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AIDS, acquired immune deficiency syndrome, Immunodeficiency syndrome, Immunodeficiency syndrome, describes the clinical picture in the final phase of infection with HIV (human immunodeficiency virus). In this phase, the infection is characterized by systemic immunodeficiency, i.e. immunodeficiency that extends to the whole body, combined with opportunistic infections. This is preceded by several phases during which the body's immunoreactivity decreases, combined with a decrease in the concentration of CD4-positive T lymphocytes in the blood. Shortly after infection with the virus, flu-like symptoms can initially appear, combined with fever and skin rashes, in some cases with a clinical picture that is comparable to mononucleosis. The concentration of virus in the blood is high, which leads to an immune response against the virus. The virus concentration drops as a result, the virus is only latently detectable in CD4-positive T lymphocytes, macrophages and in some nerve and intestinal cells during the next phase, which begins after about 6-12 months. In the T lymphocytes, of which only a small part is infected, the antigen is stimulated to multiply and to release the virus. An immune response, including against the virus, tends to lead to an increase in the virus. Subclinical symptoms during this time are initially a chronic enlargement of the lymph nodes (lymphadenopathy), later malfunctions can be detected in tests for hypersensitivity reactions of the late type. The first clinical symptoms are then viral and fungal infections of the skin and mucous membranes, until the full clinical picture of A. The general immune deficiency can lead to new infections (as in pneumonia due to Pneumocystis carinii; pneumocystosis) or to an activation of previously controlled children's infections (e.g. due to the cytomegalovirus or in tuberculosis). Tumors can also occur, such as Kaposi's sarcoma, a tumor of the blood vessels in the skin and internal organs, or lymphomas. These tumors, as well as disorders of the nervous system, can also occur before the A. stage of an infection with HIV.
However, A. is by no means a disease that has only developed in recent years. However, due to the changed habits of the last few decades, it has spread rapidly. The very different course of the disease suggests the involvement of several factors that are decisive for the course of the disease. Some researchers even go so far as to see the causes of the harmful effects not in the direct action of the virus, but in the involvement of various functions of the immune system that react to the virus and thereby damage the organism of the infected person. Although some studies have indicated the stability of HIV in wastewater, transmission remains linked to close contact with a carrier of the virus. A. cannot be transmitted through the air, insects (mosquito bites) or other animals. In the event of an infection, the virus can be detected in various body fluids (tears, saliva, sperm, blood); However, it is only transmitted - according to all that is known - when it gets directly into the bloodstream (e.g. via small skin injuries). The main routes of transmission are promiscuous homosexual and heterosexual intercourse and the shared use of hypodermic syringes by addicts. However, newborns from HIV-positive mothers can also be infected. A routine test of blood reserves for HIV means that there is no longer any risk of infection as a result of a blood transfusion, at least in the Federal Republic of Germany.
Because of the long symptom-free phase in many infected people, the number is much higher than that of the visibly sick. HIV is therefore also counted among the lentiviruses (Latin lentus = slow). The virus can be inactive for a long time. After one year 0.3%, after 7 years 30% and after 10 years 45% of those infected have developed A. A dramatic increase was noted where infections were present but few people were acutely ill, i.e. in Africa, in the slums of large American cities, and in Thailand and India. The trend that A. is also spreading among the heterosexual population continues. In France, for example, a third of the infections among heterosexuals were reported without further risk factors, while the number of new infections among homosexuals has partially decreased. It is estimated that around 50 million people were infected with HIV by 1999, including over 10 million Africans. In southern Africa, up to 50% of the population in some population groups are believed to be carriers of HIV. From the beginning of the epidemic to March 1998, 208,000 HIV infections were registered in Europe, 50,000 of them in Germany (16,000 of these infected people died).
Contrary to initial reports, HIV2 is not limited to Africa. This second strain of HIV accounts for a similarly high proportion of infections in Bombay as in Africa. Contrary to the initial opinion, it is now assumed that HIV2 is just as pathogenic as HIV1. The two virus families are less related to each other than to the monkey viruses that are closest to them. HIV1 is more closely related to a recently discovered chimpanzee virus, while HIV2 is more closely related to a rhesus monkey virus. The family tree of the two virus families probably split up around 900 years ago. Some of the monkey viruses do not cause disease in their host. Apparently the viruses in these animals are under control. The strong differences in the course of the disease in humans can partly be attributed to the great variability of the virus, which leads to a kind of mini-evolution in the carrier. Recombination between different virus genomes can also occur. In addition to the T cells initially identified as the carrier of the virus, the virus has now also been detected in macrophages and monocytes and thus in other classes of cells that play an important role in an immune response. The fact that the virus can also be found in the dendritic cells of the lymph nodes suggests that the virus was transmitted via these cells: during an immune response, the dendritic cells present antigen fragments on their surface and thus attract the T cells that carry them Recognize fragments. These T cells can be infected by the virus. In addition to immune cells, the virus is also found in fibroblasts, intestinal cells, endothelial cells and cells of neuronal origin. A special importance is ascribed to the superantigens, the activation of which could explain the selective destruction of a large number of blood cells. The activation of cellular "suicide programs" (apoptosis), which play a role in the development of the immune system, is also used to explain the decrease in blood cells.
Animal models for AIDS. In the search for ape species that are easier to keep than the chimpanzees that are most closely related to humans and still provide a model for A., ​​it turned out that porcupine monkeys, in contrast to the closely related rhesus monkeys and long-tailed macaques, can be infected with HIV1. This leads to swelling of the lymph nodes and fever, but not to symptoms similar to A. The virus and antiviral antibodies could also be detected. The monkey virus SIV (abbreviation for simian immunodeficiency virus) was also used to study the course of the disease induced by this virus in monkeys. The SI virus also causes a deadly immune deficiency in monkeys. It was possible to achieve immune protection by vaccination with killed SIV. Subsequent control experiments do not rule out the possibility that immune protection comes about because the monkey's immune system reacts to contaminants in the vaccine from the human T cells in which the virus was grown. Another animal model is the equine virus EIAV (abbreviation for equine infectious anemia virus), which was also used in the development and testing of vaccines. One cat model is FIV (abbreviation for feline immunodeficiency virus), such as HIV a lentivirus (named after the slow progression of the disease), and FeLV (abbreviation for feline leukemia virus). Viruses of the FLVC (abbreviation for friend leukemia virus complex) investigated.
Cell model for AIDS. A cell line (U1) with monocyte / macrophage similarity was successfully used as a model for infection with HIV. Few of the cells produce viruses in culture (presumably similar to many cells during the latency phase in a patient). But you can with TNFα or phorbol esters are stimulated to virus production.
Cytokines and AIDS. In A. there are changes in the concentration of interleukins. The worst affected is Il-2, which is mainly produced by T cells and, in addition to T cells itself, also stimulates the activity of natural killer cells (NK cells) and interferon-γ synthesis. The defect in IL-2 production and the expression of the receptor for IL-2 is to be seen in connection with the defects in the T cells of the A. patients. Il-1 and Il-6 are also affected in patients, both mainly produced by macrophages, which can also be infected by HIV. Both interleukins activate lymphocytes, Il-6 also acts as an acute phase protein, especially in the liver. Both interleukins are stimulatory by mononuclear cells of the blood of patients taking in vitro-Conditions produced, which are not the case with normal cells. Of the interferons (INFα, INFβ and INFγ, where only INFα and INFγ produced by leukocytes and considered immune interferons) is the INF produced by T cellsγ decreased in A. patients - probably an important factor in susceptibility to viral infections and tumors. The TNF mainly produced by macrophagesα is also considered important for the development of the disease. The level is increased in A. patients and leads to the activation of HIV replication and the formation of syncytia in HIV-infected cell cultures. In addition, TNF couldα be involved in the lysis of non-infected cells. The observed changes in the cytokine concentrations could partly be confirmed in animal models for A. (see above), where there are more possibilities for experimental interventions. On the basis of the results of observations in humans and in animal models, A. can be regarded as a disregulation of the immune system in which the change in the cytokine concentration plays an important role. The change in the immune imbalance is also important for the autoimmune reactions that can be observed in A. Phenomena appear that show similarities with phenomena of the aging process, which is why A. was also described by some of those affected as "aging in fast motion".
AIDS vaccine. When developing vaccines (vaccines) against the causative agent of immunodeficiency A. attempts are made both to use a prophylactic vaccine - i.e. a vaccine that protects against infection with the virus against the disease - and a therapeutic vaccine that is used to treat after infection with the virus can be used to develop. Because of the great variability of the virus, the conserved regions that are most suitable for a vaccine were determined by comparing different virus isolates. These are areas that are necessary for the virus to function and therefore cannot be changed, e.g. the areas of the virus envelope that mediate the binding to the CD4 molecules of the T cells. In order to achieve a prophylactic vaccination, the immune system can be stimulated to produce antibodies by chemically or genetically inactivated viruses or by fragments of HIV (the conserved areas are particularly suitable). A clear correlation between the in-vitro-Ability of antibodies to neutralize the virus, and one in vivo-Protection cannot be determined, however. In monkeys, immune protection against SIV can only be achieved through a long and intensive vaccination schedule. The initial clearer successes in vaccinating monkeys against A. turned out to be artifacts, caused by the cultivation of the virus in human cell lines, which turned out to be the actual immunogen. The duration of the immune protection was also limited to several months. Problems arise when these immunization regimens are to be used to treat those who are already infected. Whenever the immune system of an already infected person is activated by active immunization, there is a risk of activating the HIV dormant in the CD4 T cells. One way out here would be passive immunization, which has been successfully carried out in animal experiments. Antibodies from mice against the conserved area of ​​the virus envelope protected chimpanzees from infection with HIV. Another alternative is immunization with antibodies that look similar to the virus envelope and, like the viruses, bind to the receptors of the T cells and thereby block them for the viruses. A completely different strategy is preferred by other researchers, who see strengthening the cellular defense as the best method to prevent the outbreak of A. in HIV-infected people. In fact, some people infected with HIV have neither antibodies against the virus nor the typical A. symptoms. In contrast, their titer of virus-specific T cells is increased. In animal experiments, immunization with low levels of virus antigen stimulates cellular defense, while higher levels induce specific antibodies. Only in the first case are the animals protected. Immunization with DNA, not with proteins from the virus, is also being tested. Defective viruses, which are supposed to prevent the replication of the complete virus in patients, and retroviral constructs, in which toxins are activated in infected cells and kill them, are also tested in cell culture. It is currently uncertain whether it will be possible to develop a protective vaccine (i.e. one that protects against infection). The development of therapeutic vaccines (for the treatment of the disease) could lead to success even earlier. Inoculation with the viral glycoprotein 160 caused an increase in the titer of neutralizing antibodies and an increase in the proliferative response of T cells. The decrease in CD4-positive T cells could also be stopped. Problems continue to be caused by the variability of the virus and the fact that it is often transmitted in cells and thus difficult to access for the immune system. As with the flu vaccination, regional vaccines with specificity for individual virus subtypes may need to be developed. The use of virus-like particles (VLP; particles that are e.g. produced in yeast by jumping genes and are considered to be particularly immunogenic) as vehicles for HIV proteins is in the clinical trial phase. Another advantage is the easier purification of proteins that are associated with the VLPs and are intended to be used for vaccines. Hypotheses according to which A. is to be regarded as an autoimmune disease, however, question the success of vaccinations, at least in the A. stage of the disease.
therapy. Combination therapy is increasingly gaining acceptance in the treatment of A., with a combination of nucleotide analogs (AZT, DDI and DDC) mainly used so far. In addition to other proteins of the virus (e.g. the products of the did- and rev-Gene) an attempt is made to inhibit the protease necessary for the maturation of the virus. A small protein molecule is used, which blocks the active center of the protease. The most favorable time to start chemotherapy is currently the subject of intense discussion. Some American studies saw an early administration of AZT, before the onset of the typical A. symptoms, as the most promising route. The European Concorde study, on the other hand, found that treatment only makes sense when symptoms are already appearing. According to this study, in which 1,700 infected people participated, AZT does not delay the occurrence of symptoms if taken early, nor does it increase the chance of survival. In any case, some time after the start of therapy with AZT, resistant variants of the virus appear, against which the drug is no longer effective. With early treatment with AZT, the effectiveness of the drug would be exhausted when the most difficult phase of the disease begins. The previously used parameter for assessing the condition of an HIV-infected person, the titer of CD4 T cells, was also questioned as a criterion in this study. Ribozymes that are directed against the viral RNA have also proven themselves in cell culture. The proposal to treat A. with immunosuppressants (immunosuppression) is based on the fact that HI viruses can potentially be activated by every immune response in the T cells, the majority of which are dormant. Patients who received organ transplants and HIV-contaminated blood transfusions before the antibody test was started received immunosuppressive drugs after surgery. Some of these patients soon died, others appeared to have A.to be as well or better protected as other people infected with HIV. Immunosuppressants in particular, which inhibit T cells, i.e. the target cells of HIV (cyclosporine and FK 506), seem to be effective. Obviously, this therapy is in contrast to a concept of treatment that relies on the effectiveness of active immunization. Which is the best way to treat A. will have to be shown on the patient with whom in-vitro- Results often appear in a different light. - Further approaches for a therapy: fusions between CD4, the receptor for HIV, and a toxin are supposed to dock on infected cells and kill them; Inhibitors of the RNase necessary for the maturation of HIV are said to inhibit the replication of the virus; the hydrophobicity of the viral gag gene product is said to be changed by the administration of analogs of myristic acid (which is normally attached to the gene product in the cell); the localization of the gag gene product would change and it would no longer be able to function. The introduction of genes that prevent the replication of HIV into the potential target cells of the virus is usually carried out with retroviruses, whereby regulatory sequences of the virus are also used in some cases. The risks of infections through these constructs as well as the risks of the occurrence of mutations and recombinations with this method still have to be estimated. Similar to cancer therapy, attempts are also made to stimulate the cellular immune response by removing the body's own cells, which are genetically modified and injected back into the organism. A genetic change is, for example, the introduction of the gene for the viral envelope into these cells in order to stimulate the immune response against this gene product. A further hope is to take the blood cells of a patient, to clean them from infected cells outside the body and then to return the cleansed cell population to the patient. Prerequisites are sensitive detection methods for infected cells and a subsequent stimulation of the immune system to replace the lost cells. It is also important to carefully study the kinetics of the various cytokines during an infection with HIV. TNF and IL-6, for example, presumably promote the replication of the virus and are therefore a possible target of a therapeutic intervention; other cytokines (interferon-α) block viral replication in vitro.