Impact of amino acid variations in Gag and protease of HIV type 1 CRF01_AE strains on drug susceptibility of virus to protease inhibitors.
BACKGROUND
Protease (PR) inhibitors (PIs) were designed against subtype B virus of human immunodeficiency virus type 1 (HIV-1), but believed to retain its activity against most of the other subtypes. CRF01_AE PR (AE-PR) contains background mutations that are presumed to alter the drug susceptibility of PR. In addition, amino acid variations found in HIV-1 Gag potentially affect the drug susceptibility or catalytic efficiency of PR.


METHODS
We studied the impact of naturally occurring amino acid substitutions found in AE-PR and CRF01_AE Gag (AE-Gag) on the drug susceptibility of PR to 9 currently available PIs, using the pNL4-3-derived luciferase reporter virus containing AE-Gag and/or AE-PR genes derived from drug treatment-naïve, HIV-1-infected Thai patients.


RESULTS
Sequencing analysis revealed that several mutations were detected in deduced amino acid sequences of AE-PR and AE-Gag genes, as compared to these genes of pNL4-3. Drug susceptibility tests revealed that AE-PR showed a variety of susceptibilities to 9 PIs compared with pNL4-3 PR. In addition, AE-Gag significantly reduced the drug susceptibility of AE-PR and pNL4-3 PR.


CONCLUSIONS
Our results suggest that amino acid variations in AE-PR and AE-Gag play roles in determining the drug susceptibility of CRF01_AE viruses to PIs.
Jinnopat
Piyamat
P
Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections, Nonthaburi, Thailand.
Isarangkura-na-ayuthaya
Panasda
P
Utachee
Piraporn
P
Kitagawa
Yukiko
Y
de Silva
U Chandimal
UC
Siripanyaphinyo
Uamporn
U
Kameoka
Yoko
Y
Tokunaga
Kenzo
K
Sawanpanyalert
Pathom
P
Ikuta
Kazuyoshi
K
Auwanit
Wattana
W
Kameoka
Masanori
M
D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D015658:HIV Infections / Q000453:epidemiology / Q000821:virology; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013785:Thailand / Q000453:epidemiology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics*
D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease