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Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
|---|---|
| Personen und Körperschaften: | , , , , , , , , |
| In: | Antimicrobial Agents and Chemotherapy, 53, 2009, 11, S. 4726-4732 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| author_facet |
Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang |
|---|---|
| author |
Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang |
| spellingShingle |
Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang Antimicrobial Agents and Chemotherapy Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors Infectious Diseases Pharmacology (medical) Pharmacology |
| author_sort |
alexander, louis |
| spelling |
Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.00494-09 <jats:title>ABSTRACT</jats:title><jats:p>Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4<jats:sup>+</jats:sup>T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4<jats:sup>+</jats:sup>-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4<jats:sup>+</jats:sup>-T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4<jats:sup>+</jats:sup>-T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4<jats:sup>+</jats:sup>-T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.</jats:p> Inhibition of Envelope-Mediated CD4<sup>+</sup>-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors Antimicrobial Agents and Chemotherapy |
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| title |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_unstemmed |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_full |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_fullStr |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_full_unstemmed |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_short |
Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_sort |
inhibition of envelope-mediated cd4<sup>+</sup>-t-cell depletion by human immunodeficiency virus attachment inhibitors |
| topic |
Infectious Diseases Pharmacology (medical) Pharmacology |
| url |
http://dx.doi.org/10.1128/aac.00494-09 |
| publishDate |
2009 |
| physical |
4726-4732 |
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<jats:title>ABSTRACT</jats:title><jats:p>Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4<jats:sup>+</jats:sup>T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4<jats:sup>+</jats:sup>-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4<jats:sup>+</jats:sup>-T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4<jats:sup>+</jats:sup>-T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4<jats:sup>+</jats:sup>-T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.</jats:p> |
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| author | Alexander, Louis, Zhang, Sharon, McAuliffe, Brian, Connors, David, Zhou, Nannon, Wang, Tao, Agler, Michele, Kadow, John, Lin, Pin-Fang |
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| description | <jats:title>ABSTRACT</jats:title><jats:p>Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4<jats:sup>+</jats:sup>T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4<jats:sup>+</jats:sup>-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4<jats:sup>+</jats:sup>-T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4<jats:sup>+</jats:sup>-T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4<jats:sup>+</jats:sup>-T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.</jats:p> |
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| spelling | Alexander, Louis Zhang, Sharon McAuliffe, Brian Connors, David Zhou, Nannon Wang, Tao Agler, Michele Kadow, John Lin, Pin-Fang 0066-4804 1098-6596 American Society for Microbiology Infectious Diseases Pharmacology (medical) Pharmacology http://dx.doi.org/10.1128/aac.00494-09 <jats:title>ABSTRACT</jats:title><jats:p>Human immunodeficiency virus type 1 (HIV-1) envelope (Env) binding induces proapoptotic signals in CD4<jats:sup>+</jats:sup>T cells without a requirement of infection. Defective virus particles, which represent the majority of HIV-1, usually contain a functional Env and therefore represent a potentially significant cause of such CD4<jats:sup>+</jats:sup>-T-cell loss. We reasoned that an HIV-1 inhibitor that prohibits Env-host cell interactions could block the destructive effects of defective particles. HIV-1 attachment inhibitors (AIs), which potently inhibit Env-CD4 binding and subsequent downstream effects of Env, display low-nanomolar antiapoptotic potency and prevent CD4<jats:sup>+</jats:sup>-T-cell depletion from mixed lymphocyte cultures, also with low-nanomolar potency. Specific Env amino acid changes that confer resistance to AI antientry activity eliminate AI antiapoptotic effects. We observed that CD4<jats:sup>+</jats:sup>-T-cell destruction is specific for CXCR4-utilizing HIV-1 strains and that the fusion blocker enfuvirtide inhibits Env-mediated CD4<jats:sup>+</jats:sup>-T-cell killing but is substantially less potent than AIs. These observations, in conjunction with observed antiapoptotic activities of soluble CD4 and the CXCR4 blocker AMD3100, suggest that this AI activity functions through a mechanism common to AI antientry activity, e.g., prevention of Env conformation changes necessary for specific interactions with cellular factors that facilitate viral entry. Our study suggests that AIs, in addition to having potent antientry activity, could contribute to immune system homeostasis in individuals infected with HIV-1 that can engage CXCR4, thereby mitigating the increased risk of adverse clinical events observed in such individuals on current antiretroviral regimens.</jats:p> Inhibition of Envelope-Mediated CD4<sup>+</sup>-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors Antimicrobial Agents and Chemotherapy |
| spellingShingle | Alexander, Louis, Zhang, Sharon, McAuliffe, Brian, Connors, David, Zhou, Nannon, Wang, Tao, Agler, Michele, Kadow, John, Lin, Pin-Fang, Antimicrobial Agents and Chemotherapy, Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors, Infectious Diseases, Pharmacology (medical), Pharmacology |
| title | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_full | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_fullStr | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_full_unstemmed | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_short | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| title_sort | inhibition of envelope-mediated cd4<sup>+</sup>-t-cell depletion by human immunodeficiency virus attachment inhibitors |
| title_unstemmed | Inhibition of Envelope-Mediated CD4+-T-Cell Depletion by Human Immunodeficiency Virus Attachment Inhibitors |
| topic | Infectious Diseases, Pharmacology (medical), Pharmacology |
| url | http://dx.doi.org/10.1128/aac.00494-09 |