Abstract
Ad5 is a common cause of respiratory disease and an occasional cause of gastroenteritis and conjunctivitis, and seroconversion before adolescence is common in humans. To gain some insight into how Ad5 infection affects the immune system of rhesus macaques (RM) 18 RM were infected with a host-range mutant Ad5 (Ad5hr) by 3 mucosal inoculations. There was a delay of 2 to 6 weeks after the first inoculation before plasmacytoid dendritic cell (pDC) frequency and function increased in peripheral blood. Primary Ad5hr infection suppressed IFN-γ mRNA expression, but the second Ad5hr exposure induced a rapid increase in IFN-gamma mRNA in peripheral blood mononuclear cells (PBMC). Primary Ad5hr infection suppressed CCL20, TNF and IL-1 mRNA expression in PBMC, and subsequent virus exposures further dampened expression of these pro-inflammatory cytokines. Primary, but not secondary, Ad5hr inoculation increased the frequency of CXCR3+ CD4+ T cells in blood, while secondary, but not primary, Ad5hr infection transiently increased the frequencies of Ki67+, HLADR+ and CD95+/CCR5+ CD4+ T cells in blood. Ad5hr infection induced polyfunctional CD4 and CD8+ T cells specific for the Ad5 hexon protein in all of the animals. Thus, infection with Ad5hr induced a complex pattern of innate and adaptive immunity in RM that included transient systemic CD4+ T cell activation and suppressed innate immunity on re-exposure to the virus. The complex effects of adenovirus infection on the immune system may help to explain the unexpected results of testing Ad5 vector expressing HIV antigens in Ad5 seropositive people.
Highlights
Since the initial description in the 1950s, adenoviruses have been known as a cause of common childhood respiratory illnesses [1,2,3,4]
We found that Ad5hr infection, after repeated mucosal inoculation, had transient effects on blood plasmacytoid dendritic cell frequency and function and altered the mRNA levels of antiviral and pro-inflammatory cytokines in peripheral blood mononuclear cells (PBMC)
There was a significant increase in the mean number of plasmacytoid dendritic cell (pDC) in blood of the Ad5hr infected rhesus macaques (RM) relative to pre-infection levels at 2 weeks (p,0.01, Fig 1A) and 18 weeks (p,0.05, Fig 1A) after the first Ad5hr inoculation
Summary
Since the initial description in the 1950s, adenoviruses have been known as a cause of common childhood respiratory illnesses [1,2,3,4]. The biology of wild type adenoviruses is considerably different from adenoviral vectors designed for gene therapy or as vaccine vectors. Adenoviral vectors carry gene deletions to create space for transgenes and/or to attenuate replication, and they are known to induce strong inflammatory responses following administration in humans and animal models [12,13]. Adenovirus infections and adenoviral vectors induce neutralizing antibodies and T cell immunity in nonhuman primates (NHP) and humans [10,18,19,20,21,22,23,24,25].
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