Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients.
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, R284 and N348 had statistically significant changes between the groups (P=0.007 and P< or =0.001, respectively). In treatment-experienced patients, 17.3% had R284K, whereas 24.5% had N348I substitutions. Both R284 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, N348I and K451R. Both R284K and K451R 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.
Gilead Sciences, Inc., Durham, NC, USA. Joshua.Waters@gilead.com
Joshua M
JM
Waters
Wesley
W
O'Neal
Kirsten L
KL
White
Charles
C
Wakeford
Eric B
EB
Lansdon
Jeanette
J
Harris
Evguenia S
ES
Svarovskaia
Michael D
MD
Miller
Katyna
K
Borroto-Esoda
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000480:Alkynes; D019943:Amino Acid Substitution / Q000187:drug effects; D048588:Benzoxazines / Q000627:therapeutic use; D003521:Cyclopropanes; D024921:Drug Resistance, Multiple, Viral; D014644:Genetic Variation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D009154:Mutation / Q000187:drug effects*; D063065:Organophosphonates / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000235:genetics; D018119:Stavudine / Q000627:therapeutic use; D000068698:Tenofovir
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000068698:Tenofovir; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus; D000225:Adenine; C098320:efavirenz