General Principles of Virology

Viruses are very small microorganisms, usually many times smaller than bacteria. Unlike bacteria, viruses can replicate only inside the cells of their host. In this respect, all viruses are obligate intracellular parasites. It must be emphasized that viruses are not cells, per se, but instead are particles that infect and replicate inside of cells. A mature virus particle is known as a virion. Compared with other organisms, virions have a relatively simple structure that consists of the genome, the capsid, and the envelope. The genome is the inner core of the virion, which is composed of single- or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules, but not both.

Viruses are the simplest of all organisms. The cells of more complex organisms have much larger nucleic acid strands or multiple strands, which make up chromosomes. The viral capsid is a protein coat that surrounds and protects the genome. It also plays a role in the process of fusion between the virions and the host cells. Fusion occurs when virions attach themselves to host cells in preparation for infecting the cells. The envelope is the outermost layer of the virion and is present in some, but not all, viruses. It has a lipoprotein structure containing viral antigens that are often chemically specific for various proteins on the surface of the host cell membranes. This biochemical specificity, when present, also facilitates the fusion process. The human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS), functions in this manner.

The viral genome then passes through the plasma membrane into the cytoplasm of the host cell. It later enters the cell nucleus, where the replication process begins. The virion may use its own or host enzymes (or both) to direct the replication process. In the host cell nucleus, the viral genome uses the cell’s genetic material (the nucleic acids RNA and DNA) to synthesize viral nucleic acids and proteins. These are then used to construct complete new virions. These new virions then exit the infected host cell by budding through the plasma membrane and go on to infect other host cells, where the replication process continues. The changes in the cell associated with viral replication are known as the cytopathic effect and usually result in the destruction of the host cell. Repeated over time, host cell destruction gives rise to the pathologic effects of the virus, which can eventually impair or even kill the host organism.

Although this cytopathic effect is the most common outcome, there are other possible outcomes of viral infection. One is viral transformation, which involves mutation of the host cell DNA or RNA and can result in malignant (cancerous) host cells. Viruses that can induce cancer in this way are known as oncogenic viruses. More common is latent, or dormant, infection in which the virions remain inside host cells but do not actively replicate to any significant degree. For example, HIV infection may have a lengthy dormant phase of 10 years or longer before giving rise to AIDS in an infected person. HIV infection is discussed in greater detail later in the chapter in the section on retroviruses.

Herpes Simplex Viruses

Although there can be anatomic overlap between the two types of herpesviruses, HSV-1 infection is most commonly associated with perioral blisters and is therefore often thought of as oral herpes. In contrast, HSV-2 infection is most commonly associated with blisters on both male and female genitalia and is therefore commonly referred to as genital herpes. Although they usually do not cause serious or life-threatening illness, both infections are annoying and highly transmissible through close physical contact (e.g., kissing, sexual intercourse). Outbreaks of painful skin lesions occur intermittently, with periods of latency (no sores or other symptoms) occurring between acute outbreaks. Although antiviral medications are not always required and are not curative, they can speed up the process of remission and reduce the duration of painful symptoms. This is especially true if the medications are started early in a given outbreak. Patients may be prescribed an ongoing lower dose of antiviral drug for prophylaxis of outbreaks. HSV infections can become serious, even life-threatening, when the patient is immunocompromised or a newborn infant. Neonatal herpes is often a life-threatening infection, and babies with this disease are often treated in neonatal intensive care units with intravenous antiviral drugs. However, treatments may fail, causing infant death and/or permanent disability. Therefore, the best strategy is to prevent transmission to the newborn infant. For this reason, obstetricians will usually recommend delivery by cesarean section (“C-section”) for any mother with active genital herpes lesions.

Varicella-Zoster Virus

Varicella-zoster virus (VZV) is a type of herpesvirus (HHV-3) that most commonly causes chickenpox (varicella) in childhood, remains dormant for many years, and can then reemerge in later adulthood as painful herpes zoster lesions known as shingles.

Chickenpox is usually an uncomfortable but self-limiting disease of childhood. However, it is highly contagious and easily spread by either direct contact with weeping lesions or via droplet inhalation. It may also lead to significant scarring. The serious condition known as Reye’s syndrome (fatty liver damage with encephalopathy) may also complicate varicella, as can other viral infections such as influenza. Herpes zoster, more commonly known as shingles, is caused by the reactivation of VZV from its dormant state, often decades after a case of childhood chickenpox. It is also referred to simply as zoster. Its most common manifestation is in the form of skin lesions that follow nerve tracts, known as dermatomes, along the skin surface. The most common site of these lesions is around the side of the trunk, although they can appear in other areas (e.g., along trigeminal nerve dermatomes of the face). Zoster lesions are often quite painful, and some patients even require opioids for pain control. In addition, postherpetic neuralgias (long-term nerve pain) remain following shingles outbreaks in up to 50% of elderly patients. Early administration of antiviral drugs such as acyclovir may speed recovery, but this effect is usually not dramatic. The best results are generally seen when the antiviral drug is started within 72 hours of symptom onset.

Antivirals (Non-HIV)

Mechanism of Action and Drug Effects

Most of the current antiviral drugs work by blocking the activity of a polymerase enzyme that normally stimulates the synthesis of new viral genomes. The result is impaired viral replication, which results in viral concentrations low enough to allow elimination of the virus by the patient’s immune system. If this does not occur, the virus may either enter a dormant state or remain at a low level of replication with continuous drug therapy.

Indications

Contraindications

Most of the antiviral drugs used to treat non-HIV viral infections are surprisingly well tolerated. The only usual contraindication for most of these drugs is known severe drug allergy. However, a small number of contraindications are listed for a few of the antiviral drugs. Amantadine is contraindicated in lactating women, children younger than 12 months of age, and patients with an eczematous rash. Famciclovir is contraindicated in cases of allergy to the drug itself or to a similar drug called penciclovir, which is used topically to treat herpes labialis (perioral sores). Cidofovir has a strong propensity for renal toxicity, and it is contraindicated in patients who already have severely compromised renal function as well as those receiving concurrent drug therapy with other highly nephrotoxic drugs. It is also contraindicated in cases of allergy to probenecid, because probenecid is recommended as concurrent drug therapy with cidofovir to help alleviate its nephrotoxicity. Ribavirin also has additional specific contraindications besides drug allergy. Because of the drug’s teratogenic potential, it is also contraindicated in pregnant women and even in their male sexual partners. The aerosol form must not be used by pregnant women or by women who may become pregnant during exposure to the drug. This includes health care providers administering the drug in aerosol form, because of the potential for second-hand inhalation on the part of the health care provider.

Interactions

Dosages

For dosage information on some of the commonly used antiviral drugs, see the table on this page.