Persistence and reactivation of human adenoviruses in the gastrointestinal tract

Abstract

Reactivation of persistent human adenoviruses (HAdVs) is associated with high morbidity and mortality in paediatric haematopoietic stem cell transplant (HSCT) recipients. Although invasive HAdV infections mainly arise from the gastrointestinal (GI) tract, the specific sites of HAdV persistence are not well characterised. We prospectively screened biopsies from 143 non-HSCT paediatric patients undergoing GI endoscopy and monitored serial stool specimens from 148 paediatric HSCT recipients for the presence of HAdV by real-time PCR. Persistence of HAdV in the GI tract was identified in 31% of children, with the highest prevalence in the terminal ileum. In situ hybridisation and immunohistochemistry identified HAdV persistence in lymphoid cells of the lamina propria, whereas biopsies from five transplant recipients revealed high numbers of replicating HAdV in intestinal epithelial cells. The prevalence of HAdV species, the frequencies of persistence in the GI tract and reactivations post transplant indicated a correlation of intestinal HAdV shedding pre-transplant with high risk of invasive infection. HAdV persistence in the GI tract is a likely origin of infectious complications in immunocompromised children. Intestinal lymphocytes represent a reservoir for HAdV persistence and reactivation, whereas the intestinal epithelium is the main site of viral proliferation preceding dissemination. The findings have important implications for assessing the risk of life-threatening invasive HAdV infections.

Adenovirus persistence, reactivation, and clinical management

“…The proportion of children displaying HAdV persistence in intestinal biopsies and the percentage of pediatric allogeneic SCT recipients showing viral reactivation during the post-transplant period were quite similar in the studies performed [14,33]. This concept is further supported by the fact that the distribution of HAdV species found in children with intestinal persistence of the virus was virtually identical to that observed in patients displaying reactivation after allogeneic SCT [14]. This concept is further supported by the fact that the distribution of HAdV species found in children with intestinal persistence of the virus was virtually identical to that observed in patients displaying reactivation after allogeneic SCT [14].…”

“…Analysis by a pan-HAdV PCR assay indicated presence of the virus along the entire GI tract, with the highest prevalence in the ileum, in approximately one-third of the individuals tested [14]. Analysis by a pan-HAdV PCR assay indicated presence of the virus along the entire GI tract, with the highest prevalence in the ileum, in approximately one-third of the individuals tested [14].…”

Structure of the Adenovirus Type 4 (Species E) E3-19K/HLA-A2 Complex Reveals Species-Specific Features in MHC Class I Recognition

“…Although healthy adults can generally control the virus, a large number of infected individuals develop persistent lifelong infections. In immunocompromised individuals, such as children, transplant recipients, and AIDS patients, Ad infections can be severe and even fatal (5–9). The ability of Ad to persist in infected cells presupposes that the virus is capable of interfering with host antiviral cellular immune responses.…”

Co-infection with human polyomavirus BK enhances gene expression and replication of human adenovirus

“…In conclusion, since both adenoviruses and polyomaviruses are able to enter long term latency following primary infection and both are very common in patients undergoing hematopoietic stem cell transplantation [4, 20, 46–48], enhanced replication of HAdV due to BKVPyV co-infection seems to be alarming and may have an adverse effect for immunocompromised patients. We are aware that increased replication of adenovirus in patients with co-infection is, at least in a part, a result of deep immune deficiency.…”