Abstract
The molecular cause(s) for early onset heart failure in people living with HIV-1 infection (PLWH) remains poorly defined. Herein, longitudinal echocardiography was used to assess whether NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice reconstituted with human hematopoietic stem cells (Hu-NSG mice) and infected with HIV-1ADA can recapitulate the salient features of this progressive human disease. Four weeks post infection, Hu-NSG mice of both sexes developed left ventricular (LV) diastolic dysfunction (DD), with 25% exhibiting grade III/IV restrictive DD with mitral regurgitation. Increases in global longitudinal and circumferential strains and declines in LV ejection fraction and fractional shortening were observed eight weeks post infection. After twelve weeks of infection, 33% of Hu-NSG mice exhibited LV dyskinesia and dyssynchrony. Histopathological analyses of hearts seventeen weeks post infection revealed coronary microvascular leakage, fibrosis and immune cell infiltration into the myocardium. These data show for the first time that HIV-1ADA-infected Hu-NSG mice can recapitulate key left ventricular cardiac deficits and pathophysiological changes reported in humans with progressive HIV-1 infection. The results also suggest that HIV-1 infected Hu-NSG mice may be a useful model to screen for pharmacological agents to blunt LV dysfunction and associated pathophysiologic causes reported in PLWH.
Highlights
Advances in and adherence to combination anti-retroviral therapies have resulted in significant increases in life expectancy for people living with HIV-1 infection (PLWH)[1]
The percentages of CD4+ T cells in blood declined in HIV-1 infected Hu-NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice from 76.6 ± 0.4 to 37.2% ± 2.1 while CD8+ T cells gradually increased over the same period (Supplemental Fig. 1)
The principal finding of the present study is that HIV-1-infected Hu-NSG mice develop progressive left ventricular (LV) diastolic and systolic heart failure (HF), akin to that reported with HIV infection reported pre-cART56era
Summary
Advances in and adherence to combination anti-retroviral therapies (cART) have resulted in significant increases in life expectancy for people living with HIV-1 infection (PLWH)[1]. A consequence of the increased longevity is an increase in the prevalence of cardiovascular diseases (CVD) including heart failure (HF) for which the mechanisms remain poorly defined and pharmacologic strategies to attenuate them are limited[2,3] from (https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics). The underlying cause(s) for impairments in cardiac functions in PLWH remain poorly understood, clinical data suggest that chronic inflammation associated with long-term cART usage, co-infections, alcohol and drugs of abuse may be promoting/potentiating metabolic dysregulation and aging-related diseases in this population[2,3,5,6]. Transgenic rodent models have successfully delineated the contributions of the HIV-1 auxiliary proteins, Nef, gp[120] and Tat in the development of HIV-1 associated HF24,27–31 Since these models do not support productive replication of this human-specific virus, the impact of antiretrovirals and inflammation in the setting of HIV-1 infection remains inadequately addressed. A small animal model replicating HIV pathogenesis would facilitate the studies on mechanisms involved in the development and progression of HF and to test the therapeutic interventions
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