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

Abstract

32Herpes simplex virus 1 (HSV) is a ubiquitous human virus resident in a majority of the global 33 population as a latent infection. Acyclovir (ACV), is the standard of care drug used to treat primary 34 and recurrent infections, supplemented in some patients with intravenous immunoglobulin (IVIG) 35 treatment to suppress deleterious inflammatory responses. We found that HSV, ACV and IVIG 36 can all independently disrupt the gut bacterial community in a sex biased manner when given to 37 uninfected mice. Treatment of HSV infected mice with ACV or IVIG alone or together revealed 38 complex interactions between these drugs and infection that caused pronounced sex biased 39 dysbiosis. ACV reduced Bacteroidetes levels in male but not female mice, while levels of the 40 Anti-inflammatory Clostridia (AIC) were reduced in female but not male mice, which is significant 41 as these taxa are associated with protection against the development of GVHD in hematopoietic 42 stem cell transplant (HSCT) patients. Gut barrier dysfunction is associated with GVHD in HSCT 43 patients and ACV also decreased Akkermansia muciniphila, which is important for maintaining 44 gut barrier functionality. Cumulatively, our data suggest that long-term prophylactic ACV treatment 45 of HSCT patients may contribute to GVHD and potentially impact immune reconstitution. These 46 data have important implications for other clinical settings, including HSV eye disease and genital 47 infections, where ACV is given long-term. 48 49 Author Summary. 50 51 Primary and reactivated HSV and VZV infections are treated with Acyclovir (ACV), an 52 antiviral drug that blocks viral DNA synthesis. In some patients IVIG is used as adjunctive therapy 53 to block deleterious inflammation. Long term preventative treatment of patients who receive stem 54 transplants for various blood cancers has been successful in preventing life threatening 55 reactivated HSV and VZV infections, but GVHD remains a major factor limiting transplant 56 3 success. Studies reported here reveal that HSV infection, ACV and IVIG given alone can all 57 disrupt the gut microbiota and that complex interactions between these drugs and infection results 58 in even more pronounced sex biased changes in the gut bacteria community structure. 59 Importantly, ACV treatment decreased the levels of specific bacterial taxa, including the anti-60 inflammatory Clostriodia and Bacteroidetes that have been shown to protect against development 61 of GVHD in stem cell transplant patients. These data suggest that long term preventative 62 treatment of patients with ACV may contribute to GVHD in transplant patients and have negative 63 consequences in other HSV induced diseases treated long term with ACV. The health effects of 64 long term ACV and IVIG treatments warrant further clinical studies. 65 66 Introduction. 67 68 Herpes Simplex Virus type 1 (HSV), a ubiquitous human virus is the major cause of HSV 69 encephalitis (HSE), the most prevalent sporadic encephalitis resulting from either primary 70 infection ...

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