Several viruses also interfere with chemokine responses by producing either decoy chemokine receptors or chemokine homologs that interfere with natural ligandinduced signaling through chemokine receptors. Collectively, herpesviruses and poxviruses produce over 40 viral homologs of receptors belonging to the seven transmembranespanning Gproteincoupled chemokine receptor (vGPCR) superfamily. Finally, CMV has been shown to promote chronic infection that is associated with ‘exhaustion’ of antiviral CD8 T cells. CD8 T cells induced in this setting are characterized by expression of an inhibitory receptor of the CD28 superfamily, the programmed death1 (PD1) receptor (see Section 724), activation of which by its ligand PDL1 suppresses CD8 Tcell effector function. Blockade of the PDL1–PD1 interaction restores antiviral CD8 effector function and decreases the viral load, indicating that ongoing activation of this pathway is involved in impaired viral clearance. A similar mechanism has been implicated in RNA viruses that can establish chronic infections, such as hepatitis C virus (HCV). Suffice it to say that the range of strategies that viruses have evolved to subvert immune clearance mechanisms is quite remarkable, and the discovery of these mechanisms continues to have a major impact on our understanding of host–pathogen relationships.
13-24 Some latent viruses persist in vivo by ceasing to replicate until immunity wanes.
As mentioned in the previous section, a major class of viral agents that cause latent infections in humans are the herpesviruses, large, enveloped DNA viruses that are characterized by their ability to establish lifelong infections. While we have considered a number of strategies by which these viruses subvert immunity, they have also evolved mechanisms to maintain their genome within the nucleus of infected cells indefinitely without replicating. In contrast to an actively lytic, or productive, phase of the viral life cycle, wherein the virus replicates and lyses its cellular host, herpesviruses can establish latency, or a lysogenic phase, by expression of a small region of their genome called the latency associated transcript (LAT). In addition to suppressing the transcription of the remaining viral genome, the LAT produces factors that interfere with apoptotic death of the host cell, both interfering with immune mechanisms that might clear the cell and prolonging the cell’s lifespan—and that of the viral genome it harbors. An example is herpes simplex virus (HSV), the cause of cold sores, which infects epithelial cells and then spreads to sensory neurons serving the infected area. An effective immune response controls the epithelial infection, but the virus persists in a latent state in the sensory neurons. Factors such as sunlight, bacterial infection, or hormonal changes reactivate the virus, which then travels down the axons of the sensory neuron and reinfects the epithelial tissues (Fig. 13.26). At this point, the immune response again becomes active and controls the local infection by killing the epithelial cells, producing a new sore. This cycle can be repeated many times.
Fig. 13.26 Persistence and reactivation of herpes simplex virus infection. the initial infection in the skin is cleared by an effective immune response, but residual infection persists in sensory neurons such as those of the trigeminal ganglion, whose axons innervate the lips. When the virus is reactivated, usually by some environmental stress and/or alteration in immune status, the skin in the area served by the nerve is reinfected from virus in the ganglion and a new cold sore results. this process can be repeated many times.