728 Transgenic Targeting of HIV vpr to Cardiac Myocytes Causes Cardiac Mesenchymal Tumors W Lewis*, Y K Miller, C Haase, M Ganta, M Kozak, T Ludaway, J McNaught, R Russ, J Steltzer, R Long, and J Oshinski Emory Univ., Atlanta, GA, USA
Background: HIV-1 is implicated etiologically in AIDS cardiomyopathy, but mechanisms remain unclear. HIV-1 viral protein R (vpr) is reported to impact on cell differentiation and fate.
Methods: To understand the role of HIV-1 vpr in AIDS cardiomyopathy, the gene for HIV-1 vpr was targeted transgenically to murine cardiac myocytes using ?-myosin heavy chain promoter. Hearts were examined histologically, ultrastructurally, molecularly via microarray analysis of RNA, and through magnetic resonance imaging (MRI) in vivo.
Results: Six transgenic lines were established. Cardiac vpr was expressed at high levels in one transgenic line (Vprb); others exhibited lower expression (Vpra,c,d,e,h). Vpr RNA was present exclusively in myocardium of transgenic lines without expression in other tissues. Survival was decreased from control and varied with transgenic line expression and age. Vprb transgenic lines grew moribund with profound congestive heart failure at 8 weeks. Lower expression transgenic line lines (Vpra,c,d,e,h) survived up to 8 months with atrial tumors. MRI revealed masses in the cardiac atria with defective atrial contraction. Gross and microscopic examination of transgenic lines confirmed the presence of congestive heart failure with massive dilation of the atria. Histologic examination confirmed presence of massive atrial cardiac mesenchymal tumors and atrial wall thinning. Tumors were relatively acellular with prominent spindle cells, abundant extracellular matrix, cartilage, and osteoid. No ectodermal elements were identified and tumors were pathologically similar amongst the transgenic line lines. TEM performed on tumor samples confirmed abundant extracellular matrix and poorly differentiated spindle cells without myocytic features. Correlative microarray data revealed 2.2- to 10-fold increases in abundance of collagen mRNA (14 gene products), and 2.7- to 14-fold increase in abundance of lysyl oxidase mRNA (4 gene products), an enzyme for connective tissue biosynthesis.
Conclusions: HIV-1 Vpr expressed transgenically in murine myocardium resulted in cardiac cell structural changes, profound congestive heart failure, and changes in expression of extracellular matrix proteins. These transgenic lines may help elucidate events of cardiac cellular growth and differentiation in AIDS cardiomyopathy.
