T-cell receptor vbeta8.1 peptide reduces coxsackievirus-induced cardiopathology in aged mice.

Viral myocarditis is an important cause of heart failure and cardiomyopathy. Immunosenescence, characterized by a dramatic reduction in immune responsiveness, can increase susceptibility to cardiopathology from viral infections. The T-cell receptor (TCR) Vbeta 8.1 peptide, a 16-mer peptide, has shown immuno-regulating and immunostimulating effects in viral-induced immunodeficiency. In our study, 18-mo-old C57Bl/6 female mice were treated twice with TCR Vbeta8.1 peptide and 10 d before sacrifice were injected ip with coxsackievirus B3. Cardiac histopathology was assessed for lesion severity. Splenocyte cyto-kine production (interleukin-2, -4, -6, interferon-gamma) and heart viral titers were determined. Our data suggest that immunosenescence suppressed both T helper (Th1) and Th2 cytokine production and that treatment with TCR Vbeta8.1 peptide induced cytokine stimulation close to levels seen in young mice. Nontreated aged mice developed some degree of myocarditis (75% mild and 25% severe), whereas only 35% of the peptide-treated aged group developed cardiopathology, with 25% being mild and 10% severe. Heart tissue from nontreated aged mice infected with coxsackievirus had a higher viral titer than hearts of aged mice equally infected but treated with the peptide. In conclusion, TCR Vbeta8.1 peptide induced immunoregulation, and inhibited or reduced coxsackievirus B3-induced cardiopathology in aged mice.

Dilated cardiomyopathy in retrovirally infected mice: a novel model for silent viral DCM?

Dilated cardiomyopathy (DCM) is a clinically relevant disease that can occur independently or secondary to other diseases such as HIV infection and AIDS. To study this latter process, we used a model in which mice are infected with the LP-BM5 murine AIDS (MAIDS) retrovirus. Cardiac function of control and infected mice was determined through the in vivo analysis of left ventricular pressure-volume loops. Furthermore, the role of myocarditis was investigated through immunohistochemistry for T-cell, B-cell, and macrophage cardiac infiltrates and Northern blot analysis for tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS). End-systolic and end-diastolic volumes were significantly increased and ventricular stiffness was significantly decreased in infected mice, consistent with DCM; however, no staining for inflammatory cellular infiltrates or TNF-alpha and iNOS was seen. These data support the conclusion that the LP-BM5 HIV model virus causes DCM in the absence of chronic cardiac inflammation. These findings support MAIDS retroviral infection as a new model of idiopathic DCM in which myo-carditis does not occur.

T-cell receptor V beta 8.1 peptide reduces coxsackievirus-induced cardiopathology during murine acquired immunodeficiency syndrome.

Infection of people with human immunodeficiency virus (HIV) as well as LP-BM5 infection in mice results in progressive deterioration of the immune system in the majority of untreated hosts. Peptide immunotherapy has been shown to be effective in the stimulation or immunoregulation of T-helper 1 (T(H)1) and T-helper 2 (T(H) 2) response subsets. In murine acquired immunodeficiency syndrome (AIDS), T(H)1 deficiency enables the host to be susceptible to coxsackievirus infection, inducing cardiopathology in a short period. T-cell receptor (TCR) Vbeta8.1 peptide, a 16-mer peptide containing the entire CDR1 segment and part of the FR2 region of human Vbeta8, showed both an immunoregulating and immunostimulating effect in murine AIDS. TCR Vbeta8.1 peptide acts on T cells promoting interleukin-2 production and therefore enhancing a cell-mediated immune response. It retarded development of cardiopathology due to coxsackievirus infection. Retrovirus-infected mice treated with the peptide showed a longer life span than the nontreated, retrovirus-infected animals.

Cocaethylene and heart disease during murine AIDS.

Cocaethylene is an active cocaine metabolite believed to play a causative role in the increased incidence of sudden cardiac death in individuals who co-administer alcohol and cocaine. Prolonged and excessive abuse of cocaine and alcohol will result in marked alteration of host immunity to increased susceptibility to infection. To test the chronic direct effect of cocaethylene on the heart function, a conductance catheter system (CCS) was used in vivo in this study. To test whether cocaethylene injection exacerbates coxsackievirus B3 (CVB3) or cytomegalovirus (CMV) cardiomyopathy during murine AIDS, female C57BL/6 mice were infected with LP-BM5 retrovirus and superinfected with CVB3 or CMV. Daily, mice were injected intraperitoneally with cocaethylene in 0.9% saline solution (concentration increased gradually from 15 to 25 mg/ml). Histopathology of heart tissue was analyzed in all groups, and cytokines of spleen were measured in the CMV-infected groups. Results showed there was little effect on the cardiovascular system after cocaethylene injection. Cocaethylene injection during murine retrovirus infection greatly exacerbated the pathogenesis of CVB3 or CMV infection, whereas CMV-infected mice showed relatively moderate cardiac pathology compared with CVB3 infection. Both CMV and retrovirus infection suppressed the Th1 response. Our data suggest that cocaethylene treatment shifts the cytokine balance and suppresses Th1 response particularly, facilitating increased CVB3- or CMV-induced myocarditis.