The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors.
OBJECTIVE
Relatively little is known about the development of resistance to protease inhibitors (PIs) in non-B subtypes. In subtype B viruses, L89 is commonly found at position 89 in the HIV protease (PR) gene, whereas M89 is commonly observed as a polymorphism in other subtypes. We compared the frequencies of substitutions at position 89 in PR in tissue culture selections and in clinical databases of PI-naive and PI-experienced populations.


METHODS
Representative subtype A/CRF01_AE (n = 2 and 3) and subtype C (n = 5) isolates were cultured in MT-2 cells and cord blood mononuclear cells (CBMCs), respectively, under increasing drug pressure with PIs, and drug resistance mutations were identified.


RESULTS
The M89 natural polymorphism in non-B subtypes commonly led to the appearance of an M89T mutation in selections with atazanavir in subtypes A/AE and C, and was accompanied by other previously recognized atazanavir mutations. The M89T mutation contributed to phenotypic resistance to atazanavir and cross-resistance to lopinavir and nelfinavir, but not to other PIs. A shift from a L89 natural polymorphism to L89I/M arose in two of five subtype C selections with PIs. M89I/V/T mutations were acquired by 10%-11% of individuals harbouring non-B subtypes who were failing PI-based regimens, but were rarely observed in drug-naive persons and in patients failing non-PI-based regimens.


CONCLUSIONS
The M/L89 natural polymorphism present in non-B subtypes may lead to the M89T mutational pathway conferring resistance to atazanavir, lopinavir and nelfinavir.
Division of Infectious Diseases, Department of Medicine, Queens University, Kingston, Ontario, Canada. jm209@queensu.ca
Jorge L
JL
Martinez-Cajas
Mark A
MA
Wainberg
Maureen
M
Oliveira
Eugene L
EL
Asahchop
Florence
F
Doualla-Bell
Irene
I
Lisovsky
Daniela
D
Moisi
Ella
E
Mendelson
Zehava
Z
Grossman
Bluma G
BG
Brenner
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D002478:Cells, Cultured; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D061466:Lopinavir / Q000494:pharmacology; D019888:Nelfinavir / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000494:pharmacology; D014776:Virus Cultivation
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019888:Nelfinavir