302 How viruses cause disease Flashcards
How many people were living with HIV in 2021?
38.4 million
What type of virus is HIV?
A retrovirus
Family: Retrovirdae
Subfamily: Orthoretroirnae
Genus: Lentivirus
What is the zoonic origin of HIV-1?
Chimpanzees and gorillas
What is the zoonic origin of HIV-2?
Sooty mangabeys (a monkey)
What are SIV’s?
Simian immunodeficiency viruses
They naturally infect a wide range of African nonhuman primates and are the souse of HIV-1 and HIV-2
What are the 4 genetically distinct groups HIV-1 is subdivided into?
M, N, O, and P
What are the 9 distinct groups that HIV-2 is subdivided into?
A-I
What is the global distribution of HIV subtypes?
M has a global distribution
N, O, and P and HIV-2 are confined to West central Africa
What are the 9 distinct genotypes of HIV-1 group M?
A-D, F-H , J, K
What are the different sub-subtypes of HIV-1 group M?
A1-A4, F1, F2
What are CRF’s?
Circulating recombinant forms
What are URF’s?
Unique recombinant forms
How do CRF’s and URF’s form?
Through recombination of different subtypes
Which area in the world has the highest HIV-1 genetic diversity?
Central Africa
Describe the structure of the HIV-1 virus
100nm in diameter
gp120 and gp41 membrane proteins
Has an envelope (outer membrane), matrix, viral capsid, 2 identical molecules of ssRNA, RT, and IN
What is RT in viruses?
Reverse transcriptase
What is IN in viruses?
Integrase
What is integrase in viruses?
It’s the viral enzyme that catalyses the integration of virally derived DNA into the host cell DNA in the nucleus
Describe the HIV life cycle
- Attachment and fusion into the host cell and uncoating once inside the host cell
- Reverse transcription
- Integration
- Transcription
- Translation into proteins that assemble into a virus
- Budding and maturation of the virus
At which part of the HIV life cycle do attachment inhibitors work on?
On the attachment part
At which part of the HIV life cycle do fusion inhibitors work on?
The fusion and uncoating part
What is the risk of transmission of HIV through different methods?
Blood transfusion 90%
Mother to child 23%
Drug injection equipment 0.63%
Percutaneous needle stick injections 1.4%
Insertive anal intercourse 011%
Receptive penile-vaginal intercourse 0.08%
Insertive penile-vaginal intercourse 0.04%
What are risks that increase HIV transmission?
-Other STI’s because there a higher number of target cells
-High viral load
Why can’t antiretroviral treatment (ART) eliminate infection?
Because it can’t eliminate the integrated viral DNA from infected cells
What role does the adaptive immune system play in the initial host response of HIV infection?
HIV declines after acute infection because of HIV-specific CD8+ cytotoxic T-cells
Overtime, they fail to durably control the virus because HIV is able to create cytotoxic T-lymphocyte (CTL) escape mutants
What does CTL stand for?
Cytotoxic T-lymphocyte
How does HIV evade the immune response?
-Increasing glycosylation of envelope as a shielding mechanism
-Evasion from cellular restriction factors (APOBEC3)
-Generating cytotoxic T-lymphocyte escape mutants
What is pathogenesis of HIV?
-Slow depletion of circulating tissue-based CD4+ T-cells
-Cause a constant state of immune-activation, activation of the endothelium and of the coagulation system
-Profound alteration of lymphoid tissues
-Increases plasmatic circulation of polysaccharides
-Causes a proinflammatory state
What is the effect of slow depletion of circulating tissue-based CD4+ T-cells?
They’re essential for regulating the immune response, depletion leads to immunosuppression with development of opportunistic infections and AIDS-related malignancies
What are AIDS-related malignancies?
Cancers that are more likely to develop with a HIV infection
Eg. Kaposi sarcoma, non-Hodgkin lymphoma, cervical cancer, Hodgkin lymphoma, and cancers of the mouth, throat, liver, lung, and anus
What is the effect of a constant state of immune-activation, activation of the endothelium and of the coagulation system?
-There are increased proinflammatory cytokines
- Low CD4/CD8 ratio
-Exhaustion and senescence of T-cells and monotypes
What is the effect of alteration of lymphoid tissues by HIV infection?
It causes an increase in microbial translocation due to the disruption of the physiological gut barrier
What is the effect of Increased plasmatic circulation of polysaccharides?
It’s a component of the bacterial cell wall
It enhances persistent immune activation
What is the effect of a constant proinflammatory state on the body?
-Premature ageing observed in people living with HIV
-Multiorgan disease:
Premature onset of atherosclerosis and MI
Neurocognitive decline
Liver disease (non-fatty liver disease)
Metabolic syndrome
Osteoporosis
Onset non-AIDS related cancers
Overall increased mortality
What is the pathogenesis of HIV in other sites beyond the immune system?
-In the CNS, the virus can affect astrocytes via a CD4-independent mechanism
-HIV can infect renal epithelial cells in the kidneys
These mechanisms are the basis of the onset of HIV-associated neurocognitive disorder (HAND) and HIV-associated nephropathy (HIVAN)
What % of patients develop symptoms of HIV?
50-90%
They’re easy to miss, transient symptoms that overlap with common infections
Characterised by high viral load
High inflammatory response causes systemic symptoms
What are some viral differential diagnoses of primary HIV infection?
Epstein-Barr virus
Cytomegalovirus
Primary herpes simplex virus
Influenza
Early-stage hepatitis
Parvovirus B19
Rubella
What is Epstein-Barr virus?
EBV can cause infectious mononucleosis (mono)
What is Parvovirus B19?
Most commonly causes fifth disease, a mild rash illness that usually affects children
What is Rubella?
AKA German measles
It’s a rare illness that causes a spotty rash
What are some bacterial differential diagnoses of HIV infection?
Streptococcal disease
Secondary syphilis
Lyme disease
Rickettsial disease
Disseminated gonococcal infection
What is Lyme disease?
A bacterial infection that can be spread to humans by infected ticks
Rarely deadly, easily treated if diagnosed early
What is Rickettsial disease?
A group of bacteria that spread by the bite of an infected tick or mite
Symptoms:
Fever.
Headache.
Rash (sparse maculopapular or papulovesicular eruptions on the trunk and extremities)
Muscle aches
What is a disseminated gonococcal infection?
AKA DGI
It occurs when the sexually transmitted pathogen Neisseria gonorrhoeae invades the bloodstream and spreads to distant sites in the body
What are some parasitic differential diagnoses of HIV infection?
Acute toxoplasmosis
What is acute toxoplasmosis?
An infection with a parasite called Toxoplasma gondii
People often get the infection from eating undercooked meat, having contact with cat faeces, or it can be passed to a baby during pregnancy
Most people infected with the parasite do not have symptoms
What are some non-infectious differential diagnoses of HIV infection?
Adult Still disease
Systemic lupus erythematosus
Systemic vasculitis
Drug reaction
What is Adult Still disease?
A rare type of inflammatory arthritis that features fevers, rash and joint pain
What is Systemic lupus erythematosus?
A chronic autoimmune disease that can cause severe fatigue and joint pain
What are the Fiebig stages of HIV infection?
-Eclipse: No plasmatic markers because initial replication of virus happens at the inoculation site
-1 (5 days): HIV RNA becomes detectable in plasma
-2 (10days): Positive p24 antigen (Ag) in plasma
-3 (14 days): seroconversion (anti-HIV antibodies present)
-4 (19 days): Indeterminate Western blot
-5 (88 days): Reactive Western blot for p31 Ag
-6 (88+ days): Reactive Western blot with positive p31 Ag
What is seroconversion?
When the body starts producing detectable levels of HIV antibodies
What is the Indeterminate Western blot in HIV?
Banding pattern on a Western blot test that failed to meet the criteria for positivity
What is the purpose of the Fiebig stages?
They describe the emergence of virologic and immunologic markers following infection with HIV
What is the definition of the AIDS stage in HIV infection?
CD4 count <200 cells/mm3 (advanced HIV infection)
Onset of opportunistic infections and malignancies
What are some AIDS stage opportunistic infections?
-Recurrent bacterial infections usually only found among <6 years olds
-Candiditis of bronchi, trachea, or lungs
-Cryptococcosis (extrapulmonary)
-Cytomegalovirus disease
-Herpes simples (chronic ulcers >months duration, or bronchitis, pneumonitis, or oesophagitis)
-Salmonella septicaemia
-Toxoplasmosis of the brain
-Recurrent pneumonia
What is a cytopathic effect of viruses?
Morphological changes of the cells caused by the infecting virus
Give examples of cytopathic effects of viruses
-Inhibition of cell transcription/translation
-Changes in membrane permeability
-Alterations of the cytoskeleton or trafficking pathways
-Cell-cell fusion
-Induction of apoptosis
What is the cytopathic effect of Venezuelan equine encephalitis virus (VEE)?
It causes a direct cytopathic effect on neurones
What are immune complexes?
Aggregates of viruses and antibodies that form within small blood vessels and lead to the development of inflammation (vasculitis)
What diseases are immune complexes responsible for?
Glomerulonephritis
How doe viruses promote the onset of cancer?
-Immunosuppression (Eg. HIV and Kaposi’s sarcoma)
-Chronic inflammation (HCV and HCC)
-Cellular transformation (HPV and cervical cancer)
What is Kaposi’s sarcoma?
A cancer caused by viral infection that affects the mouth and skin
First appears as purple, red, or brown lesions on the skin
