ANTIVIRAL DRUGS

the number of antiviral drugs is very small compared to drugs against bacterial infections (the major
reason for the difference is the difficulty in obtaining selective toxicity against virus & their replication
is involved w/ the normal synthetic processes of the cell)
limitation:
= are relatively ineffective (bec many cycles of viral replication occur during the incubation period
when the patient is well; by the time the patient has a recognizable systemic viral disease, the virus has
spread throughout the body & it is too late to interdict it)
= emergence of drug-resistant viral mutants

Potential sites for antiviral chemotherapy

Site of Action Effective drugs

Early events (entry or uncoating of the virus) Amantadine
Nucleic acid synthesis by viral DNA & RNA Acyclovir, ganciclovir, vidarabine, vidarabine
polymerase Idoxuridine, trifluridine, azidothymidine, dideoxyinosine,
dideoxycytidine, ribavirin
Other virus-specific enzymes
Protein synthesis directed by viral mRNA
Cleavage of precursor polypeptides
Assembly of the particle, including the matrix
protein
Release of the particle by budding

@ Inhibition of early events:

A. amantadine = used to prevent influenza A infections

= it inhibits uncoating of the virus: absorption & penetration occur normally, but
transcription by the virion RNA polymerase does not
@ Inhibition of viral nucleic acid synthesis:

** Inhibitors of Herpesviruses:

A. acyclovir = is active primarily against herpes simplex virus types 1 & 2 & varicella-zoster
virus
= is due to the virus-encoded thymidine kinase, w/c phosphorylates acyclovir much more
effectively than does the cellular thymidine kinase
= bec only herpes simplex virus & varicella-zoster virus encode a kinase that efficiently
phosphorylates the drug; no activity against cytomegalovirus

B. ganciclovir = active against cytomegalovirus esp retinitis in AIDS & other infections caused
by this virus

C. vidarabine = effective against herpes simplex virus type 1 infections such as encephalitis &
dermatitis but is less effective & much more toxic than acyclovir
= on entering the cell, the drug is phosphorylated by cellular kinases to the triphosphate,
w/c inhibits the herpesvirus-encoded DNA polymerase more effectively than the cellular
DNA polymerase

D. idoxuridine = is clinically useful in the topical treatment of herpes simplex virus

keratoconjunctivitis
= it causes the formation of faulty progeny DNA & mRNA

E. trifluridine = mechanism of action is similar as idoxuridine

** Inhibitors of retroviruses: [the selective toxicity of the ff drugs is based on their ability to
inhibit DNA synthesis by the reverse transcriptase of human immunodeficiency virus
(HIV)]

F. azidothymidine = also inhibits growth of virus in cell culture; is currently the drug of choice in
patients w/ AIDS

G. dideoxyinosine = causes chain termination during DNA synthesis by the reserves transcriptase
 of HIV & is used to treat patients who are intolerant of or resistant to AZT

H. dideoxycytidine = same as dideoxyinosine

** Inhibitors of other viruses:

I. ribavirin = inhibits the synthesis of guanine nucleotides, w/c are essential for both DNA &
RNA viruses
= used clinically to treat pneumonitis caused by respiratory syncytial virus in infants &
to treat severe influenza B infections

@ Inhibition of viral protein synthesis:

A. interferon = effective in the treatment of some patients w/ chronic hepatitis B & C infections

B. methisazone = specifically inhibits the protein synthesis of poxviruses, such as smallpox &
vaccinia viruses
= by blocking the translation of late mRNA

VIRAL VACCINES

@ 2 types of vaccines:
1. live virus -in general, live vaccines are preferred to vaccines containing killed virus bec their
protection is GREATER & LONGER-LASTING
- w/ live vaccines, the virus multiplies in the host, producing a prolonged antigenic
stimulus, & both IgA & IgG are elicited when the vaccine is administered by the natural
route of infection
- booster doses are also recommended esp w/ measles & polio vaccines
- 3 concerns about the use of live vaccines:
a. they are composed of attenuated viral mutants, w/c can revert to virulence either
during vaccine production or in the immunized person
b. live vaccine can be excreted by the immunized person
c. a 2nd virus could contaminated the vaccine if it was present in the cell cultures used to
prepare the vaccine.

2. killed virus - usually given intramuscularly, do not stimulate a major IgA response
- Disadvantages:
> produce a shorter duration of protection
> less protective
> induce fewer IgA Abs
- Advantages:
> they cannot revert to virulence
> are more heat-stable = so can be used more easily in tropical climates

@ Current viral vaccines (1993)

USAGE VACCINE LIVE / KILLED VIRUS

Common Measles Live
Mumps Live
Rubella Live
Polio Both
Influenza Killed
Hepatitis B Killed
Rabies Killed
Special situations Yellow fever Live
Japanese encephatlitis Killed
Adenovirus Live
Smallpox Live

@ Characteristics of live and killed viral vaccines

Characteristic Live Vaccine Killed Vaccine

Duration of immunity Longer Shorter
Effectiveness of protection Greater Lower
Immunoglobulins produced IgA and IgG IgG
Reversion to virulence Possible No
Stability to rm temp Low High
Excretion of virus & transmission to nonimmune Possible No
contacts

Features of viruses that infect the respiratory tract

Virus Disease Lifelong Vaccine Viral

Immunity to Available Latency
Disease
RNA viruses
Influenza A virus influenza no + -
Parainfluenza virus croup no - -
Respiratory bronchiolitis incomplete - -
syncytial virus
(RSV)
Rubella virus rubella yes + -
Measles virus measles yes + -
Mumps virus parotitis, yes + -
meningitis
Rhinovirus common cold no - -
Coronavirus common cold no - -
Coxasackievirus Herpangina, no - -
pleurodynia
DNA viruses
Herpes simplex gingivostomatitis no - +
virus type 1
Epstein-Barr virus infectious yes - +
mononucleosis
Varicella-zoster chickenpox, yes - +
virus shingles
Adenovirus pharyngitis no +2 +

2. Mumps Virus

Disease Mumps
Important Properties (refer to the table above)
= humans are the natural host

Transmission & Epidemiology

transmitted via respiratory droplets
occurs worldwide w/ peak incidence in the winter

Pathogenesis & Immunity

the virus infects the upper respiratory tract & then spreads through the blood to infect the parotid
glands, testes, ovaries, pancreas, & in some cases meninges
lifelong immunity occurs in persons who have had the disease
mumps occur only once
maternal Ab passes the placenta & provides protection during the 1st 6 mons of life

Clinical Findings
after an incubation period of 18-21 days, a prodromal stage of fever, malaise, & anorexia is followed
by tender swelling of the parotid glands, either unilateral or bilateral
there is a characteristic increase in parotid pain when drinking citrus juices
disease is benign & resolves spontaneously w/in a week
2 complications are of significance:
1. orchitis in postpubertal males, w/c if bilateral, can result in sterility
= unilateral orchitis does not lead to sterility
2. meningitis = benign & self-limited & w/o sequelae
= mumps virus, coxsackievirus & echovirus are the 3 most frequent causes of viral
(aseptic) meningitis

Laboratory Diagnosis
viral isolation through cell culture from saliva, spinal fluid, or urine
hemagglutination inhibition & CF = 4-fold rise in Ab titier is diagnostic
mumps skin test = used to detect previous infection

Treatment
no antiviral therapy

Prevention
immunization (live, attenuated vaccine)
= effective & long-lasting (at least 10 yrs)
= given to children at 15 mons of age, usually in combination w/ measles & rubella vaccines
= bec its live, it should not be given to immunocompromised persons or pregnant women
immune globulin is not useful for prevention

3. Respiratory Syncytial Virus (RSV)

Disease pneumonia & bronchiolitis in infants

Important properties (refer to the table above)

= the fusion protein causes cells to fuse, forming syncytia, w/c give rise to the name of the virus
= humans & chimpanzees are the natural host

Transmission &Epidemiology
transmitted via respiratory droplets & by direct contact of contaminated hands w/ the nose or mouth
cause outbreaks every winter & in hospitalized infants (the latter outbreaks can be controlled by hand
washing & use of gloves, w/c interrupt transmission by hospital personnel

Pathogenesis & Immunity

in infants RSV infection is more severe & often involves the lower respiratory tract
adults mild uppter respitory infections
localized infection, viremia does not occur
maternal Ab passed to the infant may react w/ the virus & damage the respiratory tract cells
trials w/ a killed vaccine resulted in more sever disease
immunity is incomplete so may have multiple infections due to RSV

Clinical Findings
infants = lower respiratory tract disease (bronchiolitis & pneumonia predominates)
older children & adults = upper respiratory infections resemble the common cold
Laboratory Diagnosis
isolation in cell culture
immunofluorescence on smears of respiratory epithelium
at least a 4-fold rise in Ab titer is diagnostic

Treatment
aerosolized ribavirin is recommended for severely ill hospitalized infants

Prevention
no vaccine
nosocomial outbreaks can be limited by hand washing and use of gloves

4. Parainfluenza Viruses

Disease
croup & pneumonia in children
disease resembling the common cold in adults

Important Properties (refer to the table above)

Transmission & Epidemiology

transmitted via respiratory droplets
worldwide primarily in the winter months

Pathogenesis & Immunity

cause upper & lower respiratory tract disease w/o viremia
parainfluenza 1 & 2 are major causes of croup & pharyngitis

Clinical Findings
known as the main cause of croup (acute laryngotracheobronchitis) in children under 5 yrs of age; also
cause a variety of respiratory disease such as common cold, pharyngitis, bronchitis & pneumonia
croup is characterized by a harsh cough & hoarseness

Laboratory Diagnosis
viral isolation in cell culture
4-fold or greater rise in Ab titer
Treatment & Prevention
no antiviral therapy nor vaccine available

III. TOGAVIRUSES

1. Rubella Virus

Diseases rubella (German measles) & congenital rubella syndrome

Important Properties
composed of one piece of single-stranded RNA
icosahedral nucleocapsid
lipoprotein envelope
has positive-strand RNA (unlike paramyxoviruses) & has no virion polymerase
surface spikes contain hemagglutinin
human are the natural host

Transmission & Epidemiology

transmitted via respiratory droplets
occurs worldwide; epidemics occur every 6-9 years

Pathogenesis & Immunity

initial replication of the virus occurs in the nasopharynx & local lymph nodes; then spreads via the
blood to the internal organs & skin
natural infection leads to lifelong immunity
2nd cases of rubella do not occur; similar rashes are caused by other viruses, such as coxsackieviruses
& echoviruses
Ab crosses the placenta & protects the newborn

Clinical Findings
A. Rubella = is a milder, shorter disease than measles
= after an incubation period of 14-21 days, a brief prodromal period w/ fever & malaise is
followed by a maculopapular rash w/c starts on the face & progresses downward to involve the
extremities & typically lasts for 3 days
= posterior auricular lymphadenopathy is characteristic

B. Congenital Rubella Syndrome

= when a pregnant woman is infected during the 1st trimester esp the 1st month, significant
congenital malformations can occur as a result of maternal viremia & fetal infection
= increased rate of abnormalities during the early weeks of pregnancy is attributed to the very
sensitive organ devt that occurs at that time
= malfunctions include the ff:
heart (patent ductus arteriosus)
eyes (cataracts)
brain (deafness & mental retardation)
= children infected in utero can CONTINUE TO EXCRETE rubella virus for months following birth
public hazard bec virus can be transmitted to pregnant women
= congenitally infected infants have significant IgM titers & persistent IgG titers long after maternal Ab
has disappeared

Laboratory Diagnosis
cell culture = produces cytopathic effect (CPE)
hemagglutination test or ELISA = 4-fold or greater rise in Ab titer between the acute-phase &
convalescent-phase sera
in pregnant woman exposed to rubella virus, the presence of IgM Ab indicates recent infection
1:8 or greater titer of IgG Ab indicates immunity & consequent protection of the fetus

Treatment no antiviral therapy

Prevention
live, attenuated vaccine = effective & long-lasting ( at least 10 yrs)
= given to children at 15 months of age, usually in combination w/ measles & mumps
= given also to unimmunized young adult women if they are not pregnant & will use
contraception for the next 3 months
= not give to immunocompromised patients
immune globulin administration does not prevent fetal infection in pregnant women exposed to rubella
virus
to protect pregnant women from exposure to rubella virus, many hospital require their personnel to
demonstrate immunity, either by serologic testing or by proof of immunization

2. other Togaviruses
other medically important togaviruses are descrigbed on arboviruses

IV. RHABDOVIRUSES

@ Rabies virus

Disease rabies

Important Properties
single-stranded RNA enclosed w/in a bullet-shaped capsid surrouded by a lipoprotein envelope
genome has a negative polarity
rabies virus has a broad host range = it can infect all mammals
street virus = virus isolated directly from infected animals
fixed virus = virus continuously passaged in rabbit brains; the fixed virus was used in the original
Pasteur type of the vaccine

Transmission & Epidemiology

transmitted by the bite of a rabid animal except rodents & rabbit, mostly dogs
bats are remarkable for their ability to transmit the virus while remaining healthy

Pathogenesis & Immunity

the virus multiplies locally at the bite site & then infects the sensory neurons & moves by axonal
transport to the CNS; multiplies in the CNS & then travel down the peripheral nerves to the salivary
glands & other organs; from the salivary glands, it enters the saliva to be transmitted by the bite
no viremic stage
 infected neurons contain an eosinophilic cytoplasmic inclusion called NEGRI BODY
no record of immunity bec few have survived rabies

Clinical Findings
the incubation period varies according to the location of the bite from as short as 2 wks to 16 wks or
longer
it is shorter when bites are sustained on the head rather than on the leg, bec virus has a shorter distance
to travel to reach the CNS
w/in a few days, signs such as confusion, lethargy & increased salivation develop
most notable is the painful spasm of the throat muscles on swallowing hydrophobia ( an aversion
to swallowing water bec it is so painful)
w/in several days, the disease progresses to seizures, paralysis, & coma & some death

Laboratory Diagnosis
1. animal
= rapid diagnosis: examination of brain tissue using either fluorescent Ab to rabies virus or histologic
staining of Negri bodies in the cytoplasm of hippocampal neurons
= viral isolation: cell culture (but takes too long)

2. humans
= isolation of virus by cell culture
= rise in titer of Ab to the virus
= negri bodies can be demonstrated in corneal scrapings & in autopsy specimens of the brain

Treatment
no antiviral therapy only supportive treatment is available

Prevention
2 approaches to prevention of rabies in humans:
1. preexposure = immunization w/ rabies vaccine should be given to individuals in high-risk
groups such as veterinarians, zoo keepers, & travelers to hyperendemic areas
= rabies vaccine (HDCV) contains inactivated fixed virus grown in human diploid
cells, but duck embryo vaccine or nerve tissue vaccines are also available

2. postexposure = involves the use of bothe the vaccine & human rabies immune globulin
(RIG), obtained from hyperimmunized persons) + immediate cleaning of the wound
= tetanus immunization should also be considered

the decision to give postexposure immunization depends on a variety of factors:

1. the type of animal (all wild-animal attacks demand immunization)
2. whether an attack by a domestic animal was provoked
3. the severity of the bite & its location
4. whether rabies is endemic in the area
5. the advice of local public health officials should be sought

if the decision is to immunize, both HDCH & RIG are recommended

** HDCV = five doses are given
** RIG = given only ones
captured animal should be observed for 10 days &sacrificed if symptoms develop
the vaccine for cats & dogs immunization consists of live, attenuated rabies grown in chick embryos
vaccination must be repeated at intervals

RNA NONENVELOPED VIRUSES

I. PICORNAVIRUSES
 = small (20-30 nm) nonenveloped, composed of an icosahedral nucleocapsid & a single-stranded
RNA genome
= the genome RNA has positive polarity
= replication in the cytoplasm of cells
= are activated by lipid solvents (like ether) bec they dont have envelope
= this family includes 2 medically important groups:
A. enteroviruses
= infect primarily the enteric tract
= replicate optimally at 37C
= stable in acid conditions (pH 3-5); thus they are able to survive exposure to gastric acid

B. rhinoviruses
= found in the nose & throat (hence their name)
= grow better at 33C
= are acid labile (thats why restricted to the nose & throat only)

Features of viruses commonly infecting the intestinal tract

Virus Nucleic Acid Disease Lifelong Vaccine Antiviral

Immunity to Available Therapy
Disease
Poliovirus RNA Poliomyelitis Yes (type- + -
specific)
Echoviruses RNA Meningitis, etc. No - -
Coxsackievirus RNA Meningitis, No - -
carditis, etc.
Hepatitis A virus RNA Hepatitis Yes - -
(enterovirus 72)
Rotavirus RNA Diarrhea No - -
Norwalk virus RNA Diarrhea Unknown - -
Adenovirus DNA Diarrhea Unknown - -

A. Enteroviruses

1. Poliovirus

Disease poliomyelitis

Important Properties
have 3 serologic (antigenic) types based on different antigenic determinants on the outer capsid
proteins, thus protection from disease requires the presence of Ab against each of the 3 types

Transmission & Epidemiology

transmitted by the fecal-oral route
replicates in the oropharynx & intestinal tract
humans are the only natural hosts
poliomyelitis occurs worldwide esp in areas where hygience & sanitation are poor & children are
exposed at an early age & experience mostly asymptomatic infections

Pathogenesis & Immunity

after replicating in the oropharynx & small intestine, the virus spreads through the bloodstream to the
CNS
in CNS, poliovirus replicates in the motor neurons causing death of these cells & results in paralysis of
the muscles innervated by those neurons
infection provides lifelong type-specific immunity (consists both intestinal IgA & humoral IgG to the
specific serotype)

Clinical Findings:
incubation period is usually 10-14 days
the range of responses to poliovirus infection includes:
a. inapparent, asymptomatic infection
b. abortive poliomyelitis = most common clinical form (mild, febrile illness)
= most patients recover spontaneously
c. nonparalytic poliomyelitis = manifests as an aseptic meningitis w/ fever, headache & a stiff
neck; resolves spontaneously
d. paralytic poliomyelitis = flaccid paralysis is the predominant finding; permanent motor
 nerve damage; painful muscle spasm

Laboratory Diagnosis
isolation of virus = from the throat, stool or spinal fluid
= virus causes a cytopathic effect (CPE) w/c can be identified by neutralization method
using a specific antisera
by rise in Ab titer

Treatment
no antiviral therapy
treatment is limited to symptomatic relief & respiratory support
physiotherapy for the affected muscles

Prevention
immunization of both killed (Salk) & the live, attenuated (Sabin) vaccines
both vaccines induce humoral Abs w/c neutralize virus entering the blood & prevent CNS infection &
disease
live vaccine = is currently preferred
= advantages: i. Interrupsts fecal-oral transmission
ii. given orally unlike the killed vaccine w/c must be injected
= disadvantages:
i. reversion of the attenuated virus to virulence will occur
ii. cause disease in immunodeficient persons
iii. infection of the gastrointestinal tract by other enteroviruses can limit replication of
vaccine virus & reduce protection
iv. must be kept refrigerated to prevent heat inactivation of the live virus
killed vaccine = used in 2 special instances:
i.. initial vaccination of unimmunized adults (bec the risk of disease from the live
vaccine is higher in adults than in children)
ii. vaccination of immunodeficient individuals
passive immunization w/ immune serum globulin is available for protection of unimmunized
individuals known to have been exposed & newborns

2. Coxsackieviruses
= named for the town of Coxsackie, NY, where they were first isolated

Disease
Group A viruses = herpangina & hand-foot-&-mouth disease
Group B viruses = pleurodynia, myocarditis, & pericarditis

Important Properties
size & structure of the virion & the nature of the genome RNA are similar to those poliovirus

Transmission & Epidemiology

are transmitted by fecal-oral route
respiratory aerosols also play a role
occurs worldwide primarily in the summer & fall

Pathogenesis & Immunity

Group A viruses = have a predilection for skin & mucous membranes
Group B viruses = in various organs such as the heart, pleura, pancreas & liver
both groups affect the meninges & motor neurons to cause paralysis
immunity following infection is provided by type-specific IgG Ab

Clinical Findings
A. Groups A = herpangina: char by fever, sore throat & tender vesicles in the oropharynx
Hand-foot-and-mouth disease: char by vesicular rash on the hands & feet
B. Group B = pleurodynia/epidemic myalgia/devils grip/Bornholm disease
= myocarditis & have a similar role in juvenile diabetes in humans
C. Caused by both groups = aseptic meningitis, mild paresis & transient paralysis

Laboratory Diagnosis:
cell culture or suckling mice
rise in titer of neutralizing Abs
 Treatmetn & Prevention
no antiviral drug therapy nor vaccine available

3. Echoviruses
the prefix ECHO is an acronym for Enteric Cytopathic Human Orphan
called orphans bec they were not initially associated w/ any disease
cause a variety of diseases: aseptic meningitis, upper respiratory infection, febrile illness w/
& w/o rash, etc.
structure is similar to other enteroviruses
transmitted by fecal-oral route & occur worldwide
one of the leading cause of aseptic (viral) meningitis
diagnosis: cell culture but serologic tests are of little value
no antiviral therapy or vaccine available

4. Other Enteroviruses
Enterovirus 70 = main cause of acute hemorrhagic conjunctivitis
= complete recovery occurs & no therapy
Enterovirus 71 = one of the leading causes of viral CNS disease
Enterovirus 72 = is hepatitis A virus

B. Rhinoviruses

Disease main cause of the common cold

Important Properties
replicate better at 33C than at 37
acid labile

Transmission & Epidemiology

2 modes of transmission:
1. direct = from person to person via aerosols of respiratory droplets
2. indirect = respiratory droplets are deposited on the hands or on a surface such as a table then
transported by fingers to the nose or eyes
occurs worldwide & causing disease in the fall & winter
higher prevalence in children than adults

Pathogenesis & Immunity

the portal of entry is the upper respiratory tract & the infection is limited to that region probably bec
they grow poorly at 37C
immunity is serotype-specific & is a function of nasal secretory Ab

Clinical Findings
after incubation period of 2-4 days, sneezing, nasal discharge, sore throat, cough & headache are
common & a chilly sensation occurs
illness lasts about 1 week
note that other viruses such coronaviruses, adenoviruses, influenza C virus & coxsackieviruses also
cause common cold syndrome

Laboratory Diagnosis
viral isolation from nasal secretion in cell culture
serologic tests are not done

Treatment & Prevention

no specific antiviral therapy is available
vaccines appear impractical bec of the large # of serotypes
paper tissues impregnated w/ disinfectants such as iodine, limit transmission when used to remove
rhinoviruses from fingers contaminated w/ respiratory secretions
high doses of Vit C have little ability to prevent rhinovirus-induced colds

II. REOVIRUSES
 = REO is an acronym for Respiratory Enteric Orphan
= when the virus was discovered, it was isolated from the respiratory & enteric tracts& was not
associated w/ any disease
= Rotaviruses are the most important human pathogens in this family

@ Rotavirus

Disease most common cause of gastroenteritis in young children

Important Properties
segmented, double-stranded RNA genome w/ an icosahedral capsid w/o an envelope
the virion contains an RNA-dependent RNA polymerase (a virion polymerase is required bec human
cells do not have an RNA polymeralse that can synthesize mRNA from a double-stranded RNA
template

Transmission & Epidemiology

transmitted by the fecal-oral route
infection occurs worldwide

Pathogenesis & Immunity

rotavirus replicates in the mucosal cells of the small intestine loss of salt, glucose & water leads to
diarrhea (nonbloody)
immunity is unclear

Clinical Findings
infection is characterized by nausea, vomiting & watery, nonbloody diarrhea
gastroenteritis is most serious in young children (concern is dehydration & electrolyte imbalance)
minor symptoms in adults
Laboratory Diagnosis:
radioimmunoassay or ELISA = using a stool
4-fold or greater rise in Ab titer
cell culture & immunoelectron microscopy = not routinely done

Treatment & Prevention

no antiviral therapy nor vaccine is available
prevention rests on sanitation

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Disease: Acquired immunodeficiency syndrome (AIDS)

Important Properties:
1. HIV is one of the human T cell lymphotrophic retroviruses
2. infects & kills helper (CD4) T lymphocytes = resulting in the loss of cell-mediated immunity & a
high probability & susceptibility to opportunistic infections
3. may infect other cells also like macrophages & monocytes, that have CD4 protein on their surfaces
4. cause slow infections w/ long incubation periods
5. Fig. 45-1: Cross-section of HIV
= in the interior, 2 molecules of viral RNA are shown associated with reverse transcriptase; surrounding
those structures is an icosahedral nucleocapsid composed of p24 proteins; on the exterior are the 2
envelope proteins, gp120 & gp41, w/c are embedded in the lipid bilayer derived from the cell membrane
6. typical retroviral genes:
a. gag gene = encodes the internal core proteins, the most impt is p24, an Ag used in
serologic tests
b. pol gene = encodes several proteins including the virion reverse transcriptase, w/c synthesizes
DNA by using the genome RNA as a template
c. env gene = encodes gp160, a precursor glycoprotein that is cleaved to form the 2 envelope
(surface) glycoproteins, gp120 & gp41
d. tat gene = means transactivation of transcriptase, a regulatory gene w/c encodes a
protein that enhances viral gene transcription
= reduces the ability of cytotoxic T cells to kill HIV-infected cells
7. Important Ags of HIV:
a. gp120 & gp41 = are the type-specific envelope glycoproteins
= the gene that encodes gp120 mutates rapidly; Ab against gp120 neutralizes the
infectivity of HIV, but the rapid appearance of gp120 variants will make production of an
effective vaccine difficult
= the high mutation rate may be due to lack of an editing function in the reverse
transcriptase
b. p24 = the group-specific Ag
= Ab against p24 do not neutralize HIV infectivity but serve as impt serologic
markers of infection
8. infects human & certain primates BUT HIV is NOT AN ENDOGENOUS VIRUS of humans
9. viruses similar to HIV:
a. HIV-2 = proteins of HIV-2 are only about 40% identical to those of the original HIV isolates
b. Simian immunodeficiency virus (SIV) = isolated from monkeys w/ AIDS-like illness
= the proteins of SIV resemble those of HIV-2 more closely than they resemble those of
the original HIV isolates
c. HTLV-IV = infects T cells but does not kill them & is not associated w/ any disease

Summary of Replicative Cycle:

1. the initial step in entry of HIV into the cell is the binding of the virion gp120 envelope protein to the CD4
protein on the cell surface
2. the virion gp41 protein then mediates fusion of the viral envelope w/ the cell membrane & the virion enter
the cell
3. after uncoating, the virion RNA-dependent DNA polymerase transcribes the genome RNA into double-
stranded DNA, w/c integrates into the host cell DNA
4. the virion assemble in the cytoplasm & are released from the cell by budding
5. much of the virus remains cell-associated & may be difficult to neutralize w/ Ab

Transmission & Epidemiology:

1. transmission of HIV occurs primarily by sexual contact & by transfer of infected blood (esp in promiscuous
homosexual men, intravenous drug abusers, & hemophiliacs; heterosexual transmission is predominant in
African countries; transmission from health care personnel to patients is very rare)
2. perinatal transmission from infected mother to neonate also occurs, either transplacentally or via breast
milk
3. infection occurs by the transfer of either HIV-infected cells or free HIV (HIV that is not cell-associated)
4. dose of HIV required to cause infection is much higher than that of HBV
5. since 1981, when AIDS was 1st reported, it is estimated worldwide that 8-10 million or more people are
infected

Pathogenesis & Immunity:

1. HIV infects helper T cells & kills them, resulting in suppression of cell-mediated immunity; this
predisposes the host to various opportunistic infections & certain cancer cells like Kaposis sarcoma &
lymphoma (but HIV are not found in these cancer cells so HIV does not directly cause these tumors)
2. HIV acts as a superantigen, w/c indiscriminantly activates many helper T cells & leads to their demise
3. persistently infected cells continue to produce HIV, w/c explains that a person infected w/ HIV is
considered to be infected for life
 4. 90% of AIDS pxs have Abs against HIV (but these Abs neutralize the infectivity of the virus poorly) = this
indicates that immunity is incomplete & that infectious virus & Abs can coexist
5. abnormalities of B cells also occurs, aside from detrimental effects on T cells

Clinical Findings:
1. the clinical picture of HIV infection can be divided into 3 stages:
a. early, acute stage = 2-4 weeks after infection; Abs to HIV appear w/in 2 months after infxn
= fever, lethargy, sore throat, generalized lymphadenopathy, maculopapular rash,
leukopenia but # of CD4 cells is normal
b. middle, latent stage = a long latent period, measured in years
= px is asymptomatic & viremia is low or absent but a large amount of HIV is being
produced by the lymph node cells
= AIDS-related complex (ARC) syndrome can occur during this latent period
= frequent manifestation of the signs & symptoms of acute stage
c. late immunodeficiency stage =manifested by a decline in the # of CD4 cells to below 200/mm 3
& an increase in the frequency & severity of opportunistic infections

Fig. 45-3: Time course of HIV infection. Note that the level of virus in high early in the infxn,
drops to a low level for several years, & then rises during the immunodeficiency stage. The level
of CD4 lymphocytes remains more or less normal for many years but then falls. This results in
the immunodeficiency stage, w/c is characterized by opportunistic infections & malignancies

2. 2 most characteristic manifestation of AIDS

a. Pneumocystis pneumonia
b. Kaposis sarcoma
3. other opportunistic infections:
a. viral infxns = herpes simplex, herpes zoster, & CMV infxn & progressive multifocal
leukoencephalopathy
b. fungal infxns = thrush by Candida albicans, cryptococcal meningitis & histoplasmosis
c. protozoal infxns = toxoplasmosis & cryptosporidiosis
d. bacterial infxns = disseminated Mycobacterium avium-intracellulare & Mycobacterium
tuberculosis
4. neurologic problems = dementia & neuropathy

Laboratory Diagnosis:
1. ELISA = detection of Abs; presumptive diagnosis of HIV infection
2. Western blot analysis = in cases of false-positives; the definitive diagnosis
3. isolation by culture = not available to all
= the polymerase chain reaction (PCR) is a very sensitive & specific technique used to
detect HIV DNA w/in infected cells

Treatment:
1. Azidothymidine (AZT, zidovudine, Retrovir) = is the treatment of choice
= prolongs survival & reduces the # of opportunistic infections but does not eliminated the virus
2. Dideoxyinosine (ddI, didanosine, Videx) = is recommended for those who are intolerant of AZT

Prevention:
1. No vaccine for human is available
2. taking measures to avoid exposure to the virus (ex. using condoms, not sharing needles, & discarding blood
that is contaminated w/ HIV)
 MINOR VIRAL PATHOGENS

Characteristics Representative Virus(es)

DNA enveloped viruses
DNA nonenveloped viruses
RNA enveloped viruses
RNA nonenveloped viruses
Herpes B virus, human herpesvirus 6, molluscum contagiosum virus,
cowpox virus, monkeypox virus
Parvovirus B19
Coronoviruses, Ebola virus, Hantaan virus, Japanese encephalitis virus,
Lassa fever virus, lymphocytic choroimeningitis virus, Marburg virus,
spumaviruses, Tacaribe complex of viruses
Astroviruses, encephalomyocarditis, Norwalk virus

@ These viruses are presented in alphabetical order:

1. Astroviruses = have a characteristic 5- or 5-pointed star-shaped morphology

= cause watery diarrhea esp in children
2. Coronaviruses = w/ club-shaped surface spikes that resemble a corona
= cause upper respiratory tract infection (colds) in adults
3. Ebola virus = is named for the river in Zaire that was the site of an outbreak of hemorrhagic
fever in 1976; member of the filovirus family
= disease begins w/ fever, headache, vomiting.& diarrhea; later bleeding into the GIT
occurs, followed by shock & disseminated intravascular coagulation
= mortality rate approaches 100%
4. Encephalomyocarditis virus = causes either encephalitis or mild febrile illness
= member of the picornavirus family
5. Hantaan virus = cause of Korean hemorrhagic fever (KHF); member of the bunyavirus family
= main reservoir: rodents, mice & voles
= transmission to humans: aerosols of various secretions or excretions; transmission between
humans does not occur
= ribavirin may be an effective treatment
6. Herpes B virus = cause a rare, fatal encephalitisin persons in close contact w/ monkeys & their
tissues (ex. zookeepers or cell culture technicians)
= diagnosis is made only by recovering the virus
= treatment: acyclovir
= prevention: * using protective clothing & masks to prevent exposure to the virus
* immune globulin containing Ab to herpes B virus should be given
after a monkey bite
7. Human Herpesvirus 6 = cause of exanthem subitum (roseola infantum), a common dse in infants,
characterized by high fever & transcient rash
= virus is lymphotropic & infects B cells primarily
8. Japanese Encephalitis virus = common cause of epidemic encephalitis
= member of flavivirus family
= transmitted to humans by certain species of Culex mosquitoes endemic to Asian rice fields
= 2 main reservoir: birds & pigs
= dx: isolation of virus & detecting IgM Ab in serum or spinal fluid
 = prevention: * consists of an inactivated vaccine & pesticides to control the
mosquito vector
* immunization for individuals living in endemic areas for several
months or longer
9. Lasse Fever virus = causes a severe, often fatal hemorrhagic fever characterized by multiple-organ
involvement
= member of the arenavirus family (arena means sand)
= most striking feature is the sandlike particles on their surface, w/c are ribosomes
= primary reservoirs: rodents Mastomys
= transmission: by contamination of food or water with animal urine
= dx: isolating the virus or by detecting a rise in Ab titer
= treatment: ribavirin, reduces the mortality rate if given early
= prevention: centers around proper infection control practices & rodent control
10. Lymphocytic Choriomeningitis virus = member of the arenavirus family
= a rare cause of aseptic meningitis & is indistinguishable from the other viral causes
= CSF show an increased # of cells, mostly lymphocytes, w/ an elevated protein level & normal
or low sugar level
= reservoir: mouse
= virus transmitted to humans via food or water contaminated by mouse urine or feces
= human are accidental dead-end hosts
= dx: isolating the virus from CSF & by detecting an increase in Ab titer
11. Marburg virus = similar to Ebola virus that both cause hemorrhagic fevers
= members of the filovirus family
= the common feature of the infected individuals was the exposure to African green monkeys
from Uganda
= dx: isolation of the virus & detecting a rise in Ab titer
= prevention: no vaccine available
2ndary cases among medical personnel have occurred, therefore,
stringent infection control practices must be instituted to
prevent nosocomial spread
12. Molluscum Contagiosum virus = one of the 2 causes of warts in the adult genital region, the other
being the human papillomavirus
= transmission: by direct skin contact, sexual intercourse (accounts for the genital
lesion)
= member of poxvirus family
= lesions are usually removed by surgery, electrocautery or cryotherapy
= even w/o treatment, the lesions will resolve spontaneously in a few years
13. Norwalk virus = one cause of gastroenteritis; member of calicivirus family
= transmission: virus is transmitted by the fecal-oral route & occurs worldwide;
(uncommon in children)
= temporary immunity: less than 2 years
= dx: either immunoelectron microscopy or radioimmunoassay can be used
= treatment & prevention: no antiviral therapy nor preventive measures other than hand
washing
14. Parvovirus B19 = is the 1st parvovirus to be confirmed as a cause of human disease
= common disease cause is erythema infectiosum (a self-limited dse of children that is
characterized by a slapped-cheeK rash
= preferentially infects immature red blood cell precursors & kills them
15. Poxviruses of Animal Origin = 4 poxviruses cause disease both in animals & man (poxlike
lesions): a. cowpox virus
b. pseudocowpox virus
c. orf virus = contagious pustular dermatitis in sheep & vesicular
lesions on the hands of sheepshearers
d. monkeypox = causes human dse that resembles smallpox
16. Spumaviruses = subfamily of retroviruses = cause a foamy appearance in culture cells (can
present problem in the production of viral vaccines if the contaminate the cell cultures
used to make the vaccine)
= no known human pathogens
17. Tacaribe Complex of viruses = contains 2 human pathogens: (both cause hemorrhagic fever-
characterized by fever & bleeding into the GIT, skin, other organs; the bleeding is due to
thrombocytopenia)
i. Junin virus in Argentina
ii. Machupo virus in Bolivia
= agricultural workers are at high risk; endemic in rodent population
= transmitted to humans by accidental contamination of food & water by rodent excreta
= dx: either by isolation of the virus or rise in Ab titer
= no antiviral therapy or vaccine is available