Evaluation of coxsackievirus infection in children with human immunodeficiency virus type 1-associated cardiomyopathy

In a matched case-control study of the association between coxsackieviruses and cardiac impairment, 24 human immunodeficiency virus (HIV) type 1-infected children with cardiac impairment were compared with 24 HIV-1-infected control subjects. Serologic evidence of coxsackievirus infection was present in all children, with no significant difference in geometric mean antibody titers between case patients and control subjects. Conditional logistic regression to test for an association between coxsackievirus antibody titer and the presence or absence of cardiac impairment, by any indicator, showed an odds ratio of 1.11 (95% confidence interval, 0.58-2.10; P = .75), indicating no association between coxsackievirus infection and cardiac impairment. Coxsackievirus antibody titers correlated positively with total IgG levels in nonrapid progressors but not in rapid progressors. Paired serum samples taken before and after diagnosis of cardiac impairment in 5 patients showed no evidence of intervening coxsackievirus infection. These results do not identify a causal role for coxsackieviruses for cardiomyopathy in HIV-1-infected children

Temperature-Sensitive Mutant of Coxsackievirus B3 Establishes Resistance in Neonatal Mice That Protects Them During Adolescence Against Coxsackievirus B3-Induced Myocarditis

Inoculation of neonatal CD-1 mice by multiple routes with an amyocarditic temperature-sensitive (ts) mutant (ts 1) derived from a myocarditic parent variant of coxsackievirus B3 (CVB3(m)) resulted in approximately half of the neonates surviving to adolescence. Challenge of the ts 1 survivors with CVB3(m) did not induce myocarditis, as assessed by histological examination of heart tissues. Virus was not detected in heart tissues of adolescent ts 1 survivors, but inoculation of these mice with CVB3(m) resulted in virus concentrations similar in titers to those found in CVB3(m)-inoculated normal adolescent mice. The ts 1 survivors did not contain detectable levels of anti-CVB3(m) neutralizing antibody, but upon challenge with CVB3(m) they produced antibody more rapidly and to higher titers than did normal CD-1 adolescents after primary inoculation with CVB3(m). Cell-mediated immunity in ts 1 survivors was compared with that of normal mice after challenge with CVB3(m). The capacity for production of migration inhibitory factor was assessed by the agarose droplet cell migration inhibition assay, using peritoneal exudate cells and a CVB3(m) cell lysate or KCl-extracted antigens from heart tissues of CVB3(m)-inoculated mice. Migration inhibitory factor activity was not detected in cultures of splenic leukocytes from ts 1 survivors of CVB3(m)-inoculated ts 1 survivors, but it was readily detected in cultures of splenic leukocytes from CVB3(m)-inoculated normal adolescent mice. The [(3)H]thymidine stimulation assay, performed with splenic lymphoid cells and purified CVB3(m) particles, revealed that lymphocytes from normal mice, whether inoculated with CVB3(m) or not, were not stimulated by CVB3(m) particle antigens, whereas lymphoid cells from a significantly higher proportion of ts 1 survivors, whether inoculated with CVB3(m) or not, responded with a stimulation index ≥2.0. The cells responding with positive stimulation were T lymphocytes. A higher proportion of normal mice and ts 1 survivors, both inoculated with CVB3(m), contained splenic cytotoxic T lymphocytes with higher reactivity against CVB3(m)-infected neonatal skin fibroblasts than against normal skin fibroblasts, as assessed by a (51)Cr release assay. The group of uninoculated ts 1 survivors present as a high proportion of individuals with cytotoxic T-lymphocyte reactivity against both uninoculated and CVB3(m)-inoculated skin fibroblasts. However, ts 1 survivors and normal mice possessed the same proportions of splenic lymphocytes carrying either allele for Lyt 1 and Lyt 2 surface markers. The results suggest two mechanisms by which ts 1 survivors exhibit resistance to CVB3(m) induction of myocarditis, namely, the rapid production of high-titered anti-CVB3(m) neutralizing antibody in response to CVB3(m) inoculation and altered cell-mediated immune responses against CVB3(m)-induced viral or novel cellular antigens. The data are compatible with the notion that an immune deviation mechanism, thought to be controlled through a mechanism requiring suppressor cell activity which inhibits macrophage activation in ts 1 survivors, protects these mice from induction of myocarditis

Diabetes Acceleration or Prevention by a Coxsackievirus B4 Infection: Critical Requirements for both Interleukin-4 and Gamma Interferon

Type 1 diabetes acceleration in nonobese diabetic (NOD) mice through coxsackievirus B4 (CVB4) infection requires a preexisting critical mass of autoreactive T cells in pancreatic islets, and in the absence of this insulitic threshold, CVB4 infection leads to long-term disease protection. To understand this acceleration and protection process, we challenged 8- and 12-week-old NOD mice containing a disruption in interleukin-4 (IL-4) or gamma interferon (IFN-γ) genes (NOD IL-4(−/−) and NOD IFN-γ(−/−), respectively) with a diabetogenic, pancreatropic Edwards strain of CVB4. The elimination of IL-4 did not alter the rate of insulitis or diabetes development in NOD mice, while the elimination of IFN-γ delayed these events several weeks. CVB4 infection in 8-week-old mice only significantly accelerated the onset of diabetes in a subset of standard, but not IL-4- or IFN-γ-deficient, NOD mice. Long-term diabetes protection was established in standard NOD mice as well as in the NOD IFN-γ(−/−) mice that did not rapidly develop disease following CVB4 infection at 8 weeks of age. When mice were infected at 12 weeks of age, the onset of diabetes was accelerated in NOD IL-4(−/−) mice, while neither acceleration nor long-term protection was elicited in NOD IFN-γ(−/−) mice. No differences were observed in the kinetics of CVB4 clearance in pancreases from NOD, NOD IL-4(−/−), and NOD IFN-γ(−/−) mice. Collectively, these results suggest that at the insulitis threshold at which CVB4 infection can first accelerate the onset of diabetes in NOD mice, IL-4 as well as IFN-γ contributes to this pathogenic process. The protective mechanism against diabetes elicited in NOD mice infected with CVB4 prior to the development of a critical threshold level of insulitis requires neither IL-4 nor IFN-γ