Cytomegalovirus

Violin plots showing a lower cellular CMV-specific immune response in patients treated with letermovir 3 months following hematopoeitic stem cell transplant
Combinatorial polyfunctionality analysis of antigen specific T-cell subsets (COMPASS) generated CD4+ and CD8+ polyfunctionality scores (PFS) following stimulation with CMV IE-1 or pp65 overlapping libraries. Immunity measured approximately 3 months post HCT in letermovir recipients vs. controls who received preemptive therapy. From: Zamora, Danniel et al. 2020. Cytomegalovirus-specific T-cell Reconstitution following Letermovir Prophylaxis after Hematopoeitic Cell Transplantation. Submitted for publication.

CMV (Cytomegalovirus) is a ubiquitous human herpes virus that causes adverse clinical outcomes in immunocompromised individuals, such as hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients and those infected with human immunodeficiency virus (HIV). CMV infection is the most frequent viral complication after HCT, and current strategies using either preemptive or prophylactic antivirals have not eliminated CMV complications. CMV reactivation is also common in immunocompetent adults with critical illness, and is associated with complications including prolonged mechanical ventilation and increased duration of ICU admission and hospitalization.

Our research in immunocompromised patients takes a multifaceted approach to identifying epidemiologic risk factors for CMV infection, defining viral kinetics, and improving prevention, diagnosis and treatment strategies. By better understanding the kinetics of the reconstitution of CMV-specific immune function following transplantation, we seek to define the components of protective cellular and humoral immunity by testing multifunctional T cell responses and neutralizing Abs directed against the pentameric complex.  We are using VirScan, which yields comprehensive serological profiling of antiviral antibodies, to evaluate the impact of CMV infection and treatment regimens on overall humoral immunity. Through involvement in clinical trials, we seek to evaluate new antivirals for CMV prophylaxis and treatment, and are interested in the effects of treatment regimens on CMV-specific immune reconstitution and late-onset CMV reactivation.

Recent studies by our group in this area have demonstrated the superiority of preemptive therapy over prophylaxis for preventing CMV disease in CMV-seronegative recipients of liver transplants from seropositive donors, and have shown that letermovir prophylaxis after HCT delays CMV-specific immune reconstitution. We also seek to increase the speed and efficacy of clinical trials, and toward this goal we recently helped to establish CMV viral load kinetics as a surrogate endpoint for CMV disease in HCT recipients. An additional area of focus is improved diagnostics — in an ongoing trial, we are assessing self-collection of dried blood spots as a strategy to make weekly CMV testing more feasible at late time points after HCT. Within the immunocompetent patient population, our group recently found that antiviral prophylaxis directed at CMV increases ventilator-free days in patients with sepsis-associated respiratory failure, and these results are the basis for an upcoming large randomized phase 3 trial.