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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
HIV-1 proteases from drug-naive West African patients are differentially less susceptible to protease inhibitors
Clinical Infectious Diseases, Volume 41, No. 2, Year 2005
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Description
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. © 2005 by the Infectious Diseases Society of America. All rights reserved.
Authors & Co-Authors
Kinomoto, Masanobu
Japan, Tokyo
National Institute of Infectious Diseases
Appiah-Opong, Regina
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Brandful, James Ashun Mensah
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Yokoyama, Masaru
Japan, Tokyo
National Institute of Infectious Diseases
Nii-Trebi, Nicholas I.
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Ugly-Kwame, Evelyn
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Sato, Hironori
Japan, Tokyo
National Institute of Infectious Diseases
Ofori‐Adjei, David
Ghana, Accra
Noguchi Memorial Institute for Medical Research
Kurata, Takeshi
Japan, Tokyo
National Institute of Infectious Diseases
Barré-Sinoussi, Françoise C.
France, Paris
Institut Pasteur, Paris
Sata, Tetsutaro
Japan, Tokyo
National Institute of Infectious Diseases
Tokunaga, Kenzo
Japan, Tokyo
National Institute of Infectious Diseases
Statistics
Citations: 74
Authors: 12
Affiliations: 3
Identifiers
Doi:
10.1086/431197
ISSN:
10584838
Research Areas
Genetics And Genomics
Health System And Policy
Infectious Diseases
Study Approach
Quantitative
Study Locations
Multi-countries