Secondary Immunodeficiency 7/02/23 Flashcards
What is secondary immunodeficiency?
Acquired failure of immunological function as a result of infection or using immunosuppressive drugs.
What is an example of secondary immunodeficiency?
-Malnutrition
-Viral infections (aids)
-Therapeutic agents (x-rays, cytotoxic drugs, corticosteroids)
-B-lymphoproliferative disorders (chronic lymphocytic leukaemia, MM)
How common are secondary immunodeficiencies?
Far more prevalent than primary immunodeficiencies
When did aids first occur?
In 1980. The earliest evidence for HIV is its presence in blood samples from African patients in the late 1950s.
Where did aids come from?
Sequencing of viral genomes indicate the first Africans were infected by infections jumping from chimpanzee (HIV-1) and sooty mangabey (HIV-2) into humans. In neither of these species, nor the 39 other species of African monkey does the HIV-related virus cause a severe disease like AIDS. HIV uses CD4 as its cellular receptor-and it cannot bind in chimps therefore cannot become infected.
What are the symptoms of aids?
-Massive reduction in circulating CD4+ T cells
-Severe recurrent infections (Pneumocystis carinii)
-High incidence of aggressive forms of cancers (Kaposi sarcoma, B-cell lymphoma)
What causes HIV?
Aids is caused by infection with Human Immunodeficiency Virus which was first isolated in 1983. Human Immunodeficiency Virus is a RNA retroviruses of which there are 2 main types-HIV-1 and HIV-2. HIV-1 is the main cause of AIDS in most countries-and without treatment kills almost everyone it infects. HIV-2 is endemic to West Africa and has spread widely throughout Asia. HIV-2 is less virulent and causes a slower progression to AIDS. 30-40% of people infected with HIV-2 are long term non-progresses (to AIDS) who have low or undetectable viral loads and similar mortality rates to uninfected people. However, those with a high viral load progress as quickly to AIDS as those infected with HIV-1.
How is HIV transmitted?
The virus is transmitted inside infected CD4+ cells and macrophages and the disease is therefore spread sexually or through blood or blood products. Transmission of disease is usually through infection with blood or semen containing the HIV-1/2 virus. Sexual transmission occurs via mucosal surfaces followed by spread throughout the lymphatic system. The virus may also be transmitted from an infected mother to her infant-in which case, babies born with a high viral load progress more rapidly than those with lower viral loads.
How does the infection take over?
Infection takes place when envelope glycoprotein gp120 of HIV binds avidly to cell-surface CD4 molecules on helper T-cells, macrophages, DCs and microglia.
Dendritic cells populate the human mucosa and project their dendrites through the epithelial cells so that they are directly exposed on the mucosal surface. The binding to the CD4 molecule initiates the fusion of gp41 on the viral membrane to various chemokine co-receptors on the host cell. Early in infection the viruses use the CCR5 co-receptor present on memory T cells, macrophages and DCs, and later infect resting T cells using the CXCR4 co-receptor. Mutations or complete absence of the CCR5 receptor have been found in 1% of Caucasians and are associated with increased resistance to infection. Such mutations have not been found in people of African or Japanese descent. Interesting point-the more rapid progression of HIV infection in Africa may be linked to activation of the immune system through continual microbial insult.
What is acute HIV?
In most people infected with HIV, the virus produces an infections that resists the immune response and continues throughout life. Although the 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. From 1983 to 1997 (peak of the epidemic was 1996) there was no effective treatment for HIV, so a lot was learnt about the natural course of HIV infection and the associated immune responses caused. HIV infection begins very much like other viral infections. 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 go on to infect other cells. So in the early stages of infection the virus multiplies relatively unchecked while the innate system gives it its best shot, and the adaptive system is mobilized. After a week or so, the adaptive system is being mobilized and virus specific b cells, helper t cells and 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 in the body (the viral load) as the virus multiplies in infected cells. this is followed by a marked decrease in the viral load as virus-specific CTLs go to work.
What is chronic HIV?
With many viruses the end result of the acute phase of a viral infection is sterilization-which means that all the invading viruses are destroyed, and memory b and t cells are produced to protect against a subsequent infection by the same virus. However this is not the case with hiv-1 infection. A full blown HIV-1 infection always leads to a chronic phase that lasts that lasts for 10 or more years during this chronic phase a fierce struggle goes on between the immune system and the aids virus, a struggle which the virus always wins. During the chronic phase of infection, viral loads decrease to low levels compared with those reached during the height of the acute phase, but the number of virus specific CTLS and Th cells remains high, a sign that the immune system is still trying hard to defeat the virus. The HIV virus always wins the battle-and as the chronic phase progresses the total number of Th cells slowly decreases, because these cells 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. In the end the immune defences are overwhelmed , and the resulting profound state of immunosuppression leaves the patient open to unchecked infections by pathogens that normally would not be the slightest problem for a person with an intact immune system. Sadly these opportunistic infections can be lethal to an AIDS patient whose immune system has been destroyed.
What prevents people from getting HIV?
Mutations of CCR5 co-receptor confer increased resistance to infection. 1% European origin are heterozygous for CCR5-Δ32 variant. 10% European origin are homozygous for CCR5-Δ32 variant. Only homozygous CCR5-Δ32 individuals don’t get infected.
A HIV-infected individual who developed acute myeloid leukaemia was given an allogeneic bone marrow transplant which was homozygous for CCR5-Δ32
Cured leukaemia and HIV infection.
How is HIV able to defeat the immune system and resist antiviral drugs?
- The first reason is to do with the fact it is a virus. All viruses are basically pieces of genetic information (DNA or RNA) with a protective coat. The HIV-1 virus, the genetic information is in the form of RNA which, after the virus enters its target cell, is copied by a viral enzyme called reverse transcriptase to make a piece of copy or complementary DNA (cDNA). Next the DNA of the cell is cut by another enzyme carried by the virus, and the viral cDNA is inserted into the gap in the cellular DNA. Once the viral cDNA has been inserted into a cells DNA it can just sit there in a latent state (not growing). While the virus is in the latent state, the infected cell cannot be detected by CTLs. Sometime later, in response to signals that are not fully understood the latent virus can reactivate, more copies of the virus can be produced and these newly produced viruses can then infect other cells. It is this ability to establish a latent infection that cannot be detected by CTLS is one property of HIV-1 that makes it such a problem. The reverse transcriptase enzyme used to copy the HIV-1 RNA is very error prone-it makes 1 error (mutation) each time it copies a piece of viral RNA. This means that almost every new virus produced in an infected cell is a mutated version of the virus that originally infected that cell and the problem of course is that some of these mutations may enable the newly made viruses to evade the immune system. For example, the virus might mutate so that a viral peptide that formerly was targeted by a CTL no longer can be recognised, or no longer can be presented by the mhc molecule that the CTL was trained to focus on. When such mutations occur, that CTL will be useless against cells infected with the mutant virus, and new CTLs that recognise another viral peptide will have to be activated. Meanwhile the virus that has escaped from surveillance by the obsolete CTLs is replicating like mad, and every time it infects a new cell, it mutates again. Consequently the mutation rate of HIV-1 is so high that it can effectively stay one step ahead of CTLs or antibodies directed against it.
- Also–the type of cells that HIV-1 infects is important for its ability to overcome the immune system. HIV-1 specifically targets immune cells the helper t cells, macrophages and dendritic cells. The docking protein that HIV-1 binds to when it infects a cells is cd4, the co-receptor protein found in large number s on the cell surface of T helper cells. This protein is also expressed on macrophages and dendritic cells. By attacking these cells, HIV-1 either disrupts their function, kills the cells or makes them targets for killing by CTLs that recognise them as being virus infected so the very cells that are needed to activate CTLs and to provide them with help are damaged or destroyed by the virus.
- 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 attach 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 opsonized either by antibodies or complement are retained in lymph nodes by follicular dendritic cells-this 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 reservoirs of hiv-1-so hiv-1 takes advantage of the normal trafficking of immune system cells through the lymph nodes.
What are anti-retroviral drugs?
AntiretroviraldrugsrapidlyclearvirusfromthebloodandincreasethenumberofcirculatingCD4Tcells.ThefirstandsecondpanelsshowthatmaintenanceofHIVlevelsintheblooddependsonthecontinualinfectionofnewlyproducedCD4Tcells.Thisisbecausecellsliveforonlyafewdaysonceinfected.Thethirdandfourthpanelsshowtheeffectsofadministeringadrug(redsquares)thatblocksthevirallifecycle.Theexistingvirionsinthebloodarerapidlyclearedbytheactionsofneutralizingantibody,complement,andphagocytes.NewlyproducedCD4Tcellsarenotinfected,whereupontheylivelongerandaccumulateinthecirculation.
What are laboratory tests?
Reversal of CD4:CD8 ratio
Quantitative-PCR of HIV-RNA-measures viral load
Delayed hypersensitivity skin response (due to decreased CD4)
