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.
van de Vijver
David A
DA
Eijkman Winkler Institute, Department of Virology, University Medical Center Utrecht, G04-614, 3584 CX Utrecht, the Netherlands.
Wensing
Annemarie M J
AM
Angarano
Gioacchino
G
Asjö
Birgitta
B
Balotta
Claudia
C
Boeri
Enzo
E
Camacho
Ricardo
R
Chaix
Marie-Laure
ML
Costagliola
Dominique
D
De Luca
Andrea
A
Derdelinckx
Inge
I
Grossman
Zehava
Z
Hamouda
Osamah
O
Hatzakis
Angelos
A
Hemmer
Robert
R
Hoepelman
Andy
A
Horban
Andrzej
A
Korn
Klaus
K
Kücherer
Claudia
C
Leitner
Thomas
T
Loveday
Clive
C
MacRae
Eilidh
E
Maljkovic
Irina
I
de Mendoza
Carmen
C
Meyer
Laurence
L
Nielsen
Claus
C
Op de Coul
Eline L M
EL
Ormaasen
Vidar
V
Paraskevis
Dimitris
D
Perrin
Luc
L
Puchhammer-Stöckl
Elisabeth
E
Ruiz
Lidia
L
Salminen
Mika
M
Schmit
Jean-Claude
JC
Schneider
Francois
F
Schuurman
Rob
R
Soriano
Vincent
V
Stanczak
Grzegorz
G
Stanojevic
Maja
M
Vandamme
Anne-Mieke
AM
Van Laethem
Kristel
K
Violin
Michela
M
Wilbe
Karin
K
Yerly
Sabine
S
Zazzi
Maurizio
M
Boucher
Charles A B
CA
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