Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients

作者：Waters Joshua M^*; O'Neal Wesley; White Kirsten L; Wakeford Charles; Lansdon Eric B; Harris Jeanette; Svarovskaia Evguenia S; Miller Michael D; Borroto Esoda Katyna

来源：Antiviral Therapy, 2009, 14(2): 231-239.

DOI：10.1177/135965350901400215

Background: Antiretroviral therapy that targets HIV type-1 (HIV-1) reverse transcriptase (RT) can be linked to mutations in the thumb-connection (amino acids [AA] 241-426) and RNase H (AA 427-560) domains, which could affect drug resistance.
Methods: Genotypical and statistical analyses were performed on HIV-1 RT from 100 antiretroviral treatment-naive and 248 antiretroviral treatment-experienced patients, the majority of whom were infected with HIV-1 subtype B. The RT region was analysed in three parts: the polymerase (AA 1-240), thumb-connection (AA 241-426) and RNase H (AA 427-560) domains.
Results: The polymerase domain had statistically significant changes between the two groups at 24 AA positions that are known resistance sites. Within the thumb-connection domain, 8284 and N348 had statistically significant changes between the groups (P=0.007 and P <= 0.001, respectively). In treatment-experienced patients, 17.3% had R284K, whereas 24.5% had N3481 substitutions. Both 8284 and N348 were 100% conserved in treatment-naive patients. Within the RNase H domain, only K451 showed a statistically significant change (P <= 0.001), with K451R present in 11% of treatment-experienced patients but remaining 100% conserved among treatment-naive patients.
Conclusions: RT mutations at three positions outside of the polymerase region were associated with antiretroviral therapy: R284K, N3481 and K451 R. Both R284K and K451 R interact with the phosphate backbone of the template or primer in HIV-1 RT crystal structures and could potentially influence the positioning of the primer strand, thus affecting polymerization, the efficiency of nucleoside reverse transcriptase inhibitor excision and/or RNase H activity.

• 出版日期2009