Characterizing the Cellular Immune Response to Parainfluenza Virus 3

Abstract

Parainfluenza virus type 3 (PIV3) infections are a major cause of morbidity and mortality in immunocompromised individuals, with no approved therapies. Our group has demonstrated the safety and efficacy of adoptively transferred virus-specific T cells for the prevention and treatment of a broad range of viral infections including BK virus, cytomegalovirus, adenovirus, human herpesvirus 6, and Epstein-Barr virus. However, this approach is restricted to well-characterized viruses with known immunogenic/protective T-cell target antigens, precluding extension to PIV3. We now characterize the cellular immune response to all 7 PIV3-encoded antigens in 17 healthy donors and define a hierarchy of immunogenicity based on the frequency of responding donors and the magnitude of specific cells. We show that reactive populations of both CD4+ and CD8+ T cells are capable of producing Th1-polarized effector cytokines and killing PIV3-expressing targets. Furthermore, we confirm the clinical relevance of these cells by demonstrating a direct correlation between the presence of PIV3-specific T cells and viral control in allogeneic hematopoietic stem cell transplant recipients. Taken together, our findings support the clinical use of PIV3-specific T cells produced with our Good Manufacturing Practice-compliant manufacturing process, in immunocompromised patients with uncontrolled infections.

Risk Factors for Parainfluenza Virus Lower Respiratory Tract Disease after Hematopoietic Cell Transplantation

“…Steroid use has been consistently shown to be important for progression in this and other studies [11, 17]. Based on our study, we recommend reducing the steroid dose whenever feasible to less than 1 mg/kg when PIV is detected until a new anti-viral drug such as DAS181 or virus-specific T cell therapy are shown to be effective and available for use [26–30]. …”

Human Rhinovirus Infections in Hematopoietic Cell Transplant Recipients: Risk Score for Progression to Lower Respiratory Tract Infection

“…The risk score proposed may have implications for risk stratifying patients for more intense clinical monitoring. Additionally, risk stratification will help inform the design of future randomized clinical trials of novel therapeutics, including the growing field of virus specific T cells, which are currently being evaluated for other respiratory viruses including PIV and hMPV 43 , 44 .…”

Respiratory Virus Infections in Hematopoietic Cell Transplant Recipients

“…Currently, multiviral (including AdV) T cell manufacturing and banking from a third-party donor is a promising strategy as it might offer an immediate way to prevent AdV infections after HCT or to cure 71% of AdV infected patients after HCT (Tzannou et al, 2017). Ex vivo expanded cytotoxic T cells against PIV-3 antigens should be further tested in clinical trials (McLaughlin et al, 2016; Aguayo-Hiraldo et al, 2017).…”