Specific Viral Families: Flaviviridae

Flaviviridae

The flaviviruses are enveloped, polyhedral, (+) sense RNA viruses that are transmitted by mosquitoes and ticks. The viruses produce a variety of encephalitides or fevers in humans. The yellow fever virus is a flavivirus that cause a haemorrhagic fever—in which blood vessels in the skin, mucous membranes and internal organs bleed uncontrollably. Hepatitis C infection is also caused by a flavivirus.

Important Properties

    · Spherical enveloped virion, 40-50nm

    · Inner core protein C

    · Membrane/matrix protein M

    · Envelope with glycoprotein peplomers (E)

    · Single linear 11kb positive sense ssRNA—infectious mRNA

    · Polyadenylated tail and 5’ cap

    · Cytoplasmic replication

    · Polyprotein from genomic RNA cleaved

    · 3 structural proteins

    · Several non-structural proteins

Dengue Virus

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  · Most important arbovirus presently.

    · Transmitted through the bite of a female Aedes aegypti mosquito (the vector).

    · 4 distinct serotypes based on neutralisation test.

    · DEN-1, DEN-2, DEN-3 and DEN-4

    · DEN-2 shows greatest antigenic and genotypic distance from the others.

    · Protective immunity after infection homotypic.

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Dengue Infectious Cycle

Classic Dengue begins suddenly with an influenza syndrome consisting of fever, malaise, cough, and headache. Severe pains in muscles and joints occur. Enlarged lymph nodes, a masculopapular rash, and leukopenia are common. After a week or so, the symptoms regress but weakness may persist. Although unpleasant, this typical form of dengue is rarely fatal and has few sequelae.

Dengue Haemorrhagic Fever (DHF) is a much more severe disease, with a fatality rate that approaches 10%. The initial picture is the same as classic dengue, but then shock and haemorrhage, especially into the gastrointestinal tract and skin, develop. Dengue haemorrhagic fever occurs particularly in southern Asia, whereas the classical form is found in tropical areas worldwide.

Haemorrhagic Shock Syndrome (DSS) is due to the production of large amounts of cross-reacting antibody at the time of a second dengue infection. The pathogenesis is as dollows: The patient recovers from classic dengue caused by one of the four serotypes, and antibody against that serotype is produced. When the patient is infected with another serotype of dengue virus, an anamnestic, heterotypic response occurs, and large amounts of cross-reacting antibody to the first serotype are produced.

Pathogenesis of DHF/DSS

  1. Virulent strain theory

a. Some strains are more virulent than others

b. Molecular studies show variations in sequences amongst different strains within serotypes

c. Early evidence pointed to DEN-2

  2. Antibody enhancement

a. Main theory for DHF/DSS

b. Main cell target of DEN: Monocytes and macrophages

c. Most cases of DHF/DSS had prior infection or infants below 1 year had maternal Ab.

d. Monkey experiments showed similar enhancement.

Control of Dengue Virus

    · No antiviral therapy or vaccine for dengue is available.

    · Outbreaks are controlled by using insecticides and draining stagnant water that serves as the breeding ground for mosquitoes.

    · Personal protection includes using mosquito repellent and wearing clothing that covers the entire body.

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Yellow Fever Virus

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  · Type species of the genus flavivirus

    · Tropical disease in Latin America and Africa

    · Transmitted through the bite of a female Aedes aegypti mosquito (the vector).

    · Incubation period: 3-6 days

    · Acute yellow fever—symptoms: Viremia, headache, malaise, nausea, muscle ache, flushing of head and neck, conjuntival infection, strawberry tongue.

    · Remission after acute yellow fever manifests as severe yellow fever—symptoms: fever, vomiting, abdominal pain, prostration.

    · Symptoms progress to involve the liver, kidneys and heart: e.g. jaundice.

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Strawberry Tongue

Control of Yellow Fever Virus

    · Mosquito control (similar to dengue)

    · Immunnization with the vaccine containing live, attenuated yellow fever virus. Travelers to and residents of endemic areas should be immunized.

    · Protection lasts for up to 10 years; booster shots to be taken after that.

    · Because it is a live vaccine, it should not be given to immunocompromised people or to pregnant women.

West Nile Virus

  · Originated in Uganda

· Discovered in 1937

Symptoms

    · Usually mild to no symptoms

o Fever

o Headache, body aches

o Skin rash

o Swollen lymph glands

    · Severe Symptoms (occurring mainly in persons above 50 years old)

o Crossing blood-brain-barrier

o Encephalitis

o Meningitis

Transmission

    · Wild birds are the main reservoir of this virus

    · Vector is the mosquito, especially the Culex species

    · Humans are dead-end hosts

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West Nile Virus Transmission Cycle

Control

    · No vaccine is available for west nile virus

    · Mosquito control

Specific Viral Families: Retroviridae

Retroviridae

The retroviruses are enveloped viruses that have two complete copies of (+) sense RNA. They also contain the enzyme reverse transcriptase which uses the viral RNA to form a complementary strand of DNA, which is then replicated to form a dsDNA. For the genetic information to be transcribed and translated, this DNA migrates to the host cell nucleus and become incorporated into chromosomes of host cells. Such integrated viral DNA is known as a provirus.

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Retroviruses cause tumours and leukemia in humans. The human retroviruses invade immune defense cells called T lymphocytes and are referred to as Human T cell Leukemia Viruses (HTLV). Both HTLV-1 and HTLV-2 are associated with malignancies (leukemia and other tumours), whereas the human immunodeficiency virus (HIV) causes acquired immune deficiency syndrome (AIDS).

Important Properties

    · Spherical enveloped virion, 80-100nm

    · Ribonucleoprotein in central nucleoid (concentric or truncated cone in lentivurses) within icosahedral capsid.

    · Envelope with glycoprotein peplomers

    · 2 copies of linear plus sense ssRNA each 7-10kb

    · 3’ polyadenylated tail and 5’ cap

    · Reverse transcriptase

    · Formation of long terminal repeats before prpovirus DNA inserted into host genome

    · Genome consists of gag, pol, env genes some regulatory genes, some oncogenes.

Human Immunodeficiency Virus

HIV is one of the human T-cell lymphotropic retroviruses. HIV preferentially infects and kills helper (CD4) T lymphocytes, resulting in a loss of cell mediated immunity and a high probability that the host will develop opportunistic infections. Other cells (e.g. macrophages and monocytes) that have CD4 proteins on their surfaces can be infected also.

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Genes and Proteins of the Human Immunodeficiency Virus

Gene	Proteins Encoded by Gene	Function of Proteins
I. Structural Genes Found in All Retroviruses
gag	p24, p7 p17	Nucleocapsid Matrix
pol	Reverse Transciptase Protease Integrase	Transcribes RNA genome into DNA Cleaves precursor polypeptide Integrates viral DNA into host cell DNA
env	gp120 gp41	Attachment to CD4 protein Fusion with host cell
II. Regulatory Genes Found in Human Immunodeficiency Virus that are Required for Replication
tat	Tat	Activation of transcription of viral genes
rev	Rev	Transport of late mRNAs from nucleus to cytoplasm
III. Regulatory Genes Found in Human Immunodeficiency Virus that are NOT Required for Replication (accessory genes)
nef	Nef	Decreases CD4 proteins and class I MHC proteins on surface of infected cells; induces death of uninfected cytotoxic T cells; important for pathogenesis by SIV
vif	Vif	Stabilizes newly synthesized viral DNA and transports core through cytoplasm
vpr	Vpr	Transports viral core from cytoplasm into nucleus in non-dividng cells
vpu	Vpu	Enhances virion release from cell

Replicative Cycle of HIV

The replication of HIV follows the typical retroviral cycle.

  1. Inital step in the 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 gp120 protein then interacts with a second protein on the cell surface, one of the chemokine receptors (CXCR4 and CCR5). Individuals with mutations in the gene encoding CCR5 have protection from infection with HIV.

  3. The virion gp42 protein mediates fusion of the viral envelope with the cell membrane, and the virion enters the cell.

  4. After uncoating, the virion RNA-dependent DNA polymerase transcribes the genome RNA into double-stranded DNA, which integrates into the host cell DNA, mediated by integrase.

  5. The viral DNA can integrate at different sites in the host cell DNA, and multiple copies of viral DNA can integrate.

  6. Viral mRNA is transcribed from the proviral DNA by host cell ENA polymerase and translated into several large polyproteins.

  7. Precursor polyproteins can be assembled into nucleocapsid.

  8. As immature virions buds from the cell membrane, the polyproteins are cleaved by the viral protease. This results in the formation of mature, infectious virions.

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Transmission

    · Transfer of infected blood.

    · Sexual contact (horizontal transfer)

    · Perinatal transmission from infected mother to neonate: Either across the placenta, at birth, or via breast milk. (vertical transfer)

Pathogenesis

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  · Primary Infection

o Acute stage

o Flu-like symptoms

o Fever

o Skin rash

o Swollen skin nodes

o Due to virulence factors such as rate of replication, propensity to mutate and cytopathogenicity.

o Also due to host resistance mechanisms such as the suppression by CD8 T suppressor cells and the presence of cytotoxic T-lymphocytes.

    · Asymptomatic Stage

o No apparent disease

o Fall in CD4 T lymphocytes

o Possible signs:

§ Fatigue

§ Depression

§ Weight loss

§ Memory disorders

    · Symptomatic Stage

o AIDS-related complex

§ Diseases not considered definitive of AIDS

§ May be attributed to HIV infection

§ Indicative of defect in cell-mediate immunity

o AIDS

§ Opportunistic infections as a result of fall in CD4 T lymphocytes. (e.g. Kaposi’s Sarcoma)

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Treatment

    · Highly active antiretroviral therapy (HAART)

o Consists of two nucleoside inhibitors (zidovudine and lamivudine) and a protease inhibitor (indinavir)

o Effective in prolonging life, improving the quality of life, and reducing viral load but does not cure the chronic HIV infection i.e. a latent infection of CD4+ cells continues indefinitely.

o Such combination therapy able to combat resistance—which arise due to rapid mutations due to inefficiency of reverse transcriptase.

    · Non-specific therapeutic management

    · Immunomodulation

o Enhancement of immune system through treatment with interleukin-2 (still under study)

    · No vaccine for human use is available.

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Prevention

Taking measures to avoid exposure to the virus:

    · Using condoms

    · Not sharing needles

    · Discarding donated blood that is contaminated with HIV