The SMAC Mimetic AZD5582 is a Potent HIV Latency Reversing Agent
| Autor: | Irlbeck Dm, David M. Margolis, Sampey Gc, Brehm Jh, David Favre, Corbin D. Jones, Jean-Pierre Routy, Matt Kanke, Edward P. Browne, McAllister Ab, Nancie M. Archin, Ferris Rg, Richard M. Dunham |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
education.field_of_study biology 030302 biochemistry & molecular biology Population Provirus Inhibitor of apoptosis In vitro 3. Good health 03 medical and health sciences Cancer research biology.protein Latency (engineering) education Transcription factor Caspase Ex vivo 030304 developmental biology |
| DOI: | 10.1101/312447 |
| Popis: | The leading strategy towards eradication of human immunodeficiency virus (HIV) infection is the depletion of viral reservoirs through reversal of viral latency, followed by clearance of persistently infected cells. To date, a latency reversing agent (LRA) that reactivates a majority of the quiescent provirus population, without significant off-target effects, has not been identified. We show here that molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latency in vitro and ex vivo without the pleotropic cellular effects seen with other LRA. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFkB pathway as exemplified by rapid degradation of cellular inhibitor of apoptosis protein 1 (cIAP1), followed by a slower conversion of the inactive p100 form of NFκB2 into the active p52 transcription factor. A potent representative of this class, AZD5582, increases cell-associated HIV RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of this class of molecules in preclinical animal models. |
| Databáze: | OpenAIRE |
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