Herpes Simplex Virus Infection, Acyclovir and IVIG Treatment All Independently Cause Gut Dysbiosis.

Abstract

Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) treatment to suppress deleterious inflammatory responses. We found that HSV, ACV and IVIG can all independently disrupt the gut bacterial community in a sex biased manner when given to uninfected mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed complex interactions between these drugs and infection that caused pronounced sex biased dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant as these taxa are associated with protection against the development of GVHD in hematopoietic stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment of HSCT patients may contribute to GVHD and potentially impact immune reconstitution. These data have important implications for other clinical settings, including HSV eye disease and genital infections, where ACV is given long-term. Author SummaryPrimary and reactivated HSV and VZV infections are treated with Acyclovir (ACV), an antiviral drug that blocks viral DNA synthesis. In some patients IVIG is used as adjunctive therapy to block deleterious inflammation. Long term preventative treatment of patients who receive stem transplants for various blood cancers has been successful in preventing life threatening reactivated HSV and VZV infections, but GVHD remains a major factor limiting transplant success. Studies reported here reveal that HSV infection, ACV and IVIG given alone can all disrupt the gut microbiota and that complex interactions between these drugs and infection results in even more pronounced sex biased changes in the gut bacteria community structure. Importantly, ACV treatment decreased the levels of specific bacterial taxa, including the anti-inflammatory Clostriodia and Bacteroidetes that have been shown to protect against development of GVHD in stem cell transplant patients. These data suggest that long term preventative treatment of patients with ACV may contribute to GVHD in transplant patients and have negative consequences in other HSV induced diseases treated long term with ACV. The health effects of long term ACV and IVIG treatments warrant further clinical studies.