The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes.
BACKGROUND
The genetic barrier, defined as the number of mutations required to overcome drug-selective pressure, is an important factor for the development of HIV drug resistance. Because of high variability between subtypes, particular HIV-1 subtypes could have different genetic barriers for drug resistance substitutions. This study compared the genetic barrier between subtypes using some 2000 HIV-1 sequences (>600 of non-B subtype) isolated from anti-retroviral-naive patients in Europe.


METHODS
The genetic barrier was calculated as the sum of transitions (scored as 1) and/or transversions (2.5) required for evolution to any major drug resistance substitution. In addition, the number of minor protease substitutions was determined for every subtype.


RESULTS
Few dissimilarities were found. An increased genetic barrier was calculated for I82A (subtypes C and G), V108I (subtype G), V118I (subtype G), Q151M (subtypes D and F), L210W (subtypes C, F, G, and CRF02_AG), and P225H (subtype A) (P < 0.001 compared with subtype B). A decreased genetic barrier was found for I82T (subtypes C and G) and V106M (subtype C) (P < 0.001 vs subtype B). Conversely, minor protease substitutions differed extensively between subtypes.


CONCLUSIONS
Based on the calculated genetic barrier, the rate of drug resistance development may be similar for different HIV-1 subtypes. Because of differences in minor protease substitutions, protease inhibitor resistance could be enhanced in particular subtypes once the relevant major substitutions are selected.
Eijkman Winkler Institute, Department of Virology, University Medical Center Utrecht, G04-614, 3584 CX Utrecht, the Netherlands.
David A
DA
van de Vijver
Annemarie M J
AM
Wensing
Gioacchino
G
Angarano
Birgitta
B
Asjö
Claudia
C
Balotta
Enzo
E
Boeri
Ricardo
R
Camacho
Marie-Laure
ML
Chaix
Dominique
D
Costagliola
Andrea
A
De Luca
Inge
I
Derdelinckx
Zehava
Z
Grossman
Osamah
O
Hamouda
Angelos
A
Hatzakis
Robert
R
Hemmer
Andy
A
Hoepelman
Andrzej
A
Horban
Klaus
K
Korn
Claudia
C
Kücherer
Thomas
T
Leitner
Clive
C
Loveday
Eilidh
E
MacRae
Irina
I
Maljkovic
Carmen
C
de Mendoza
Laurence
L
Meyer
Claus
C
Nielsen
Eline L M
EL
Op de Coul
Vidar
V
Ormaasen
Dimitris
D
Paraskevis
Luc
L
Perrin
Elisabeth
E
Puchhammer-Stöckl
Lidia
L
Ruiz
Mika
M
Salminen
Jean-Claude
JC
Schmit
Francois
F
Schneider
Rob
R
Schuurman
Vincent
V
Soriano
Grzegorz
G
Stanczak
Maja
M
Stanojevic
Anne-Mieke
AM
Vandamme
Kristel
K
Van Laethem
Michela
M
Violin
Karin
K
Wilbe
Sabine
S
Yerly
Maurizio
M
Zazzi
Charles A B
CA
Boucher
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D019380:Anti-HIV Agents / Q000494:pharmacology; D003062:Codon; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D015751:Genes, pol; D005843:Geography; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D017422:Sequence Analysis, DNA
D019380:Anti-HIV Agents; D003062:Codon; D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease