Pathogenesis of Persistent Infections

The term persistent infections embraces such a wide variety ol different conditions that it is not surprising to find that there are several mechanisms whereby the causative viruses bypass the host defenses that eliminate virus in acute infections. The mechanisms include factors related primarily to the virus on the one hand and to the host defenses on the other, although the two kinds of factors interact in some instances (Table 10-5).

Abrogation of the Cytocidal Capacity of the Virus

Restricted Expression of Viral Genes

Obviously a virus cannot persist in a cell it destroys. Therefore, long-term persistence of a potentially cytocidal virus can occur only if the viral genome remains fully or partially silent. Accordingly, latency is maintained only as long as no viral gene with the capacity to kill the cell is expressed. As a rule the few early genes that are transcribed are actually instrumental in the maintenance of latency. Latency is eventually overridden, perhaps following immunosuppression and/or by the action of a cytokine or hormone that de-represses transcription of the whole viral genome, leading to reactivation of viral synthesis. This paradigm is best illustrated by the herpesviruses.

Latency in Nonpermissive, Resting, or Undifferentiated Cells

A particular species of virus may undergo productive replication in one cell type but nonproductive latent infection of another. For example, EB virus may replicate productively in a mucosal epithelial cell but assume the latent slate in B lymphocytes; hence, one cell type may serve as a repository which, following reactivation, may seed the other. Even in a given cell type, permissiveness may be determined by the state of cellular differentiation or activation. For instance, papillomaviruses replicate only in fully differentiated epithelial cells. Again, HIV replicates in CD4+ T cells activated by an appropriate cytokine but remains latent in resting CD4+ T cells. Moreover, HIV enjoys a quite different type of association with cells of the monocyte/ macrophage lineage, and monocyte-tropic variants tend to be replaced by lymphocyte-tropic variants in the same patient as the years go by.

Noncytocidal Viruses

Arenaviruses and retroviruses are two excellent examples of noncytocidal viruses that establish chronic infections in their rodent hosts without killing the cells in which they replicate and causing little or no damage until certain complications may develop later in life.

Evasion of the Immune Response

Evasion of Neutralization by Antibody

Prions are composed of what is basically a normal cellular protein containing just one or a few amino acid substitutions. Accordingly, they are non-immunogenic, eliciting neither antibody nor a cellular response; they do not

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