HIV- pathogenesis Flashcards
Describe the stages of infection seen in the patient after contracting HIV in respect to CD4 count, viraemia (virus in blood) and antibody levels (anti-p24 Ab)/ T-cell levels (represents immune response)
During the primary phase illness, there is a peak in replication for the virus and so viraemia is high but then dips to the lowest levels at the end of this stage
Antibody levels see a sharp increase as a response to this
CD4 count is steady
In the asymptomatic phase (can last over 10 years), viraemia stays low whilst the immune system is keeping it that way
CD4 count start to decline near the end
AIDS stage comes last, seeing a decline in antibodies and CD4 count whilst viraemia increases rapidly
HIV was thought to be a true latent virus (one that stays dormant for a long time but can be activated lots of times e.g cold sores). Describe the symptoms of why HIV was thought to be one?
Long clinical asymptomatic phase
Low levels of virus detected in peripheral blood of asymptomatic patients
Viral replication in vitro only detected in activated T-cells
It was then decided that HIV exhibited clinical latency but not cellular latency. Why was this decided?
The cell turnover is very rapid (half life is
What are the mechanisms used by the virus compared to the host?
Virus: CD4 cell destruction by cytopathology (direct killing) and indirect killing by gp120 Loss of CD4 function Lymph node destruction Viral replication
Host: Cytotoxic T-cell response Antibody response CD8 antiviral factors Chemokines
Near the end of the asymptomatic phase, the balance shifts between the virus and immune system. What happens?
More CD4+ cells killed than produced
Lymph node destruction interferes with immune response
Loss of CD4+ Th11 function
Accumulation of viral variants overwhelms the immune system
What sort of symptoms are seen in the primary infection stage and clinical latency stage?
Primary infection:
Mononucleosis-like syndrome
Fever, malaise, rash, diarrhoea, lymphadenopathy
Clinical latency:
Often no symptoms but sometimes fatigue, weight loss, thrush, shingles
Normal levels of CD4 cells are around 2000/mm^3. HIV infection reduces this. What sort of additional infections do you see with levels of 200-500 CD4 cells/mm^3?
Generalised lymphadenopathy Oral lesions espcandidiases Reactivation of herpes zoster (shingles) Reactivation of latent Mycobacterium tuberculosis Basal cell carcinoma of skin Molluscum contagiosum (poxvirus) Condyloma acuminata (papillomavirus)
What sort of additional infections do you see when levels of CD4 cells are less than 200/mm^3?
Protozoal infections (fungus-like infections) such as Pneumocystis carinii, Taxoplasma gondii, cryptosporidia, microsporidia
Bacterial infections such as Treponema pallidum, Mycobacterium avium intracellulare
Fungal infections such as Candida albicans, cyptococcus neoformans
Viral infections such as CMV, HSV, EBV lymphoma, Kaposi’s sarcoma, anogenital carcinoma
Additional infections is an indirect way that HIV causes its pathogenicity. AIDS is the direct way. It kills T-cells in the immune system, but what other effects does it have on the human body?
2/3 patients gets AIDS dementia complex (ADC) which is the infection of brain macrophages and glial cells (form the architecture of brain- not the neurones)
Symptoms are dementia, motor and behavioural abnormalities and seizures. Developmental problems are seen in children with HIV as their brain is developing
Weight loss is due to infection of gut epithelial macrophages and causes diarrhoea, malabsorption due to blunting of the villae
Also get effects in the lung due to replication in the lung macrophages
What is the official definition of HIV given by the World Health Organisation?
A progressive qualitive and quantitative decline in the CD4+ Th1 lymphocyte subset
HIV types 1 and 2 infect CD4+ cells. Which two major cell groups have CD4 on their surface?
T-lymphocytes
Monocyte derived antigen presenting cells (e.g dendritic cells_
What do T and B-lymphocytes do normally?
B-lymphocytes produce antibodies
T-lymphocytes kill any infected/damaged or cancer cells
T-lymphocytes can be divided into more types. Two types that are important are CD8+ (they simply have CD8 cells on their surface hence the name) Cytotoxic T-cells and CD4+ T-helper cells. What do these do?
Cytotoxic T-cells recognise infected or cancer cells and directly kill those
T-helper cells help the cytotoxic T-cells or B-lymphocytes
T-helper cells can further be divided into Th1 cells and Th2 cells. What do these do?
Th1 cells produce a range of cytokines (e.g IL-2 and IL-12) which help stimulate the productivity of Cytotoxic cells
These Th1 cells are the ones that become infected with HIV
Th2 cells produce cytokines (e.g IL-4 and IL-10) which stimulate B cells to produce antibodies
Apart from T and B cells, what other cells are targeted?
Monocytes (mononuclear phagocytes) which are antigen-presenting cells. These can be macrophages which ingest and breakdown foreign bodies circulating and then present peptides to the T-cells to activate the adaptive immune response.
They can also be dendritic cells which obtain antigen tissues (e.g skin and peripheral blood). They then go to the lymph nodes and activate T-cells. Large amounts of extracellular virus found trapped on the surface of follicular dendritic cells
How does HIV get into the cell: What is the structure of the primary receptor of these cells, CD4? What is its normal function?
4 extracellular domains with short cytoplasmic tail
Binds to Class 2 MHC on antigen presenting cells and also binds to IL16
How does HIV get into the cell: What is the secondary receptor for HIV to get in? What is their structure? What is their normal function?
Chemokine receptors
They have 7 transmembrane domains (N-terminus outside and C terminus in cytoplasm)
Their normal function is to bind to chemokines (chemoattractants that are secreted from immune cells at sites of inflammation or injury- these create gradients in which T-cells migrate down to get to site)
Chemokine receptors are the secondary receptors for HIV to enter the cell. What is the difference between alpha-chemokine receptors and beta-chemokine receptors?
Alpha ones bind to those with two cysteine residues separated by another amino acid (CxC)
Beta ones bind to those with cysteine residues adjacent to eachother
How does HIV get into the cell: HIV first has to bind to the receptors mentioned earlier. Describe the process in which this happens.
gp120 (glycoprotein trimer present on HIV surface) binds with CD4 then to the chemokine receptor via the charged residues found in the receptor
HIV can be categorised into two groups dependent on which kind of chemokines they target. Which viruses infect early on in the acute phase and asymptomatic phase?
R5 viruses use CCR5 beta-chemokine receptoes (remember two CC means two cysteine residues adjacent to eachother)
These have been termed non-syncytium inducing which means they are unable to fuse cells into a multinucleate fusion (very toxic to cell)
They replicate in primary T-cells and macrophages but don’t replicate in transformed T-cells
HIV can be categorised into two groups dependent on which kind of chemokines they target. Which are evident later on in the infection around AIDS?
X4 viruses use CXCr4 alpha-chemokine receptor
Able to fuse cells and replicate in transformed T-cells
The reason it is able to switch to this receptor is due to a mutation in the V3 loop of gp120- the charge of amino acids is negative to positive where the mutation has taken place
Why are R5 viruses called M-tropic?
Why are X4 viruses called T-tropic?
Because they can infect Macrophages as these express CCR5 on their surface
Because they can infect T-cells which express CXCR4 receptors
Can also get dual tropic viruses that can infect both
Can there be resistance to HIV?
Yes, some people have mutations in both CCR5 genes which is a 32 bp deletion making an inactive protein- not found in African and Asian populations but is in 1% of white populations
The people are perfectly healthy
It is not known whether heterozygotes for this mutation are partially protected or not
Early in infection, the virus is very homogeneous and preferentially macrophage-tropic (CCR5 receptors). Why is it not surprising considering the route of entry of HIV?
Many macrophages in urogenital/anal mucosa- CCR5 highly expressed in these mucosal macrophages
In parental transmission, it also seems those R5 (M-tropic) viruses are selected for- thought to be an ecape mechanism to enable viruses to survive in the presence of an uncompromised immune system
Dendritic cells are exploited to get the virus around the body. How?
Immature dendritic cells (iDC) take up antigens/ dead cells etc. and migrate to the lymphoid tissues/ lymph nodes where there are lots of T-cells
They then present the antigens to the T-cells so they can combat any infection.
HIV exploits this system so that the virus is transmitted to T-cells
What is DC-SIGN? What does it normally do?
A molecule present on the surface of dendritic cells that normally binds to protein on surface of T-cells (has a lectin domain which binds to carbohydrate residues)
DC-SIGN binds HIV envelope glycoprotein and induces endocytosis. This is beneficial for the virus as it is held in a membrane compartment. This increases their half life and lets them remain infectious for a longer time that those free in the serum
Apart from DC-SIGN, can HIV viruses infect T-cells?
Yes, using CCR5 receptors, they can actually infect the cell not being endocytosed first
How do the viruses enclosed in the DC molecules then infect T-cells?
Form a virological synapse where the virions travel across the cleft to the T-cell (The virus fuses with DC membrane then migrates across)
Protected from any immune response
Can viruses travel from T-cell to T-cell in the same way as from a DC cell to a T-cell?
Yes, needs gp120:CD4/CCR5 interactions
How can the virus get from one cell to another in a long-range situation?
Through membrane nanotubes (visualised by flourescent labelling)
