Conservation patterns of HIV-1 RT connection and RNase H domains: identification of new mutations in NRTI-treated patients.
BACKGROUND
Although extensive HIV drug resistance information is available for the first 400 amino acids of its reverse transcriptase, the impact of antiretroviral treatment in C-terminal domains of Pol (thumb, connection and RNase H) is poorly understood.


RESULTS
We wanted to characterize conserved regions in RT C-terminal domains among HIV-1 group M subtypes and CRF. Additionally, we wished to identify NRTI-related mutations in HIV-1 RT C-terminal domains. We sequenced 118 RNase H domains from clinical viral isolates in Brazil, and analyzed 510 thumb and connection domain and 450 RNase H domain sequences collected from public HIV sequence databases, together with their treatment status and histories. Drug-naïve and NRTI-treated datasets were compared for intra- and inter-group conservation, and differences were determined using Fisher's exact tests. One third of RT C-terminal residues were found to be conserved among group M variants. Three mutations were found exclusively in NRTI-treated isolates. Nine mutations in the connection and 6 mutations in the RNase H were associated with NRTI treatment in subtype B. Some of them lay in or close to amino acid residues which contact nucleic acid or near the RNase H active site. Several of the residues pointed out herein have been recently associated to NRTI exposure or increase drug resistance to NRTI.


CONCLUSIONS
This is the first comprehensive genotypic analysis of a large sequence dataset that describes NRTI-related mutations in HIV-1 RT C-terminal domains in vivo. The findings into the conservation of RT C-terminal domains may pave the way to more rational drug design initiatives targeting those regions.
Santos
André F A
AF
Laboratório de Virologia Humana, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Lengruber
Renan B
RB
Soares
Esmeralda A
EA
Jere
Abhay
A
Sprinz
Eduardo
E
Martinez
Ana M B
AM
Silveira
Jussara
J
Sion
Fernando S
FS
Pathak
Vinay K
VK
Soares
Marcelo A
MA
D000595:Amino Acid Sequence; D001483:Base Sequence; D017124:Conserved Sequence; D017931:DNA Primers; D015658:HIV Infections / Q000188:drug therapy* / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016914:Ribonuclease H / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H