Secondary Immunodeficiency Flashcards
1
Q
What is the defintion of secondary immunodeficiency?
A
The failure of immunological function as a result of infection rather than as a result of defects in genes encoding components of the immune system.
2
Q
Examples of secondary immunodeficiencies.
A
- Malnutrition
- Viral infections
- Therapeutic agents: X-rays, cytotoxic drugs and corticosteroids
- B-lymphoproliferative disorders: chronic lymphocytic leukaemia and myeloma are associated with varying degrees of hypogammaglobulinemia (where the immunoglobulin level is depressed below the normal range)
3
Q
Acquired Immunodeficiency Syndrome (AIDS)
A
- First seen in 1980’s
- Caused by infection with human immunodeficiency virus (HIV) which was first isolated in 1983
- Earliest evidence is in blood samples from African patients in the late 1950’s
- HIV uses CD4 as its cellular receptor and it cannot bind in chimps, therefore cannot become infected
Clinical Features - Massive reduction in circulating CD4+ T cells
- Severe recurrent infections eg. pneumocystis carinii
- High incidence of aggressive forms of cancer
4
Q
Human Immunodeficiency Virus (HIV)
A
- RNA of retroviruses of which there are two main types: HIV-1 and HIV-2
- HIV-1 is the main cause if AIDS in most countries and kills almost everyone it affects without treatment
- HIV-2 is endemic to West Africa and has spread widely throughout Asia. It is less virulent and causes a slower progression to AIDS. 30-40% of people infected with HIV-2 are long-term non-progressors to AIDS who have low or undetectable viral loads (viral load is measured as the number of HIV-2 genomes per millilitre of blood). However, those with a high viral load progress as quickly to AIDS as those infected with HIV-1
- During HIV infections, HIV recruits 273 human proteins, for its own benefit, many of which prevent the immune system from terminating HIV infections
- The HIV virsuses are members of the lentivirus group which are budding viruses whose genome is relatively complexand tightly compressed
- The disease causes widespread immune dysfunction, with a protracted latent period but progressive decrease in CD4 cells leading eventually to severely depressed CMI. Once the CD4 count fallw below 200 cells/cumm, an individual becomes susceptible to opportunistic infections
- There were two main features of the AIDS patients that indicated that this disease was a type of immunodeficiency: the high incidence of infections which were only seen in immunocompromised individuals
5
Q
Infection by HIV
A
- The virus is transmitted inside infected CD4+ cells and macrophages so the disease is spread sexually (blood or semen containing the HIV virus). Sexual transmission occurs via mucosal surfaces followed by the spread throughout the lymphatic system. The virus may also be transmitted from an infected mother to her infant, in which cases, babies born with a high viral load progress more rapidly than those with lower viral loads
- Infection takes place when envelope glycoprotein gp120 of HIV binds avidly to cell-surface CD4 molecules on helper-T cells, macrophages, dendritic cells and microglia
- Dendritic cells populate the human mucosa and project their dendrites through the epithelial cells so that they are directly exposed to the mucosal surface. The binding of the CD4 molecules initiates the fucion of gp41 on the viral membrane to various chemokine receptors on the host cell
- Early in the infection, the viruses use the CCR5 co receptor present on memory T-cells, macrophages and dendritic cells, and later infect resting T-cells using the CXCR4 co-receptor. Mutations in the CCR5 receptor have been found in 1% of Caucasians but have not been found in people of African or Japanese descent
6
Q
Life cycle of HIV in human cells
A
- The gp120 envelope protein of the virus binds to CD4, enabling gp120 to also bind to a receptor (either CCR5 or CXCR4)
- The binding releases gp41, causing fusion of the viral envelope with the plasma membrane and release of the viral core into the cytoplasm
- The RNA genome is released and reverse transcribed into double stranded cDNA
- The DNA migrates to the nucleus in asociation with the viral integrase and becomes integrated into the cell genome as a provirus
- Activation of the T-cell causes low level transcription of the provirus into mRNA that directs the synthesis of the early proteins Tat and Rev. These proteins chnage the pattern of provirus transcription to produce mRNA encoding the protein constituents of the virion and RNA molecules corresponding to the HIV genome
- Envelope proteins travel to the plasma membrane, whereas other viral proteins and other viral genomic RNA assemble into nucleocapsids
- New virus particles bud from the cell acquiring their lipid envelope and envelope glycoproteins in the process
7
Q
In the 20th century, most HIV-1 infections progressed to AIDS
A
- In most people infected with HIV, the virus produces an infection that resists the immune response and continues throughout life. Although thr initial acute infection is controlled so that the disease is not apparent, the virus remains and replicates, exhausting the immune system, leading to an increasing severe immunodeficiency and eventually death.
- Viruses in the initial inoculum enter human cells, and use these cells biosynthetic machinery to make many more copies of themselves
- Newly made viruses then burst out of each cell and can then go on to infect other cells
- In the earlystages, the virus multiplies relatively unchecked while the innate immune system tries its best and the adaptive immune system is mobilised
- After a week or so, the adaptive immune system is being mobilised and virsus specific B-cells, helper T-cells and and cytotoxic T lymphocytes (CTLs) are activated, proliferate and start to work
- Consequently, during this early acute phase of a viral infection, there is a dramatic rise in the number of viruses within the body as the virus multiplies in the infected cells
- This is followed by a marked decrease in viral load as CTLs begin to work
- A full blown HIV-1 infection always leads to a chronic phase which lasts for 10 years or more. During this chronic phase, there is a struggle between the immune system and AIDS virus
- During the chronic phase of infection, viral load decreases to low levels compared with those reached during the height of the acute phase, but the number of virus specific CTLs and T-helper cells remains high which is a sign that the immune system is still trying to defend off the virus
- As the chronic phase progresses, the total number of Th cells slowly decreases, as they are killed as a consequence of viral infection. Eventually, there are not enough Th cells left to provide the help needed by virus specific CTLs
- When this happens, the number of these CTLs also begins to decline and the viral load increases because there are too few CTLs left to cope with the newly infected cells
- The immune system becomes overwhelmed and the resulting profound state of immunosuppression leaves the patient open to unchecked infections by pathogens that would normally not be a problem for an individual with an intact immune system (acute, chronic, profound immunosuppression)
8
Q
Sexual transmission of HIV
A
- Infects Langerhan’s cells in rectal/vaginal mucosa
- Moves to lymph nodes and replicates
- HIV-1 infection
- Dissemination bu uraemia - acute early syndrome associated with fever, myalgia, arthralgia
- Leads to sequestration of HIV virus in lymphoid tissue which becomes a major reservoir for the next stage of infection - the clinically latent stage
Clinically latent phase: - Virus concentrated in immune complexes, held by follicular dendritic cells in lymphoid cells
- Only low levels of virus produced
- CD4+ cells destroyed
Chronic progressive phase:
-CD4+ cells are very low so that the patient is at risk of life threatening infections
9
Q
Deficiency of CCR5 co-receptor stops people getting infected with HIV
A
- Mutations of CCR5 co-receptor confer increased risk to infection (only homozygous CCR5-delta32 individuals don’t get affected)
10
Q
How can HIV-1 defeat the immune system and resist antiviral drugs?
A
- Forms a latent infection which cannot be detected by CTLs - For the HIV-1 virus, the genetic information is in the form of RNA with a protective coat which, after the virus enters its target cell, is copied by a viral enzyme called reverse transcriptase to make a piece of copy/complementary DNA (cDNA). Nex, the DNA of the cell is cut by another enzyme carried by the virus, and the viral cDNA is inserted into the gap in cellular DNA. Once the viral cDNA has been inserted into a cells DNA, it can sit there in latent state (not growing). While it is in a latent state, it cannot be detected by CTLs. Sometime later, in response to signals that are not fully understood, NfkappaB then binds to the HIV enhancer, triggering transcription. You see increased levels of tumour necrosis factor alpha in HIV infected individuals, particularly in the advanced stage, the latent virus can reactivate, more copies of the virus can be produced and these newly produced viruses can then infect other cells
- Reverse transcriptase is highly error prone, producing mutations that result in HIV-1 being one step ahead of CTLs or antibodies directed against it. It makes one mutation each time it copies a piece of viral RNA. This means that every new virus produced in an infected cell is a mutation version of the virus that originally infected the cell. Some of these mutations may enable the newly made viruses to evade the immune system. The virus that has evaded detection by the CTLs is replicating, and every time it infects a new cell, it mutates again.
- Specifically targets T-helper cells, macrophages and dendritic cells - The docking protein that HIV-1 binds to when it infects a cell is CD4, the co-receptor protein found in large numbers on the cell surface of T-helper cells, dendritic cells and macrophages. By attacking these cells, HIV-1 either disrupts their function, kills the cells or makes them targets for killing CTLs that recognise them as being virus infected. The very cells that are needed to activate CTLs and provide them with help are damaged by the virus.
- Uses immune cells to spread infection - HIV-1 can turn the immune system against itself by using processes essential for immune function to spread and maintain the viral infection. For example, HIV-1 can attch to the surface of dendritic cells and be transported by these cells from the tissues, where there are relatively few CD4+ cells into the lymph nodes where huge numbers of CD4+ cells are located. Not only are there lots of CD4+ cells within easy reach in the lymph nodes, many of these cells are proliferating, making them ideal candidates to be infected and becomes HIV-1 factories. HIV-1 viruses that have been opsonised either by antibodies or complemented are retained in lymph nodes by follicular dendritic cells which is intended to help activate B-cells. However, CD4+ T cells also pass through these follicular dendritic cells, and as they do they can be infected by the HIV-1 virus that are attached to the dendritic cells. Because virus particles typically remain bound to follicular dendritic cells for months; lymph nodes actually become resovoirs for HIV-1, so HIV-1 takes advantage of the normal trafficking of immune system cells through the lymph nodes.
11
Q
Anti-retroviral drugs
A
- Rapidly clear the virus from the blood and increase the number of circulating CD4 T cells. Maintenance of HIV levels in the blood depends on the continual infection of newly produced CD4 T-cells. This is because cells only live for a few days once infected. The administration of the drugs blocks the viral life cycle. The existing virions in the blood are rapidly cleared by the actions of neutralising antibody, complement and phagocytes. Newly produced CD4 T cellsare not infected, they live longer and accumulate in the circulation.
12
Q
Laboratory diagnosis of HIV
A
- Reversal of CD4:CD8 ratio
- Quantitative-PCR of HIV-RNA-measures viral load
- Delayed hypersensitivity skin response (due to decreased CD4)
13
Q
Treatment of HIV
A
- Issues: drug resistance and long-term toxicity of anti-retroviral agents
- Prolonged survival needs: antiretroviral agents, immunization, chemoprophylaxis, aggressive treatment of infections, aggressive treatment of malignancies, triple therapy in symptomatic patients
14
Q
Issues with HIV-1 vaccines
A
- Take advantage of the ability of B- and T-cells to remember recent invaders. By introducing the immune system to a safe version of a microbe, a vaccination prepares these adaptable weapons to respond more rapidly and powerfully if a real attack occurs at some future time.The production of memory B- and T- helper cells does not require that an antigen presenting cell be infected, so a non-infectious vaccine made from a dead virus or even a single viral protein can be used to produce a vaccine that will elicit protective antibodies
- Designing a vaccine that will produce memory killer T cells is more difficult (what is needed to destroy viruses) because so far, the only way to do this efficiently is witha vaccine than can infect antigen presenting cells.
