Session 6 Flashcards
Describe the principles of virus structure, classification and replication
[*] Viral classification is based on the nucleotides in the virus, its mode of replication, the structure and symmetry of the structural proteins (capsids) and the presence or absence of an envelope
[*] Genetic material and replication
DNA viruses:
- Double-stranded DNA viruses include poxviruses, herpesviruses, adenoviruses, papovaviruses and polymomaviruses
- Single-stranded DNA viruses include parvoviruses.
- DNA viruses usually replicate in the nucleus of host cells by producing a polymerase that reporduces viral DNA. Viral DNA is not usually incorporated into host chromosomal DNA.
RNA viruses: RNA viruses possess a single strand of RNA and adopt different reproductive strategies:
- RNA sense (positive) may serve directly as mRNA and be translated into structursl protein and an RNA-dependent RNA polymerase
- RNA antisense (negative) contains an RNA-dependent RNA polymerase that transcribes the viral genome into mRNA. Alternatively, the transcribed RNA can act as a template for further viral (antisense) RNA
- Retroviruses have single-stranded sense RNA that cannot act as mRNA. This is transcribed by reverse transcriptase and incorporated into host DNA. The subsequent transcription to make mRNA and viral genomic RNA is under control of host transcriptase enzymes.
[*] Capsid symmetry: viral nucleic aicd is covered by a protein coat of repeating units (capsids), with either icosahedrsal (spherical) or helical (arranged around a rotational axis) symmetry.
[*] Envelope: a lipid envelope derived from host cell or nuclear membrane surrounds some viruses. The host membrane may incorporae viral-encoded antigens that may act as receptors for other host cells. Enveloped viruses are sensitive to substances that dissolve the lipid membrane (e.g. either)
Describe the virology of HIV
A retrovirus:
- Genus Lentivirus, subfamily Orthoretrovirinae, family Retroviridae
- Enveloped, spherical to pleiomorphic, 80-100nm in diameter
- Diploid single-stranded positive RNA virus, non-segmented, linear, 9200 base pairs
- Gp120 is the surface protein that binds to CD4+ T cells .p24 and gp41 are other important surface proteins.
- HIV-1 most common around the world
- Groups M, O, N and P
- Subtypes of Group M: A, B, C, D, F, G, H, J, K, CRFs
- CRFs are Circulating Recombinant Forms – when 2 viruses infect one patient, they can fuse together to produce hybrid viruses; very heterogenous virus)
- HIV-2 is similar to HIV-1 but largely confined to W. Africa
- HIV-2 appears less virulent
Describe the transmission and pathogenesis of HIV
[*] Transmission of HIV
- Sexually
- By blood and body fluids
- From mother to child
[*]
- Viral RNA is transcribed to ssDNA and integrates into host genome. Once this happens you are infected for life. You can clear the virus from the blood but there are archive stroes of the virus elsewhere e.g. in the lymph nodes
- Antigenic variation is rapid
- Incubation is long with seroconversion (when antibody for HIV is made – immune response kicks in) delayed by weeks. Only 50% of cases are symptomatic.
- Seroconversion is evident in some patients as IM-like (Infectious Mononucleosis-like) or as aseptic meningitis, but many are asymtpomatic
- Progressive loss of T4 cells lead to immunodeficiency (AIDS)
- Eventually exposes patients to opportunistic infections (Kaposi sarcoma and malignancies) due to loss of cell-mediated immunity
Describe AIDS and seroconversion
- 50-70% of patients have an acute syndrome occuring 2-6 weeks after acquisition of HIV
- Only about 25% of these patients have symptoms severe enough to seek medical attention
- Non-specific symptoms: fever, malaise, arthralgias, headache and sore throught with lymphadenopathy, typical of acute viral infection
- Early invasion of the nervous system may lead to meningitis, encephalitis, peripheral neuropathy, opportunistic pneumonia or myelopathy (AIDS deeloped early on)
- Seen in about 25% of acute HIV patients: nonspecific erythematous maculopapular rash which can involve the palms and soles.
- There may also be an exanthem (widespread, reactive rash) presenting with small erosions or petechiae on the soft palate
- Signs and symptoms of patients with acute seroconversion illness usually resolve within 2-3 weeks
- It has been suggestsed that persons with a sympatomatic seroconversion syndrome may be at increased risk for a more accelerated disease course
Describe the laboratory diagnosis of HIV
- Virus can be cultured from circulating mononuclear cells
- Genome detected by PCR and p24 antigen detected prior to seroconversion
- ELISA is used for antibody screening tests
- Confirmation either by Western Blot or Line Immunoassay
- Vacciness are in the proccess of developemnt (??effectiveness??)
- Treatment with several classes of anti-retrovirals in combination as HAART
Describe the antiviral drugs available
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs) inhibit reverse transcriptase by being incoproated as faulty nucleotides.
- Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIS) inhibit reverse transcriptase directly. As resistance occurs after a single mutation, they are used in maximally suprpressive regiments only.
- Protease Inhibitors (PIs) target the HIV-encoded protease.
- Fusion Inhibitors (FIs): Enfuvirtide inhibits binding with gp134, maraviroc inhibits binding to CCR5 preventing fusion.
- Integrase Inhibitors block the insertion of the HIV viral genome into the DNA of the host cell.
- Co-receptor/Entry Inhibitors
Describe the life cycle of HIV
- Free virus
- Binding and Fusion: virus binds to a CD4 molecule and one of two co-receptors (either CCR5 or CXCR4). Receptor molecules are common on the cell surface. Then the virus fuses with the cell
- Infection: virus penetrates cell. Contents emptied into cell
- Reverse Transcription: single strands of viral RNA are converted into double-stranded DNA by the reverse transcriptase enzyme
- Integration: viral DNA is combined with the cell’s own DNA by the integrase enzyme
- Transcription: when the infected cell divides, the viral DNA is read and long chains of proteins are made
- Assembly: sets of viral protein chains come together
- Budding: Immature virus pushes out of the cell, taking some cell membrane with it.
- Immature virus breaks free of the infected cell
- Maturation: protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to make a working virus
Describe the principles of infection prevention with regard to HIV
[*] Avoidance of partners who have a high-rsik factor and unrpotected intercourse (e.g. using barrier contraception)
[*] Screening of blood proucts
[*] Health education and free needle-exchange programmes for intravenous drug users
[*] Antigenic diversity has frustrated vaccine development
[*] Antiretroviral prophylaxis should be given for infected needle-stick injuries
[*] Transmission from mother to child can occur
Describe the virology of Hepatitis B
- Genus: orthohepadnavirus, family Hepadnaviridae
- Enveloped, pleiomorphic, 22-48nm diameter forms
- Circular, partially double-stranded DNA, 3020-3320 base pairs negative sense long strand, 1700-2800 base pairs positive sense short strand
- 400 million HBV varriers
- prevalent (>8%) in Africa, Western Pacific, Asia
- Much more transmissible than HIV
- Transmitted by parenteral (IV, IM), vertical, sexual
- Age-related risk for chronicity – children are more likely to develop chronic infections
- Chronic hepatitis, cirrhosis, HCC (hepatocellular carcinoma) – liver failures takes a long time (20-30 years)
- 300000/HCC per year
- Life cycle depends on reverse transcriptase prone to mutations
- Universal vaccination (HBsAg-based) in many countries
- Hyperimmunoglobulin for transplant recipients
- Select for sAg mutants (may give false-negative on HBsAg assay)
Describe the Global Patterns of Chronic HBV infection
High (equal or greater than 8%): 45% of global population
- Lifetime risk of infection >60%
- Neonatal/early childhood (vertical) infections common)
Intermediate (2%-7%): 43% of global population
- Lifetime risk of infection 20%-60%
- Infections occur in all age groups
Low (<2%): 12% of global population
- Lifetime risk of infection: <20%
- Most infections occur in adult risk groups
Describe the routes of transmission and clinical features of Hepatitis B
[*] Routes of Transmission of HBV infection
- Vertical: mother-to-infant
- Horizontal:
- Sexual
- Percutaneous (~30%): blood, intravenous drug use, sharp injury, tattoo
[*] Clinical features:
- Incubation period: Range 2-6 months
- Clinical illness: fever, malaise, jaundice
- Acute case-fatality rate: 0.5%-1%
Symptomatic infection:
- Children:
- Adult: 30-50%
Chronic infection:
- Sex: Male > female
- Age: Infant ~90%; Children ~30%; Adult
The more symptomatic you are, the more likely you are to clear the infection espeically if you are older.
What is the outcome of Chronic HBV infection?
Describe the principles of infection prevention with regard to Hepatitis B
[*] Treatment
- Pegylated alpha-interferon
- Lamivudine, adefovir, entecavir, tenafovir, telbbivudine and clevudine have antiviral efficacy.
[*] Vaccination
- Recombinant vaccine based on HBsAg
- 3 doses (0, 1, 6 months or 0, 1, 2, 12 months)
- Response rate ~95%, effective safe
- Universal to all newborns in Hong Kong
[*] Hyper immunoglobulin (HBIg)
- Post exposure prophylaxis (HBsAg +ve positive source)
- Newborns from HBsAg +ve mthers
- Needle stick injury for healthcare workers without protection
Describe Hepatitis D
Genus Deltavirus (a viroid – plant pathogen), family/order unassigned
- HBsAg-enveloped, 36nm diameter, circular, single-strand negative RNA, 1700bp
- Worldwide, about 5% of HBV carrier infected – requires HBV to provide envelope (HBsAg)
- IVDU, sexual promiscuous, cirrhosis in 70% HCC
- Modes of transmission: HDV (as for HBV)
- Percutaneous exposures (injecting drug use)
- Per-mucosal exposures (sex contact)
Clinical features
- HBV and HDV coinfection: severe acute disease, low risk of chronic infection
- HBV with HDV superinfection: usually develop chronic HDV infection, high risk of severe chronic liver disease
What are the useful diagnostic markers for HDV?
- HDV RNA: positive in both co-infection, superinfection
- Anti-HDV total antibody: positive in both co-infection, superinfection, IgG disappear after recovery, IgM/IgG differentiation +/-
- Acute HBV markers: helpful in differentiating co-infection and superinfection
