596 
Identification of a Mutation (A400T) in the Connection Domain of the HIV-1 Reverse Transcriptase Associated to Exposure and Resistance to NRTI
Bénédicte Roquebert*1,2, Bénédicte Roquebert*1,2, P Flandre1,3, P Flandre1,3, I Malet1,2, I Malet1,2, M Wirden1,2, M Wirden1,2, Z ait-arkoub1, V Boutonnet1, A Simon1,2, A Simon1,2, C Katlama1,2, C Katlama1,2, V Calvez1,2, V Calvez1,2, A G Marcelin1,2, and A G Marcelin1,2
1Hosp Pitie-Salpetriere, Paris, France; 2Univ Pierre and Marie Curie, Paris, France; and 3INSERM U720, Hosp Pitie-Salpetriere, Paris, France
Background: Resistance mutations to nucleoside reverse
transcriptase inhibitors (NRTI) have been identified in the RT polymerase
domain (amino acid [AA] 1 to 318) and it has been recently suggested that
mutations in the RNase H domain (AA 427 to 560) could
significantly contribute to an increase of resistance to NRTI. However, there are
few data concerning the connection domain (AA 319 to 426). The aim of this
study was to compare in vivo the
prevalence of RT mutations, particularly in the connection and the RNase H domains in naive and in NRTI pre-treated patients
and to determine some specific associations between NRTI resistance mutations
and mutations within the other RT domains.
Methods: We analyzed the RT (codons
1 to 426) and RNase H (codons
427 to 560) sequences of 64 naive and 118 NRTI pre-treated patients. We
investigated the association between presence of a mutation and the treatment
status (naive or not) using Fisher’s exact test. From the 560 codons tested, we determined which results were statistically
significant by applying Benjamini and Hochberg method
(FDR <0.1). The relationship between specific mutation and number of thymidine analog mutations (TAM) and International AIDS
Society (IAS) mutations was investigated using Cochran-Armitage
test.
Results:
Most of the mutations belonging to the 2006 IAS list (41, 65, 67, 69,
70, 74, 75, 103, 108, 181, 184, 190, 210, 215, 219), some mutations previously
described to be associated to NRTI exposure (43, 203, 208, 228), and 1 mutation
in the RT connection domain (400) were significantly more prevalent in
pre-treated than in naïve patients. Mutation A400T was associated to mutations
at codons 41, 67, 70, 74, 118, 184, and 215. There
was an association between the presence A400T mutation and the number of TAM
and IAS mutations (p = 0.0008 and p = 0.0002). No relationship between
A400T mutation and HIV-1 subtype was observed.
Conclusions: A mutation (A400T) located in the RT
connection domain clusters with NRTI-resistance mutations and could be considered
as secondary mutation, selected in presence of specific NRTI resistance
mutations. Biochemical studies are warranted to determine its own impact on the
level of resistance to NRTI.
|
