Defective Interfering Viral Particles in Acute Dengue Infections

Abstract

While much of the genetic variation in RNA viruses arises because of the error-prone nature of their RNA-dependent RNA polymerases, much larger changes may occur as a result of recombination. An extreme example of genetic change is found in defective interfering (DI) viral particles, where large sections of the genome of a parental virus have been deleted and the residual sub-genome fragment is replicated by complementation by co-infecting functional viruses. While most reports of DI particles have referred to studies in vitro, there is some evidence for the presence of DI particles in chronic viral infections in vivo. In this study, short fragments of dengue virus (DENV) RNA containing only key regulatory elements at the 3′ and 5′ ends of the genome were recovered from the sera of patients infected with any of the four DENV serotypes. Identical RNA fragments were detected in the supernatant from cultures of Aedes mosquito cells that were infected by the addition of sera from dengue patients, suggesting that the sub-genomic RNA might be transmitted between human and mosquito hosts in defective interfering (DI) viral particles. In vitro transcribed sub-genomic RNA corresponding to that detected in vivo could be packaged in virus like particles in the presence of wild type virus and transmitted for at least three passages in cell culture. DENV preparations enriched for these putative DI particles reduced the yield of wild type dengue virus following co-infections of C6–36 cells. This is the first report of DI particles in an acute arboviral infection in nature. The internal genomic deletions described here are the most extensive defects observed in DENV and may be part of a much broader disease attenuating process that is mediated by defective viruses.

Genome-Wide Patterns of Intrahuman Dengue Virus Diversity Reveal Associations with Viral Phylogenetic Clade and Interhost Diversity

“…The repeated detection of such defective genomes (Table 2) raises the possibility of their maintenance through genetic complementation with functional full-length genomes, as has been observed in other studies (1,41). Indeed, some of these deletions are Nicaraguan (NI) clade specific, with most being propagated across epidemics and appearing in multiple consecutive years (Table 2).…”

“…The detection of such deletions in multiple samples and in multiple epidemics is suggestive either of cocirculation and/or maintenance with fulllength genomes through epidemic seasons or of frequent genesis during viral replication in human and/or mosquito hosts (1,41).…”

Sequence Analysis of In Vivo Defective Interfering-Like RNA of Influenza A H1N1 Pandemic Virus

“…One hypothesis is that the translational products might have a role in virus multiplication, but to date, no experimental evidence has been found to support the influence of DI polypeptides on replication or to show they have an interfering advantage over the standard virus or other DI viruses (27). Recently, the presence of defective interfering particles was shown in sera of patients with acute dengue infections (28). The dengue virus (DENV) DI RNAs also had internal genomic deletions retaining the critical 5= and 3= ends of the genome.…”

Design Requirements for Interfering Particles To Maintain Coadaptive Stability with HIV-1

“…DIPs have been reported for several important human and animal pathogens, including murine leukemia virus (3), Rous sarcoma virus (4), vesicular stomatitis virus (5), influenza virus (6), and dengue fever virus (7,8). Presumably, the characteristic errorprone replication of RNA viruses leads to frequent generation of defective mutants (1,2).…”