug-resistance mutations (assessed by consensus sequencing) in bronchoalveolar lavage compared to blood specimens collected during failing ART [26], also suggest that the lung may be a site of increased or differential HIV-1 replication.…”