HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer

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dc.contributor.authorde Campos, Walter R Lopesen_ZA
dc.contributor.authorChirwa, Nthatoen_ZA
dc.contributor.authorLondon, Graceen_ZA
dc.contributor.authorRotherham, Lia Sen_ZA
dc.contributor.authorMorris, Lynnen_ZA
dc.contributor.authorMayosi, Bongani Men_ZA
dc.contributor.authorKhati, Makobetsaen_ZA
dc.date.accessioned2015-11-23T12:37:03Z
dc.date.available2015-11-23T12:37:03Z
dc.date.issued2014en_ZA
dc.description.abstractHIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM.en_ZA
dc.identifier.apacitationde Campos, W. R. L., Chirwa, N., London, G., Rotherham, L. S., Morris, L., Mayosi, B. M., & Khati, M. (2014). HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer. <i>PLoS One</i>, http://hdl.handle.net/11427/15354en_ZA
dc.identifier.chicagocitationde Campos, Walter R Lopes, Nthato Chirwa, Grace London, Lia S Rotherham, Lynn Morris, Bongani M Mayosi, and Makobetsa Khati "HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer." <i>PLoS One</i> (2014) http://hdl.handle.net/11427/15354en_ZA
dc.identifier.citationde Campos, W. R. L., Chirwa, N., London, G., Rotherham, L. S., Morris, L., Mayosi, B. M., & Khati, M. (2014). HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer. PloS one, 9(10), e110930-e110930. doi:10.1371/journal.pone.0110930en_ZA
dc.identifier.ris TY - Journal Article AU - de Campos, Walter R Lopes AU - Chirwa, Nthato AU - London, Grace AU - Rotherham, Lia S AU - Morris, Lynn AU - Mayosi, Bongani M AU - Khati, Makobetsa AB - HIV-associated cardiomyopathy (HIVCM) is of clinical concern in developing countries because of a high HIV-1 prevalence, especially subtype C, and limited access to highly active antiretroviral therapy (HAART). For these reasons, we investigated the direct and indirect effects of HIV-1 subtype C infection of cultured human cardiomyocytes and the mechanisms leading to cardiomyocytes damage; as well as a way to mitigate the damage. We evaluated a novel approach to mitigate HIVCM using a previously reported gp120 binding and HIV-1 neutralizing aptamer called UCLA1. We established a cell-based model of HIVCM by infecting human cardiomyocytes with cell-free HIV-1 or co-culturing human cardiomyocytes with HIV-infected monocyte derived macrophages (MDM). We discovered that HIV-1 subtype C unproductively (i.e. its life cycle is arrested after reverse transcription) infects cardiomyocytes. Furthermore, we found that HIV-1 initiates apoptosis of cardiomyocytes through caspase-9 activation, preferentially via the intrinsic or mitochondrial initiated pathway. CXCR4 receptor-using viruses were stronger inducers of apoptosis than CCR5 utilizing variants. Importantly, we discovered that HIV-1 induced apoptosis of cardiomyocytes was mitigated by UCLA1. However, UCLA1 had no protective effective on cardiomyocytes when apoptosis was triggered by HIV-infected MDM. When HIV-1 was treated with UCLA1 prior to infection of MDM, it failed to induce apoptosis of cardiomyocytes. These data suggest that HIV-1 causes a mitochondrial initiated apoptotic cascade, which signal through caspase-9, whereas HIV-1 infected MDM causes apoptosis predominantly via the death-receptor pathway, mediated by caspase-8. Furthermore the data suggest that UCLA1 protects cardiomyocytes from caspase-mediated apoptosis, directly by binding to HIV-1 and indirectly by preventing infection of MDM. DA - 2014 DB - OpenUCT DO - 10.1371/journal.pone.0110930 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer TI - HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer UR - http://hdl.handle.net/11427/15354 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15354
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0110930
dc.identifier.vancouvercitationde Campos WRL, Chirwa N, London G, Rotherham LS, Morris L, Mayosi BM, et al. HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptamer. PLoS One. 2014; http://hdl.handle.net/11427/15354.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2014 Lopes de Campos et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherApoptosisen_ZA
dc.subject.otherHIV-1en_ZA
dc.subject.otherMacrophagesen_ZA
dc.subject.otherCell stainingen_ZA
dc.subject.otherHIVen_ZA
dc.subject.otherCoreceptorsen_ZA
dc.subject.otherMitochondriaen_ZA
dc.subject.otherMonocytesen_ZA
dc.titleHIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-gp120 aptameren_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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