Takeya Tsutsumi

Viral infections are influenced by various microorganisms in the environment surrounding the target tissue, and the correlation between the type and balance of commensal microbiota is the key to establishment of the infection and pathogenicity. Some commensal microorganisms are known to resist or promote viral infection, while others are involved in pathogenicity. It is also becoming evident that the profile of the commensal microbiota under normal conditions influences the progression of viral diseases. Thus, to understand the pathogenesis underlying viral infections, it is important to elucidate the interactions among viruses, target tissues, and the surrounding environment, including the commensal microbiota, which should have different relationships with each virus. In this review, we outline the role of microorganisms in viral infections. Particularly, we focus on gaining an in-depth understanding of the correlations among viral infections, target tissues, and the surrounding environment, including the commensal microbiota and the gut virome, and discussing the impact of changes in the microbiota (dysbiosis) on the pathological progression of viral infections.

Aim: After the hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) around 2018, the importance of HAV vaccination was emphasized, especially for MSM‐living with human immunodeficiency virus (MSM‐LWHIV). Aimmugen^® is licensed and distributed exclusively in Japan. While administration of three doses is recommended, 85% of recipients in the general population were reported to acquire seroprotection after the second dose. In this study, we evaluated the efficacy of two or three vaccine doses along with predictors associated with the response to Aimmugen^® in MSM‐LWHIV.Methods: We retrospectively examined anti‐HA‐IgG titers of MSM‐LWHIV vaccinated with Aimmugen^® in our hospital. Patients' data were collected from medical records.Results: Between January 2018 and October 2019, 141 subjects whose median age was 46 years old, were examined. All the subjects were on antiretroviral therapy (ART) and the median CD4 count was 615/μL. The acquisition rate of protectable anti‐HA‐IgG titers after the second and third dose was 71.1% and 98.6%, respectively. In 114 subjects whose anti‐HA‐IgG titers were tested after the second‐dose, factors significantly associated with better response were prolonged ART duration and higher CD4 count. The titers of anti‐HA‐IgG after the third dose were higher in those who became seropositive after the second‐dose than those who did not.Conclusions: Three‐dose of Aimmugen^® for MSM‐LWHIV was effective while two‐dose was less effective compared to non‐HIV‐infected people. People‐LWHIV with shorter duration of ART and lesser CD4 cell count achieved lower titers of anti‐HA‐IgG and might require an additional vaccination.

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.

Since 2017, hepatitis A virus (HAV) infection has been an epidemic among men who have sex with men (MSM) in Japan. We experienced 11 MSM patients with hepatitis A who were also infected with HIV. In 1999–2000, we also experienced 5 HIV-infected patients with hepatitis A. Since conditions of current HIV-infected patients have changed owing to recent progress in anti-HIV therapies, we compared clinical features of hepatitis A between patients in 2017–2018 and those in 1999–2000. By comparing patients’ background characteristics, we found the CD4/CD8 ratio was significantly higher in the 2017–2018 group. After the onset of hepatitis, peak levels of hepatic transaminases were higher in the 2017–2018 group, suggesting the hepatocellular damage was more severe. On the other hand, neither the peak level of total bilirubin nor the nadir of prothrombin time was significantly different. We also analyzed the HAV genome derived from some of the recently infected patients and found the HAV strains were almost the same among these patients and slightly different from a previously identified strain. The recovery of immunity by recent anti-HIV therapies may result in a more severe hepatocellular damages and differences in clinical features.

Helicobacter pylori infection and liver diseases: Epidemiology and insights into pathogenesis