Viral infections can range from asymptomatic to causing disease depending on the virus and host factors. Viruses typically enter the body through mucous membranes, then spread locally or systemically. Primary viral replication occurs at the entry site, followed by cellular injury, host immune response, and potential viral clearance or persistence. Disease results from a complex interplay between the virus infecting and damaging host cells, and the host response. The outcome of infection is determined by both viral virulence and host susceptibility.

1. PRINCIPLES OF VIRAL DISEASES
The fundamental process of viral infection is the viral replicative cycle. The cellular
response to that infection may range from no apparent effect to cytopathology with
accompanying cell death to hyperplasia or cancer.
Viral disease is some harmful abnormality that results from viral infection of the host
organism.
Clinical disease in a host consists of overt signs and symptoms.
A syndrome is a specific group of signs and symptoms.
Viral infections that fail to produce any symptoms in the host are said to be inapparent
(subclinical). In fact, most viral infections do not result in the production of disease.
Important principles that pertain to viral disease include the following:
(1) many viral infections are subclinical;
(2) the same disease may be produced by a variety of viruses;
(3) the same virus may produce a variety of diseases;
(4) the disease produced bears no relationship to viral morphology; and
(5) the outcome in any particular case is determined by both viral and host factors and
is influenced by the genetics of each.

2. Viral pathogenesis is the process that occurs when a virus infects a host.
Disease pathogenesis is a subset of events during an infection that results in disease
manifestation in the host.
A virus is pathogenic for a particular host if it can infect and cause signs of disease in that host.
A strain of a certain virus is more virulent than another strain if it commonly produces more
severe disease in a susceptible host.
Viral virulence in intact animals should not be confused with cytopathogenicity for cultured
cells; viruses highly cytocidal in vitro may be harmless in vivo, and, conversely, noncytocidal
viruses may cause severe disease.
Important Features of Acute Viral Diseases

3. Types of host and cellular responses to virus infection

4. PATHOGENESIS OF VIRAL DISEASES
To produce disease, viruses must enter a host, come in contact with susceptible cells,
replicate, and produce cell injury.
Specific steps involved in viral pathogenesis are the following:
• viral entry into the host,
• primary viral replication,
• Viral spread,
• cellular injury,
• host immune response,
• viral clearance or establishment of persistent infection, and
• viral shedding.

5. A. entry and Primary replication
For host infection to occur, a virus must first attach to and enter cells of one of the body
surfaces:
• skin,
• respiratory tract,
• gastrointestinal tract,
• urogenital tract, or
• conjunctiva.
Most viruses enter their hosts through the mucosa of the respiratory or gastrointestinal
tract. Major exceptions are those viruses that are introduced directly into the
bloodstream by needles (hepatitis B, human immunodefi ciency virus [HIV]), by blood
transfusions, or by insect vectors (arboviruses).
Viruses usually replicate at the primary site of entry. Some, such as influenza viruses
(respiratory infections) and noroviruses (gastrointestinal infections), produce disease at
the portal of entry and likely have no necessity for further systemic spread. They spread
locally over the epithelial surfaces, but there is no spread to distant sites.

7. B. Viral Spread and Cell Tropism
Many viruses produce disease at sites distant from their point of entry (eg,
enteroviruses, which enter through the gastrointestinal tract but may produce central
nervous system [CNS] disease).
After primary replication at the site of entry, these viruses then spread within the host.
Mechanisms of viral spread vary, but the most common route is via the bloodstream or
lymphatics. The presence of virus in the blood is called viremia.
Virions may be free in the plasma (eg, enteroviruses, togaviruses) or associated with
particular cell types (eg, measles virus). Some viruses even multiply within those cells.
The viremic phase is short in many viral infections.
In some instances, neuronal spread is involved; this is apparently how rabies virus
reaches the brain to cause disease and how herpes simplex virus moves to the ganglia to
initiate latent infections.

8. Important Features of Acute Viral
Diseases

9. Viruses tend to exhibit organ and cell specificities. Thus, tropism determines the pattern
of systemic illness produced during a viral infection.
As an example, hepatitis B virus has a tropism for liver hepatocytes, and hepatitis is the
primary disease caused by the virus.
Tissue and cell tropism by a given virus usually reflect the presence of specific cell
surface receptors for that virus.
Factors affecting viral gene expression are important determinants of cell tropism.
Another mechanism dictating tissue tropism involves proteolytic enzymes. Certain
paramyxoviruses are not infectious until an envelope glycoprotein undergoes
proteolytic cleavage.
Viral spread may be determined in part by specific viral genes. Studies with reovirus
have demonstrated that the extent of spread from the gastrointestinal tract is determined
by one of the outer capsid proteins.

10. Mechanisms of spread of
virus through the body in
human viral infections.
+ indicates possible sites of
viral replication;
large arrows indicate sites of
shedding of virus, with
illustrative examples of
diseases in which that route
of excretion is important.
Transfer from blood is by
transfusion with hepatitis B
and by mosquito bite in
certain arboviral infections.
SSPE, subacute sclerosing
panencephalitis.

11. C. Cell Injury and Clinical Illness
Destruction of virus-infected cells in the target tissues and physiologic alterations
produced in the host by the tissue injury are partly responsible for the development of
disease.
Some tissues, such as intestinal epithelium, can rapidly regenerate and withstand
extensive damage better than others, such as the brain.
Some physiologic effects may result from nonlethal impairment of specialized functions
of cells, such as loss of hormone production.
Clinical illness from viral infection is the result of a complex series of events, and many
of the factors that determine degree of illness are unknown.
General symptoms associated with many viral infections, such as malaise and anorexia,
may result from host response functions such as cytokine production.
Clinical illness is an insensitive indicator of viral infection; inapparent infections by
viruses are very common.

12. D. Recovery from Infection
The host either succumbs or recovers from viral infection.
Recovery mechanisms include both innate and adaptive immune responses. Interferon
(IFN) and other cytokines, humoral and cell-mediated immunity, and possibly other
host defense factors are involved.
The relative importance of each component differs with the virus and the disease.
In acute infections, recovery is associated with viral clearance. However, there are times
when the host remains persistently infected with the virus.
E. Virus Shedding
The last stage in pathogenesis is the shedding of infectious virus into the environment.
This is a necessary step to maintain a viral infection in populations of hosts.
Shedding occurs at different stages of disease depending on the particular agent
involved.
It represents the time at which an infected individual is infectious to contacts.
In some viral infections, such as rabies, humans represent dead-end infections, and
shedding does not occur.

13. Host Immune Response
The outcome of viral infections reflects the interplay between viral and host factors.
Nonspecific host defense mechanisms are usually elicited very soon after viral
infection.
The most prominent among the innate immune responses is the induction of IFNs.
These responses help inhibit viral growth during the time it takes to induce specific
humoral and cell-mediated immunity.
Both humoral and cellular components of the immune response are involved in control
of viral infections.
Virus-encoded proteins serve as targets for the immune response. Virus-infected cells
may be lysed by cytotoxic T lymphocytes as a result of recognition of viral
polypeptides on the cell surface.
Humoral immunity protects the host against reinfection by the same virus. Neutralizing
antibody directed against capsid proteins blocks the initiation of viral infection,
presumably at the stage of attachment, entry, or uncoating.
Secretory IgA antibody is important in protecting against infection by viruses through
the respiratory or gastrointestinal tracts.
Some viruses infect and damage cells of the immune system (acquired
immunodeficiency syndrome (AIDS) that infects T lymphocytes and destroys their
ability to function

14. Host susceptibility and response to infection are genetically determined; these
differences are often in immune response genes. For example, susceptibility to
respiratory syncytial virus bronchiolitis was associated with innate immune genes.
Viruses have evolved a variety of ways that serve to suppress or evade the host immune
response and thus avoid being eradicated.
Viruses may mutate and change antigenic sites on virion proteins (influenza virus, HIV)
or may downregulate the level of expression of viral cell surface proteins (herpesvirus).
Virus-encoded microRNAs may target specific cellular transcripts and suppress
proteins integral to the host innate immune response (polyomavirus,herpesvirus).
Most viruses have anti-IFN strategies.
A type of immunopathologic disorder was observed in humans immunized with
vaccines containing killed measles or respiratory syncytial virus (no longer in use).
A few persons developed unusual immune responses that gave rise to serious
consequences when they later were exposed to the naturally occurring infective virus.
Dengue hemorrhagic fever with shock syndrome, which develops in persons who
already have had at least one prior infection with another dengue serotype, may be a
naturally occurring manifestation of the same type of immunopathology.
Another potential adverse effect of the immune response is the development of
autoantibodies. If a viral antigen were to elicit antibodies that fortuitously recognized
an antigenic determinant on a cellular protein in normal tissues, cellular injury or loss
of function unrelated to viral infection might result.

15. Comparison of Pathogenesis of a Viral Disease of
the Skin and of the Central Nervous System
Examples:
Mousepox, a disease of the skin,
Human poliomyelitis, a disease of the CNS.
Both viruses multiply at the primary site of entry before
systemic spread to target organs.
In mousepox, the virus enters the body through minute
abrasions of the skin and multiplies in the epidermal cells.
At the same time, it is carried by the lymphatics to the
regional lymph nodes, where multiplication also occurs.
The few virus particles entering the blood by way of the
efferent lymphatics are taken up by the macrophages of the
liver and spleen.
The virus multiplies rapidly in both organs. After release of
virus from the liver and spleen, it moves by way of the
bloodstream and localizes in the basal epidermal layers of
the skin, in the conjunctival cells, and near the lymph
follicles in the intestine.
The virus may occasionally also localize in the epithelial
cells of the kidney, lung, submaxillary gland, and pancreas.
A primary lesion occurs at the site of entry of the virus. It
appears as a localized swelling that rapidly increases in
size, becomes edematous, ulcerates, and goes on to scar
formation.
A generalized rash follows that is responsible for the
release of large quantities of virus into the environment.

16. In poliomyelitis, virus enters by way of the
alimentary tract, multiplies locally at the initial
sites of viral implantation (tonsils, Peyer
patches) or the lymph nodes that drain these
tissues, and begins to appear in the throat and
in the feces.
Secondary viral spread occurs by way of the
bloodstream to other susceptible tissues—
specifically, other lymph nodes and the CNS.
Within the CNS, the virus spreads along nerve
fibers. If a high level of multiplication occurs
as the virus spreads through the CNS, motor
neurons are destroyed, and paralysis occurs.
The shedding of virus into the environment
does not depend on secondary viral spread to
the CNS.
Spread to the CNS is readily prevented by the
presence of antibodies induced by prior
infection or vaccination.

17. Viral Persistence: Chronic and Latent Virus
Infections
Infections are acute when a virus first infects a susceptible host. Viral infections are usually self-
limiting. Sometimes, however, the virus persists for long periods of time in the host.
Long-term virus–host interaction may take several forms.
Chronic infections (also called persistent infections) are those in which replicating virus can
be continuously detected, often at low levels; mild or no clinical symptoms may be evident.
Infants infected with hepatitis B virus frequently become persistently infected (chronic carriers);
most carriers are asymptomatic.
Latent infections are those in which the virus persists in an occult (hidden or cryptic) form most
of the time when no new virus is produced. There will be intermittent flare-ups of clinical
disease; infectious virus can be recovered during flare-ups. Viral sequences may be detectable by
molecular techniques in tissues harboring latent infections.
Herpesviruses typically produce latent infections (Herpes simplex viruses, Chickenpox virus
(varicella-zoster), cytomegalovirus and Epstein-Barr virus )
Inapparent or subclinical infections are those that give no overt sign of their presence.
Persistent viral infections are associated with certain types of cancers in humans as well as with
progressive degenerative diseases of the CNS of humans.
Spongiform encephalopathies are a group of chronic, progressive, fatal infections of the CNS
caused by prions. The best examples of this type of “slow” infection are scrapie in sheep and
bovine spongiform encephalopathy in cattle; kuru and Creutzfeldt-
Jakob disease occur in humans.

18. Overview of Acute Viral Respiratory Infections
Many types of viruses gain access to the human body via the respiratory tract, by
aerosolized droplets or saliva.
Successful infection occurs despite normal host protective mechanisms.
Many infections remain localized in the respiratory tract, although some viruses
produce their characteristic disease symptoms after systemic spread (eg, chickenpox,
measles, rubella)
Respiratory infections impose a heavy disease burden worldwide. Respiratory
infections are the most common cause of mortality for children younger than 5 years
old.
Disease symptoms exhibited by the host depend on whether the infection is
concentrated in the upper or lower respiratory tract.
Definitive diagnosis requires:
• first of all by considering the major symptoms, deduced the patient’s age, the
time of year, and any pattern of illness in the community
• isolation of the virus,
• identification of viral gene sequences,
• demonstration of a rise in antibody titer.
The severity of respiratory infection can range from inapparent to overwhelming.

19. Overview of Viral Infections of the Gastrointestinal Tract
Many viruses initiate infection via the alimentary tract. A few agents, such as herpes
simplex virus and Epstein-Barr virus, probably infect cells in the mouth.
Viruses able to initiate infection by this route are all resistant to acid and bile salts.
Acute gastroenteritis is the designation for short-term gastrointestinal disease with
symptoms ranging from mild, watery diarrhea to severe febrile illness characterized
by vomiting, diarrhea, and prostration.
Rotaviruses, noroviruses, and caliciviruses are major causes of gastroenteritis.
Infants and children are affected most often.
Some viruses that produce enteric infections use host proteases to facilitate infection.
In general, proteolytic digestion alters the viral capsid by partial cleavage of a viral
surface protein that then facilitates a specific event such as virus attachment or
membrane fusion.
Enteroviruses, coronaviruses, and adenoviruses also infect the gastrointestinal tract,
but those infections are often asymptomatic.
Some enteroviruses, notably polioviruses, and hepatitis A virus are important causes
of systemic disease but do not produce intestinal symptoms.

20. Overview of Viral Skin Infections
The skin is a tough and impermeable barrier to the entry of viruses. However, a few
viruses are able to breach this barrier and initiate infection of the host.
They obtain entry:
• through small abrasions of the skin (poxviruses, papillomaviruses, herpes simplex
viruses),
• by the bite of arthropod vectors (arboviruses) or infected vertebrate hosts (rabies
virus, herpes B virus),
• By injection of blood transfusions or other manipulations involving contaminated
needles, such as acupuncture and tattooing (hepatitis B virus, HIV).
A few agents remain localized and produce lesions at the site of entry (papillomaviruses
and molluscum contagiosum); most spread to other sites.
The epidermal layer is devoid of blood vessels and nerve fibers, so viruses that infect
epidermal cells tend to stay localized. Viruses that are introduced deeper into the dermis
have access to blood vessels, lymphatics, dendritic cells, and macrophages and usually
spread and cause systemic infections.

21. Many of the generalized skin rashes associated with viral infections develop because
virus spreads to the skin via the bloodstream after replication at some other site.
Such infections originate by another route (eg, measles virus infections occur via the
respiratory tract), and the skin becomes infected from below.
Lesions in skin rashes are designated as macules, papules, vesicles, or pustules.
Macules, which are caused by local dilation of dermal blood vessels, progress to
papules if edema and cellular infiltration are present in the area.
Vesicles occur if the epidermis is involved, and they become pustules if an
inflammatory reaction delivers polymorphonuclear leukocytes to the lesion. Ulceration
and scabbing follow.
Hemorrhagic and petechial rashes occur when there is more severe involvement of
the dermal vessels.
Skin lesions frequently play no role in viral transmission. Infectious virus is not shed
from the maculopapular rash of measles or from rashes associated with arbovirus
infections. In contrast, skin lesions are important in the spread of poxviruses and herpes
simplex viruses.

22. Overview of Viral Infections of the Central Nervous System
Invasion of the CNS by viruses is always a serious matter.
Viruses can gain access to the brain by two routes:
• by the bloodstream (hematogenous spread) and
• by peripheral nerve fibers (neuronal spread).
Access from the blood may occur
• by growth through the endothelium of small cerebral vessels,
• by passive transport across the vascular endothelium,
• by passage through the choroid plexus to the cerebrospinal fluid,
• by transport within infected monocytes, leukocytes, or lymphocytes.
After the blood–brain barrier is breached, more extensive spread throughout the brain
and spinal cord is possible. There tends to be a correlation between the level of viremia
achieved by a bloodborne neurotropic virus and its neuroinvasiveness.
The other pathway to the CNS is via peripheral nerves. Virions can be taken up at
sensory nerve or motor endings and be moved within axons, through endoneural
spaces, or by Schwann cell infections. Herpesviruses travel in axons to be delivered to
dorsal root ganglia neurons.
.

23. Many viruses, including herpes-, toga-, flavi-, entero-, rhabdo-, paramyxo-, and
bunyaviruses, can infect the CNS and cause meningitis, encephalitis, or both.
Encephalitis caused by herpes simplex virus is the most common cause of sporadic
encephalitis in humans. Pathologic reactions to cytocidal viral infections of the CNS
include necrosis, inflammation, and phagocytosis by glial cells.
The cause of symptoms in some other CNS infections, such as rabies, is unclear.
Slow virus infections, progressive multifocal leukoencephalopathy (JC polyomavirus)
and subacute sclerosing panencephalitis (measles virus) are uniformly fatal.
Features of these infections include a long incubation period (months to years)
followed by the onset of clinical illness and progressive deterioration, resulting in death
in weeks to months; usually only the CNS is involved.
In contrast, the subacute spongiform encephalopathies, typified by scrapie, caused by
prions characteristic neuropathologic changes occur, but no inflammatory or immune
response is elicited.

24. Overview of Congenital Viral Infections
Few viruses produce disease in the human fetus. Most maternal viral infections do not
result in viremia and fetal involvement.
Three principles are involved in the production of congenital defects:
(1) the ability of the virus to infect the pregnant woman and be transmitted to the fetus;
(2) the stage of gestation at which infection occurs;
(3) the ability of the virus to cause damage to the fetus directly (by infection of the
fetus) or indirectly (by infection of the mother), resulting in an altered fetal
environment (eg, fever).
Rubella virus and cytomegalovirus are presently the primary agents responsible for
congenital defects in humans. Congenital infections can also occur with herpes
simplex, varicella-zoster, hepatitis B, measles, and mumps virus and with HIV,
parvovirus, and some enteroviruses.
Developmental malformations, including congenital heart defects, cataracts, deafness,
microcephaly, and limb hypoplasia, may result. Fetal tissue is rapidly proliferating.
Infections may be contracted from the mother during delivery (natal) from
contaminated genital secretions, stool, or blood, as well as during the first few weeks
after birth (postnatal) from maternal sources, family members, hospital personnel, or
blood transfusions. HIV can be transmitted by the breast milk of an infected mother.

25. Effect of Host Age
Host age is a factor in viral pathogenicity. More severe disease is often produced in
newborns. In addition to maturation of the immune response with age, there seem to be
age-related changes in the susceptibility of certain cell types to viral infection.
Viral infections usually can occur in all age groups but may have their major impact at
different times of life.
Examples include
• rubella, which is most serious during gestation;
• rotavirus, which is most serious for infants; and
• St. Louis encephalitis, which is most serious in elderly adults.

26. Diagnosis of Viral Infections
There are several different ways in which viral infections are diagnosed Most
commonly used are rapid detection methods.
These include:
• antigen detection using virus-specific monoclonal antibodies and
• nucleic acid or polymerase chain reaction (PCR) tests using specific probes to detect
viral nucleic acid. The PCR tests can be multiplexed, allowing detection of multiple
viruses concurrently.
Virus culture and serological testing for specific antibody responses are slow to provide
results but are useful for epidemiologic and research studies.
In the near future, nucleic acid-based technology using high-density microarrays and
deep sequencing will likely change approaches to viral diagnosis.

27. Summary of methods used to diagnose viral infections

28. PREVENTION AND TREATMENT OF VIRAL
INFECTIONS
Antiviral Chemotherapy
Stages during viral infections that could be targeted include
• attachment of virus to host cells,
• uncoating of the viral genome,
• viral nucleic acid synthesis,
• translation of viral proteins, and
• assembly and release of progeny virus particles.
A. Nucleoside and Nucleotide Analogs
They inhibit nucleic acid replication by inhibition of polymerases essential for nucleic
acid replication. Analogs can inhibit cellular enzymes as well as virus encoded
enzymes.
Examples of nucleoside analogs include acyclovir (acycloguanosine), lamivudine
(3TC), ribavirin, vidarabine (adenine arabinoside), and zidovudine (azidothymidine;
AZT).
Nucleotide analogs differ from nucleoside analogs in having an attached phosphate
group. Their ability to persist in cells for long periods of time increases their potency.
Cidofovir is an example.

29. B. Reverse Transcriptase Inhibitors
Nevirapine was the first member of the class of nonnucleoside reverse transcriptase
inhibitors. It acts by binding directly to reverse transcriptase and disrupting the
enzyme’s catalytic site. Resistant mutants emerge rapidly.
C. Protease Inhibitors
Saquinavir was the first protease inhibitor to be approved for treatment of HIV
infection. It inhibits the viral protease that is required at the late stage of the replicative
cycle to cleave the viral gag and gag-pol polypeptide precursors to form the mature
virion core and activates the reverse transcriptase that will be used in the next round of
infection. Inhibition of the protease yields noninfectious virus particles. Protease
inhibitors include indinavir and ritonavir and others not listed here.
D. Other Types of Antiviral Agents
Fuzeon is a large peptide that blocks the virus and cellular membrane fusion step
involved in entry of HIV-1 into cells.
The synthetic amines amantadine and rimantadine specifically inhibit influenza A
viruses by blocking viral uncoating.
Foscarnet (phosphonoformic acid) selectively inhibits viral DNA polymerases and
reverse transcriptases at the pyrophosphatebinding site.
Methisazone is an inhibitor of poxviruses. It blocked a late stage in viral replication,
resulting in the formation of immature, noninfectious virus particles.

30. Interferons
The IFNs are host-coded proteins that are members of the large cytokine family and
that inhibit viral replication. They are produced very quickly (within hours) in response
to viral infection or other inducers and are one of the body’s first responders in the
defense against viral infection. IFN was the first cytokine to be recognized. IFNs are
central to the innate antiviral immune response. They also modulate humoral and
cellular immunity and have broad cell growth regulatory activities, but the focus here is
on their antiviral effects.
Viral Vaccines
The purpose of viral vaccines is to use the immune response of the host to prevent viral
disease. Vaccination is the most effective method of prevention of serious viral
infections.
Vaccines are available against several serious viral diseases. Both killed-virus and live-
virus vaccines are available; each type has certain advantages and disadvantages.