Zidovudine resistance-associated mutations and sequence diversity in brain-derived HIV-1 reverse transcriptase

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Liu, Chen-Yi
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Human immunodeficiency virus type 1 (HIV-1) infects brain cells such as glial cells, regulating in the development of neurological diseases including HIV associated dementia (HIVD). The reverse transcriptase (RT) is essential for viral replication and thus is a target of antiviral agents such as zidovudine (ZDV). ZDV is the only proven treatment for HIVD currently. However, the appearance of ZDV resistance due to zidovudine resistance associated mutations (ZRAMs) in RT has complicated the treatment. Studies of ZDV resistance on blood-derived HIV-1 isolates have shown an association between ZDV resistance and disease progression. However, little is known about ZDV resistance and occurrence of ZRAMs in brain-derived HIV-1 and whether ZDV resistance plays a role in the development of HIVD is unclear. To determine the frequence of ZRAM and molecular features of viral mutagenesis in brain-derived HIV-1, I PCR-amplified and sequenced codons 1 through 240 of RT coding region for 10 brain-derived HIV-1 isolates from 10 AIDS patients who were classified into demented (HIVD) (N = 5) and non-demented (ND) (N = 5) groups. ZRAMs were found in HIV-1 RT from only two patients who received ZDV treatment for 35 and 39 months respectively; one in the HIVD group demonstrating two ZRAMs M41L and F215Y, and the other in the ND group displaying only one ZRAM M41L. None of the other 8 samples had ZRAMs despite the duration of ZDV therapy ranging from 2-30 months. However, 32 ther amino acid substitutions relative to the B clade RT consensus sequence were identified in brain-derived HIV-1 RT, among which 24 were unrecognized previously in the established databases. These mutations clustered nonrandomly to several regions, similar to the reference sequences in the established databases. (Abstract shortened by UMI.)