HIV-1 Proteases from Drug-Naive West African Patients Are Differentially Less Susceptible to Protease Inhibitors
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Auteurs : Masanobu Kinomoto [Japon] ; Regina Appiah-Opong [Ghana] ; J. A. M. Brandful [Ghana] ; Masaru Yokoyama [Japon] ; Nicholas Nii-Trebi [Ghana] ; Evelyn Ugly-Kwame [Ghana] ; Hironori Sato [Japon] ; David Ofori-Adjei [Ghana] ; Takeshi Kurata [Japon] ; Françoise Barre-Sinoussi [France] ; Tetsutaro Sata [Japon] ; Kenzo Tokunaga [Japon]Source :
- Clinical Infectious Diseases [ 1058-4838 ] ; 2005-07-15.
Abstract
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.
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DOI: 10.1086/431197
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Opong, Regina" sort="Appiah Opong, Regina" uniqKey="Appiah Opong R" first="Regina" last="Appiah-Opong">Regina Appiah-Opong</name><affiliation wicri:level="1"><mods:affiliation>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana</mods:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon</wicri:regionArea></affiliation></author><author><name sortKey="Brandful, J A M" sort="Brandful, J A M" uniqKey="Brandful J" first="J. A. M." last="Brandful">J. A. M. Brandful</name><affiliation wicri:level="1"><mods:affiliation>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana</mods:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon</wicri:regionArea></affiliation></author><author><name sortKey="Yokoyama, Masaru" sort="Yokoyama, Masaru" uniqKey="Yokoyama M" first="Masaru" last="Yokoyama">Masaru Yokoyama</name><affiliation wicri:level="1"><mods:affiliation>Division of Molecular Genetics, National Institute of Infectious Diseases, Tokyo, Japan</mods:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Molecular Genetics, National Institute of Infectious Diseases, Tokyo</wicri:regionArea></affiliation></author><author><name sortKey="Nii Trebi, Nicholas" sort="Nii Trebi, Nicholas" uniqKey="Nii Trebi N" first="Nicholas" last="Nii-Trebi">Nicholas Nii-Trebi</name><affiliation wicri:level="1"><mods:affiliation>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana</mods:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon</wicri:regionArea></affiliation></author><author><name sortKey="Ugly Kwame, Evelyn" sort="Ugly Kwame, Evelyn" uniqKey="Ugly Kwame E" first="Evelyn" last="Ugly-Kwame">Evelyn Ugly-Kwame</name><affiliation wicri:level="1"><mods:affiliation>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana</mods:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon</wicri:regionArea></affiliation></author><author><name sortKey="Sato, Hironori" sort="Sato, Hironori" uniqKey="Sato H" first="Hironori" last="Sato">Hironori Sato</name><affiliation wicri:level="1"><mods:affiliation>Division of Molecular Genetics, National Institute of Infectious Diseases, Tokyo, Japan</mods:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Division of Molecular Genetics, National Institute of Infectious Diseases, Tokyo</wicri:regionArea></affiliation></author><author><name sortKey="Ofori Adjei, David" sort="Ofori Adjei, David" uniqKey="Ofori Adjei D" first="David" last="Ofori-Adjei">David Ofori-Adjei</name><affiliation wicri:level="1"><mods:affiliation>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana</mods:affiliation><country xml:lang="fr">Ghana</country><wicri:regionArea>Noguchi Memorial Institute for Medical Research, University of Ghana, Legon</wicri:regionArea></affiliation></author><author><name sortKey="Kurata, Takeshi" sort="Kurata, Takeshi" uniqKey="Kurata T" first="Takeshi" last="Kurata">Takeshi Kurata</name><affiliation wicri:level="1"><mods:affiliation>Department of Pathology and National Institute of Infectious Diseases, Tokyo, Japan</mods:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pathology and National Institute of Infectious Diseases, Tokyo</wicri:regionArea></affiliation></author><author><name sortKey="Barre Sinoussi, Francoise" sort="Barre Sinoussi, Francoise" uniqKey="Barre Sinoussi F" first="Françoise" last="Barre-Sinoussi">Françoise Barre-Sinoussi</name><affiliation wicri:level="1"><mods:affiliation>Unité de Régulations des Infection Rétrovirales, Institut Pasteur, Paris, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Régulations des Infection Rétrovirales, Institut Pasteur, Paris</wicri:regionArea></affiliation></author><author><name sortKey="Sata, Tetsutaro" sort="Sata, Tetsutaro" uniqKey="Sata T" first="Tetsutaro" last="Sata">Tetsutaro Sata</name><affiliation wicri:level="1"><mods:affiliation>Department of Pathology and National Institute of Infectious Diseases, Tokyo, Japan</mods:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pathology and National Institute of Infectious Diseases, Tokyo</wicri:regionArea></affiliation></author><author><name sortKey="Tokunaga, Kenzo" sort="Tokunaga, Kenzo" uniqKey="Tokunaga K" first="Kenzo" last="Tokunaga">Kenzo Tokunaga</name><affiliation wicri:level="1"><mods:affiliation>Department of Pathology and National Institute of Infectious Diseases, Tokyo, Japan</mods:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Pathology and National Institute of Infectious Diseases, Tokyo</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: tokunaga@nih.go.jp</mods:affiliation><country wicri:rule="url">Japon</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Clinical Infectious Diseases</title><title level="j" type="abbrev">Clinical Infectious Diseases</title><idno type="ISSN">1058-4838</idno><idno type="eISSN">1537-6591</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2005-07-15">2005-07-15</date><biblScope unit="volume">41</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="243">243</biblScope><biblScope unit="page" to="251">251</biblScope></imprint><idno type="ISSN">1058-4838</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1058-4838</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">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.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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