HIV-1 proteases from drug-naive West African patients are differentially less susceptible to protease inhibitors.
BACKGROUND
Now that highly active antiretroviral therapy (HAART) is being initiated on a large scale in West Africa, it remains controversial whether protease inhibitors (PIs), originally designed and tested against human immunodeficiency virus type 1 (HIV-1) subtype B, are equally effective against the non-B subtypes that are prevalent in West African countries. In this study, we investigated whether Ghanaian HIV-1 isolates, as representatives of West African isolates, are susceptible to PIs.


METHODS
We first generated an HIV-1 protease cassette vector proviral DNA carrying a luciferase gene, which allows patient-derived HIV-1 proteases to be inserted and to be subjected to both genotypic and phenotypic assays. HIV-1 protease genes derived from 39 treatment-naive Ghanaian patients were used in this experiment as representatives of West African strains. The cloned patient-derived HIV-1 protease genes were first sequenced and then genetically compared. Phenotypic analysis was performed with Ghanaian HIV-1 protease-chimeric viruses in the presence of 6 different PIs. Structural models of HIV-1 protease homodimers were constructed by the molecular modeling software.


RESULTS
Genetic analysis of cloned patient-derived HIV-1 protease genes indicated that most of the Ghanaian HIV-1 proteases are placed as subtype CRF02_AG strains, which are phylogenetically distant from subtype B strains, and that Ghanaian HIV-1 proteases do not harbor known major mutations influencing drug resistance but commonly carry 2-3 minor mutations. Phenotypic analysis performed with HIV-1 protease-recombinant viruses in the presence of 6 different PIs revealed that Ghanaian HIV-1 proteases are differentially less susceptible to the PIs. In support of this finding of differential susceptibility, structural analysis showed a significant distortion of nelfinavir, but not of amprenavir, in the Ghanaian protease pocket, suggesting nelfinavir might be less insertable into the Ghanaian protease than into the protease of subtype B.


CONCLUSIONS
These findings provide implications for the combination of PIs during the introduction of HAART into West Africa.
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Masanobu
M
Kinomoto
Regina
R
Appiah-Opong
J A M
JA
Brandful
Masaru
M
Yokoyama
Nicholas
N
Nii-Trebi
Evelyn
E
Ugly-Kwame
Hironori
H
Sato
David
D
Ofori-Adjei
Takeshi
T
Kurata
Françoise
F
Barre-Sinoussi
Tetsutaro
T
Sata
Kenzo
K
Tokunaga
D000328:Adult; D000595:Amino Acid Sequence; D024921:Drug Resistance, Multiple, Viral; D005869:Ghana / Q000453:epidemiology; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D010802:Phylogeny; D011487:Protein Conformation; D016415:Sequence Alignment
D017320:HIV Protease Inhibitors; D016333:HIV Protease