While persistent viral infections often indicate a long history of coevolution between virus and host, the lack of serious consequences to the vast majority of those infected does not mean that debilitating or lethal consequences are not possible. This is especially the case in situations where the immune system of the infected individual is compromised or has not yet developed. Some examples of persistent infections and the complications that can arise from these infections are shown in Fig. 4.2.
Some persistent infections are characterized by chronic, low-level replication of virus in tissues that are constantly being regenerated so that damaged cells are eliminated as a matter of course. An excellent example described in more detail in Chapter 16, Part IV, is the persistent growth
Acute Infections Chronic infection/carcinoma Severe disease
Acute Infections Chronic infection/carcinoma Severe disease
and differentiation of keratinized tissue in a wart caused by a papillomavirus. In such infections, virus replication closely correlates with the cell's differentiation state, and the virus can express genes that delay the normal programmed death (apoptosis) of such cells in order to lengthen the time available for replication.
The distantly related polyoma viruses, BK virus and JC, induce chronic infections of kidney tissue. Such infections are usually asymptomatic and are only characterized by virus shedding in the urine; however, in immunosuppressed individuals infections of the brain and other organs can be seen. Thus, these persistent viruses have a role in the morbidity of late stage AIDS and in persons undergoing immunosuppression for organ transplants.
As detailed in Chapter 17, Part IV, hallmarks of herpesvirus infections are an initial acute infection followed by apparent recovery where viral genomes are maintained in the absence of infectious virus production in specific tissue. Latency is characterized by episodic reactivation (recrudescence) with ensuing (usually) milder symptoms of the original acute infection. Example viruses include HSV, EBV, and VZV.
In a latent infection, the viral genome is maintained in a specific cell type and does not actively replicate. HSV maintains latent infections in sensory neurons, whereas EBV maintains itself in B lymphocytes. Latent infections often require the expression of specific virus genes that function to ensure the survival of the viral genome or to mediate the reactivation process.
Reactivation requires active participation of the host. Immunity, which normally shields the body against reinfection, must temporarily decline. Such a decline can be triggered by the host's reaction to physical or psychological stress. HSV reactivation often correlates with a host stressed by fatigue or anxiety. VZV reactivation leads to shingles, a very painful recrudescence throughout the sensory nerve net serving the site of the latent virus. Unlike HSV reactivation, VZV reactivation results in destruction of the nerve ganglion and is associated with a generalized decline in immunity associated with aging.
Effective immunity is vital for controlling and maintaining herpesvirus latency and localizing its sites of replication. Newborns not protected by maternal immunity are subject to profound disseminated HSV infections of their CNS (see below) if they encounter the virus, for instance by infection from a mother carrying a primary acute infection. Disseminated human CMV infections are a major cause of death in individuals undergoing immune suppression as a consequence of organ transplants. Further, CMV infections of the eye are a leading cause of blindness in some patients with advanced immune deficiencies due to infection by HIV. Also, primary CMV infection of a pregnant woman is a leading cause of neurological abnormalities in developing fetuses.
Other complications arising from persistent infections
Persistent infections caused by some viruses can (rarely) lead to a neoplasm (a cancerous growth) due to continual tissue damage and resulting in mutation of cellular genes controlling cell division (oncogenes or tumor suppressor genes). Examples include infections with slow-transforming retroviruses such as human T-cell leukemia virus (HTLV), chronic hepatitis B and hepatitis C infections of the liver, certain genital papilloma virus infections, and EBV infections. The latter require the additional action of auxiliary cancer-causing factors (co-carcinogens).
Autoimmune diseases such as multiple sclerosis (MS) are thought by many investigators to result from an abnormal immune response to viral protein antigens continually present in the body due to a persistent infection. Such persistent infections need not result in the reappearance of infectious virus. For example, infection with measles virus usually leads to rash and recovery although portions of viral genomes and antigens persist in certain tissues, including neural tissue. The mechanism of this persistence is not fully understood, but it is clear that virus maturation is blocked in such cells that bear viral genomes, and viral antigens are present in reduced amounts on the cell surface. The presence of antigen leads to lifelong immunity to measles, but can result in immune complications where the host's immune system destroys otherwise healthy neuronal tissue bearing measles antigens.
The fatal disease of subacute sclerosing panencephalitis (SSPE), which is a rare complication in children occurring a few years after a measles infection, is a result of such an autoimmune response. SSPE is a rare outcome of measles infection, but other severe sequelae of measles are common. One of the most frequent is damage to eyesight. The virus replicates in the host and infects surface epithelium, resulting in characteristic rash and lesions in the mouth, on the tongue, and on the eye's conjunctiva. Virus infection of the conjunctiva can clear, but movement of eye muscles in response to light, or in the process of reading, can lead to further infection of eye musculature, leading to permanent damage, which is why individuals infected with measles should be protected from light and kept from using their eyes as much as possible.
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