Virological and Immunological Outcomes of Coinfections

Abstract

Coinfections involving viruses are being recognized to influence the disease pattern that occurs relative to that with single infection. Classically, we usually think of a clinical syndrome as the consequence of infection by a single virus that is isolated from clinical specimens. However, this biased laboratory approach omits detection of additional agents that could be contributing to the clinical outcome, including novel agents not usually considered pathogens. The presence of an additional agent may also interfere with the targeted isolation of a known virus. Viral interference, a phenomenon where one virus competitively suppresses replication of other coinfecting viruses, is the most common outcome of viral coinfections. In addition, coinfections can modulate virus virulence and cell death, thereby altering disease severity and epidemiology. Immunity to primary virus infection can also modulate immune responses to subsequent secondary infections. In this review, various virological mechanisms that determine viral persistence/exclusion during coinfections are discussed, and insights into the isolation/detection of multiple viruses are provided. We also discuss features of heterologous infections that impact the pattern of immune responsiveness that develops.

Keywords: attrition; bystander protection; coinfection; cross reactivity; diverse TCR repertoire; exclusion; persistence; virus.

FIG 1

Virological outcomes of coinfections. Coinfections involving viruses may have several virological consequences. The most common outcome of coinfection is viral interference, where one virus competitively suppresses replication of the other confecting viruses. Interference between closely related viruses eventually results in elimination of the secondary coinfecting virus and is referred to as superinfection exclusion. The instances where persistently infected cells withstand the challenge of a heterologous virus are termed superinfection suppression. Besides diminished viral replication (interference), coinfections with certain viruses may also trigger enhancement of the replication of one or both of the confecting viruses. In several other cases, coinfection has no effect on the virus replication, and thus all the coinfecting viruses can coexist (accommodation). Coinfection may modulate viral virulence and cell death, thereby altering disease severity and epidemiology. However, genetic recombination between coinfecting viruses depends on the similarity between the coinfecting viruses.

FIG 2

Immunological outcomes of heterologous viral infections. The immunological outcome is dependent upon the stage at which a subsequent viral pathogen is encountered. (A) Primary virus infection activates APCs. Subsequent infection entering following maturation of APCs culminates in efficient antigen presentation that may hasten the disease progression (immunopathology or protective immune response, depending on the nature of the immune response mounted). (B) Upon encountering antigen, activated APCs secrete cytokines that ultimately influence the type of T-cell differentiation. When the new incoming pathogen encounters already polarized T helper cells, bystander protection is mediated by these polarized Th1 cells. However, encounter with a polarized regulatory T cell can suppress immune responses against new pathogen. (C) Bystander protection from IFN-γ production may also be mediated under conditions where subsequent heterologous infection occurs during an ongoing effector CD8⁺ T-cell response. (D) When a new virus infects the host with an established memory CD8⁺ T-cell pool as a result of prior viral infection, the outcome may be cross-reactivity (can be protective or pathological), a remodeled TCR repertoire, or an altered immunodominance hierarchy. Inversely, the incoming pathogen can result in attrition (type 1 IFN dependent) of preexisting memory CD8⁺ T cells.