Viral Infections In Aging Humans

Viruses are small, composite particles of nucleic acid and protein, and are obligate, intracellular parasites; i.e., they cannot replicate outside a host cell. An individual virus contains only one type of nucleic acid, either RNA or DNA, which is protected by the associated protein from destruction by hostile substances, such as nucleases, present in its environment. Viral proteins serve two other crucial functions; first, they are responsible for attachment of virions to host cells and, second, they include a minimal array of enzymes that are necessary to cajole the host cell machinery into synthesizing new virions. Together, the nucleic acid and associated protein form the nucleocapsid. Some viruses are encased in a lipid bilayer, derived from host cell membrane, termed the "envelope." It is often studded with outward-protruding, complex molecules of glycoprotein. Viral nucleic acid (genome) may be either RNA or DNA arranged in linear or circular fashion. The nucleic acid may occur in single-stranded or double-stranded form. If the genome is single-stranded RNA, it is considered to be in the positive (plus) sense orientation if it can serve as its own mRNA and in negative (minus) sense orientation if a copy must first be made by a viral RNA transcriptase, which then serves as mRNA. Most DNA viruses display a linear, double-stranded genome although a few families are characterized by linear single-stranded (parvoviruses), circular double-stranded (papovaviruses), or even circular single-stranded (circoviruses) DNA. Comprehensive introductions to viral genomes and virus replication are provided in many excellent texts (e.g., ref. 80 and 81).

Viral infection begins with attachment of virions to host cells. Specific attachment that leads to virion penetration generally depends upon complementary interaction between viral protein (counter-receptor or anti-receptor) and specific receptors on host cells. Viruses may display a single species of protein counter-receptor or multiple species of counter-receptors in the case of some complex viruses such as herpes simplex. Whether or not a host cell is susceptible to a given virus depends upon the cell having receptors. Cells lacking receptors are not susceptible. If a host cell supports the complete reproduction of a given virus, it is termed "permissive." Some host cells can be shown to be permissive but not susceptible because they lack the appropriate receptors.

The cellular receptors for viruses are generally glycoproteins. Some of the receptors are familiar molecules known to be involved in other functions. Table 2-6 is a list of a few of those receptors. The ability of viruses to usurp surface molecules designed for some other purpose as receptors for themselves is well illustrated by human and simian immunodeficiency viruses. Those viruses utilize members of the chemokine superfamily (CXCR4, CCR5) along with CD4 as coreceptors for entrance into T cells and monocytes (reviewed in ref. 82). Chemokine receptors have been appropriated also by other viruses; e.g., myxoma virus can utilize CCR1, CCR5, CXCR4 for entrance into host cells (83). Myxoma virus is a poxvirus the receptors for which have been difficult to identify. The epidermal growth factor receptor is utilized by vaccinia virus another poxvirus.

A poxvirus that has the human as primary host is the molluscum contagiosum virus (MCV), which causes persistent, benign, skin neoplasms in children and severe opportunistic infections in AIDS victims. Both children and AIDS victims are immunodeficient (to much different degrees, of course). Elderly individuals are immunodeficient. It seems natural, therefore, to wonder whether or not the elderly are also susceptible to MCV. If so, it has not been reported (to our knowledge). Perhaps factors other than immunodeficiency are involved in rendering subjects susceptible to MCV. It would be useful to know.

The complexity of viruses is exemplified by their nomenclature, which comprises some 8 major families of DNA viruses and 14 families of RNA viruses (with more to come, no doubt). Of those 22 families, 20 include members that have medical importance (see ref. 84 for a concise overview). The first five of

Table 2-6

Some Familiar Cell Membrane Receptors for Viruses

Representative

Virus Receptor important cell infected

Adenovirus Integrin (a5^3) Respiratory epithelium

Epstein-Barr Complement type B lymphocytes

2 receptor (CD 21)

Herpes simplex Proteoglycans Oral and genital epithelium

(heparin sulfate moieties)

Influenza A, B Glycoproteins of 5Ac Neu Oropharyngeal cells

Respiratory syncytial Hemagglutinin Respiratory epithelium glycoprotein

Rhinoviruses Intercellular Nasal epithelium adhesion molecule (ICAM)

HIV-1, -2 CD4, galactosyl T lymphocytes ceramide, chemokine receptors six families listed in Table 2-7 contains members that cause respiratory disorders any of which can progress to pneumonia in the elderly. The influenza viruses of family Orthomyxaviridae are of the greatest concern because the elderly are so susceptible and because each new flu season may bring an antigenic variant arising from the "drift" and "shift" in antigenic types that are so typical of influenza viruses.

The far-right column of Table 2-7 is headed "Persistence." Two families (four types) of viruses are listed to illustrate persistence. There are three types of persistence, termed "chronic" (diffuse or focal), "latent," and "slow." Here, we are interested in latent persistence. Latency refers to the fact that some viruses may integrate into the genomes of host cells where they persist for extended periods without replicating or killing host cells and without causing disease. An outstanding example of latency in a bacterial infection is that of the Mycobacte-ria, which cause tuberculosis. The four viruses listed in the table are representative of persistence. This phenomenon may be of unrecognized importance in aging humans. It should be stressed that (to our knowledge) there is no irrefutable evidence that persistent viruses afflict the elderly inordinately. However, it should be stressed equally that (to our knowledge) there have been no systematic studies of that possibility. In the following brief paragraph, evidence is marshalled to support the idea that more attention should be focused on assessing persistent viral infections in aging humans.

Table 2-7

Significant Viruses of Aging Humans

Table 2-7

Significant Viruses of Aging Humans

Family

Virus

Disorder Persistence

Coronaviridae

Coronaviruses

Common cold

No

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