title: HIV-1 subtype C unproductively infects human cardiomyocytes in vitro and induces apoptosis mitigated by an anti-Gp120 aptamer.
abstract: 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.
authors.affiliation: Emerging Health Technologies Competency Area, Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Lopes de Campos
authors.affiliation: Emerging Health Technologies Competency Area, Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Nthato
authors.initials: N
authors.lastname: Chirwa
authors.affiliation: Emerging Health Technologies Competency Area, Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Grace
authors.initials: G
authors.lastname: London
authors.affiliation: Emerging Health Technologies Competency Area, Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Lia S
authors.initials: LS
authors.lastname: Rotherham
authors.affiliation: National Institute for Communicable Diseases, Sandringham, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
authors.affiliation: Emerging Health Technologies Competency Area, Biosciences Unit, Council for Scientific and Industrial Research, Pretoria, South Africa; Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.
authors.forename: Makobetsa
authors.initials: M
authors.lastname: Khati
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D052158:Aptamers, Peptide / Q000008:administration & dosage / Q000378:metabolism*; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000821:virology; D002474:Cell-Free System; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000821:virology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019718:Receptors, CXCR4 / Q000378:metabolism
chemical_list: D052158:Aptamers, Peptide; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4