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.
Highlights
South Africa has the highest HIV-1 prevalence that is almost exclusively subtype C [4]
Cultured human cardiomyocytes were infected by all the R5, X4 and R5/X4 subtype C HIV-1 isolates tested in the presence or absence of respective co-receptor inhibitors as evidenced by the presence of proviral DNA (Table 1)
We have showed for the first time that UCLA1 [18], a synthetic derivative of gp120 binding aptamer called B40 [19,20,21,22], mitigated HIV-1 subtype C induced apoptosis of human cord-blood stem cell-derived cardiomyocytes
Summary
South Africa has the highest HIV-1 prevalence that is almost exclusively subtype C [4]. Chronic HIV-1 infection causes a broad range of clinical complications, some of which remain poorly elucidated One such disease is HIV-associated cardiomyopathy (HIVCM). The cardio toxic effects are believed to be triggered in a caspase-dependent, mitochondria-initiated fashion, when gp120 interacts with the CXCR4 receptor on the surface of cardiomyocytes [12]. This in turn results in the induction of a negative ionotropic effect through increase in nitric oxide (NO) production via p38 mitogen activated protein kinase (p38 MAPK)iPLA2-troponin I initiated NF-kB activation [6,7,8]. The exact pathway is not fully understood but leakage of cytochrome c into the cell cytosol following permeabilization of the mitochondrial membrane triggers the activation of the caspase 9/3 complex eventually culminating in nuclear DNA fragmentation [15]
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