Recovery of Humoral Immunity Is Critical for Successful Antiviral Therapy in Disseminated Mouse Adenovirus Type 1 Infection

Abstract

Severe adenovirus infections in transplant recipients undergoing immunosuppressive therapy are of increasing concern. Controversy exists on the contribution of antiviral therapy and the host immune response to recovery from these infections. Here, we established a systemic mouse adenovirus type 1 (MAV-1) infection in cyclophosphamide (CyP)-treated BALB/c mice. CyP was administered at 100 mg per kg of body weight every other day for 2, 3, or 4 weeks, thereby inducing general but reversible leukopenia, with a major suppression of the B-cell numbers and functionality that was more pronounced than that seen with T cells. The outcome of MAV-1 infection was dependent on the duration of CyP therapy, as the mice with the most severe immunosuppression were the most vulnerable to MAV-1-induced hemorrhagic enteritis and mortality. The protective effect of concomitant antiviral therapy with cidofovir depended on the level of immunosuppression. The combination of cidofovir treatment with the withdrawal of immunosuppression was the most successful regimen for increasing survival rates. Survival was clearly correlated with the clearance of virus and increased titers of MAV-1-specific antibodies in sera. In addition, the passive transfer of MAV-1-specific immunoglobulin G into MAV-1-infected SCID BALB/c mice caused a marked delay in mortality, the extent of the delay being dependent on the titer of MAV-1-specific antibodies. Based on the critical role of the humoral immune response in the early defense against disseminated adenovirus infection, the concomitant use of adenovirus-specific immunoglobulins and antiviral therapy should be considered for transplant patients at risk for severe adenovirus infections.

Clinical features and treatment of adenovirus infections

“…In SCID mice, continued cidofovir therapy caused a marked delay in, but could not prevent fatal MAV-1-induced disease, suggesting the indispensability of an efficient host immune response for complete viral clearance [145]. This was confirmed by the positive effect of anti-MAV-1-specific IgG therapy, and by antiviral treatment of MAV-1-infected mice experiencing cyclophosphamide-induced immunosuppression [146], as the effect of cidofovir therapy depended on the level of immunosuppression. In particular, recovery of humoral immunity seemed to be critical for successful antiviral therapy in disseminated MAV-1 infection.…”

Adenovirus in Solid Organ Transplant Recipients

“…Antibody preparations, including polyclonal immunoglobulin with high-titers against RSV (Respigam, MedImmune, Inc. Gaithersburg, MD, USA), have been used in a few cases. Though these agents have biologic plausibility (45), their benefit is unclear (CIII) (29). Enhancement of adenovirus-specific immunity, through lymphocyte infusion, may improve outcomes in disseminated infections but this intervention has not been studied in the solid organ population (46,47).…”

Ganciclovir Inhibits Human Adenovirus Replication and Pathogenicity in Permissive Immunosuppressed Syrian Hamsters

“…Also, some reports noted that prophylactic treatment of transplant patients with GCV to prevent CMV infection seemed to decrease the incidence of Ad infections (30)(31)(32). Several case studies suggested that GCV used therapeutically in transplant patients has anti-Ad activity (33)(34)(35).…”