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The acquired immunodeficiency syndrome (AIDS) is the last stage of a disease caused by the human immunodeficiency virus (HIV). AIDS is characterised by a defective immune response of the organism, that is, a severe knock out of the body's defence mechanisms. For this reason AIDS does not have very specific symptoms apart from the deficient immune response, which allows a severe general infection level of the body.
Viruses are tiny parasites that use cells as host-organisms. The HIV can only penetrate and infect cells that have a protein called CD-41 on their surface. The main HIV host cell is a T-lymphocyte called T4-helper. The T4-helper cell (sometimes also called CD4 or T-helper)2 is responsible for the detection of generic malfunctioning cells (eg, due to an infection). With the T-helper cells knocked out, a generalised infection of the body becomes possible. Organisms, ranging from worms to viruses, that would otherwise only be able to infect certain exposed areas of the body, like the tongue, teeth or parts of the skin are free to spread into all of the body (eg, the brain, lungs, liver, kidneys, etc). These infections are therefore called opportunistic infections (OI). Most 'symptoms' of AIDS come from these OIs. Furthermore, the body may also lose the capability of regulating certain cell division processes, which is the reason why certain otherwise rare forms of cancer like the Kaposi sarcoma (KS, a skin cancer) and the non-Hodgkin lymphoma (NHL, a type of leukaemia) often develop in AIDS patients.
The Definition of AIDS
The strictest definition of AIDS is given by a T4-helper cell-count per microlitre of blood below 200 cells. A total T4-helper cell count below 500 cells per microlitre signalises the development of clinical AIDS. The presence of opportunistic infections together with the development of the aforementioned rare forms of cancer (KS, NHL) is also used to define AIDS. If there is no alternative explanation for these symptoms (like hereditary gene defects or a preceding chemotherapy) a patient has AIDS. These definitions may seem a bit awkward, since there is no mention of the HIV. Indeed, the detection of the virus is not strictly necessary for the diagnosis of AIDS. This has mainly historic reasons, since the discovery of HIV and the final proof that HIV causes AIDS came later and some criterion was needed to establish epidemiologic data for the then (ie, in the early 1980s) new disease. The OIs, of which a pneumocystis carnii infection of the lung (PCP - p.carnii pneumonia) is one of the most widespread, and some otherwise rare forms of cancer (KSs and/or NHLs) were what most AIDS patients had in common. To keep the epidemiologic data comparable, this definition is still widely being used today. Furthermore, the detection of HIV is not an easy procedure, it is a complicated process. Hence if the presence of HIV would be a necessary criterion, the diagnosis in underdeveloped countries would become difficult, and this would cause trouble when comparing epidemiologic data.
The Onset of the Disease
The stage of AIDS is preceded by less intense stages of the disease, which can last more than 10 years even without treatment. Some pre-AIDS stages were termed ARC (AIDS related complex) and PGL (persistent generalised lymphadenopathy - sometimes one will find the equivalent term LAS - lymphadenopathy syndrome). This nomenclature is not being used nowadays3.
The immediate HIV infection generally goes unnoticed. However, in many cases a mild disease (which can be mistaken for a common flu: fever, growth of lymph nodes, pharyngitis, diarrhoea, headache) which persists for one to two months is observed. After three weeks to three months the body starts producing HIV antibodies, which can be detected. This process is called seroconversion, and it is not known to be reversible. For this reason most HIV tests are negative before seroconversion.
In the pre-AIDS stages which can last ten years, the symptoms are not very characteristic, and include: Lack of energy, loss of weight, permanent fever and excessive sweating, untypical generalised bacterial and fungal infections, persistent skin rashes or lesions, short term memory loss, difficulty of mental concentration.
At the AIDS stage the symptoms grow stronger. Some typical symptoms are: constant fever, strong nausea, weight loss (30% and above), extreme fatigue, typical immunologic dysfunctions (allowing opportunistic infections). Clinical AIDS is marked by the appearance of the opportunistic infections (PCP, generalised Herpes Simplex, etc.) and some otherwise rare forms of cancer (KS, NHL).
The Mechanism of the HIV Infection
For clarity, some general aspects of viral infections will be briefly discussed in this paragraph. If viruses are considered living beings, then they are absolutely the most compact form. Viruses are made of a hull and of genetic material, which is contained in the hull. Their size ranges from 10 to 100 nanometers4. All viruses are parasites, that is, they need a host cell in order to 'live'. After a virus penetrates its host cell, it will build its genetic material into the host's genetic material and use the reproduction mechanisms of the cell to reproduce itself. Generally, a cell dies after millions of copies of the virus have been made.
The human immunodeficiency virus is a small spherical virus with a diameter of 100 to 120 nanometers. The viral genetic information (in the form of RNA) is wrapped around proteins forming a very compact rod-like structure. This structure is situated in the inner part of an almost spherical - strictly speaking: icosahedral5 - protein hull. This hull is also termed the capsid-hull. This hull in its turn is covered with a lipid membrane. On the surface of this membrane there are proteins, which are used to dock the virus onto the target cell surface, namely by interacting with the CD-4 protein. This allows the virus to penetrate the inner part of cells that have CD-4 proteins on their surface.
After entering the cell, the HIV lipid cover and its capsid hull will open and release the RNA and the proteins. One of the viral proteins, the reverse transcriptase (RT) will convert the RNA into DNA. Then, the DNA sequence is built into the host cell's DNA. The host cell will treat the new built-in genetic information as if it were its own. It will try to synthesise proteins according to the new code. For that reason a huge amount of new RNA copies of that DNA are synthesised by the cell's own (note: not-reverse) transcriptase.
These RNA copies are recognised by the cell's own protein synthesis machinery and millions of viral proteins are built. The proteins leave the machinery as big chunks which have to be cleaved before they can work properly. This cleavage is performed by another viral protein called the HIV-protease. After all proteins are built and cleaved, some will assemble with the RNA copies and form the compact rod-like structure. The remaining proteins form the capsid hull and assemble around this structure. This ensemble moves close to the cell membrane from the inside and forms a vesicle (which will be the lipid cover used to dock other cells). This vesicle exits the cell. After some time, the capsid hull forms the original rigid icosahedral body, and the new virus is ready to infect another cell.
To recap, there are five basic steps in the life-cycle of the virus:
- The infection (docking and penetration)
- The reverse-transcription (transformation of RNA into DNA)
- The integration of the DNA into the host's own genome
- The production of RNA and viral proteins (using the cell's own synthesis machinery, and the viral protease)
- The assembly of new virus particles and the exiting of the cell
From the elucidation of the working mechanisms of the HIV infection, certain strategies can be followed to block the proliferation of the virus by interacting with its metabolism. There are two key steps in the viral life-cycle that can be attacked: First, by blocking the reverse transcriptase (RT), which is the enzyme used to transform the RNA-genome of the virus into DNA-genome (which is built-in into the cell's own DNA). And second by inhibiting the cleavage of the virus proteins, which will then not work properly. The cleavage is performed by the HIV-protease, which can be blocked. In both cases the blocked enzymes are used by the virus exclusively.
While new and expensive treatments can extend the life expectancy of an HIV infected individual to an indeterminate number of years (10 or more), there is (at the date of writing) no final cure or a vaccine that will completely heal an infected person or prevent the contraction of the virus. At the AIDS stage the chances to increase life expectancy drop significantly. However, there have been a few reports of cases where AIDS patients recovered to a less intense stage using certain drug combinations. Below, a list of the most famous anti-HIV drugs is given (the collateral effects and the specific working mechanisms can be found at the respective fact-sheet, which can be found by searching the web for the names in parenthesis)6.
- AZT (Zidovudine (R),Retrovir(R))7
- ddC (HIVID(R))
- ddI (Videx(R))
- Lamivudine (Epivir(R))
- d4T (Zerit(R))
- abacavir (Ziagen(R))
Nucleoside analog RT-inhibitors:
Non-nucleoside RT inhibitors:
- Delavirdine mesylate (Rescriptor(R))
- Nevirapine (Viramune(R))
- Efavirenz (Sustiva(R))
- Indinavir (Crixivan(R))
- Amprenavir (Agenerase(R))
- Saquinavir (Fortovase(R))
- Nelfinavir (Viracept(R))
- Ritonavir (Norvir(R))
HIV is passed via cellular fluids: semen, blood and breast milk. HIV can also be detected in other fluids, but it is not effectively transmitted from there: Urine, feces, sweat, saliva and tears. For this reason, HIV is generally not transmitted through everyday contact (eg, by sharing kitchen or food utensils or by using the same towels and bedding) with HIV positive individuals.
Exposure of unprotected tissue to contaminated fluids has an efficiency of 90%. In other words, the contact of fluids containing HIV with lesions and glands is the main infection pathway of the HIV. Subcutaneous transmission is relatively ineffective. Infections due to small lesions on the penis, vagina, rectum and mouth don't seem to be clinically significant. The probability of acquiring HIV during sexual intercourse is relatively small (0.3%) compared to other sexually transmissible diseases. However, the risk rises if other sexually transmissible diseases are present, or during menstruation. There are reported cases of persons that acquired HIV in the first sexual contact with another HIV infected person. There are also reported cases of uninfected people who had sexual intercourse with HIV positive people hundreds of times. The maternal to fetal blood HIV transmission8 (10-40% risk during pregnancy and birth) is significantly reduced if anti-retroviral drugs (like AZT - Retrovir) are used. The HIV transmission via breast milk is relatively ineffective (0.1% - 0.02% risk per feeding), however, people often underestimate the long term exposition effects: six months breast feeding (five times a day) are enough to raise the risk to 58%.
HIV Mutants and Sub-types
Another detail worth looking at, is the presence of two different forms of HIV, namely HIV-1 and HIV-2, which show a significant difference in the onset of the disease. Furthermore, HIV, like most retroviruses, mutates easily, because the error rate of the reverse transcriptase enzyme is quite high9. This rate leads to the emergence of numerous HIV variants, which can be more aggressive, or in the worst case drug resistant. Over time, different tissues of the body generally are infected with different HIV variants.
HIV-1 is the predominant type worldwide, and it is more aggressive than HIV-2 (HIV-2 is endemic in Western Africa). HIV-1 is further subdivided into three groups of subtypes, mutants, namely M (major), O (outlier) and N (because it is between M and O). HIV-1-M subtypes (A through H) vary slightly. The geographical distribution of these subtypes is inhomogeneous.
- Subtype A: Central Africa
- Subtype B: South America, USA, EU, Thailand
- Subtype C: Brazil, India, Southern Africa
- Subtype D: Central Africa
- Subtype E: Thailand, Central African Republic
- Subtype F: Brazil, Rumania, Zaire
- Subtype G: Zaire, Gabon, Thailand
- Subtype H: Zaire, Gabon
- West Africa
Very few cases of HIV-2 infection occur outside Western Africa, because the transmission of the virus is less efficient. The genome of HIV-1 and HIV-2 are only partially homologous10. For that reason, HIV-2 is not necessarily detected by conventional laboratory tests, which detect the HIV-1 antibody. The HIV-2 infection takes longer to develop to AIDS. The course of the syndrome is less aggressive because HIV-2 has a lower impact on the immune system (compared to HIV-1) until late in the course of AIDS. The mortality rate from HIV-2 infection is only two-thirds that for HIV-1.
There are various ways to detect HIV. All of the methods are fallible and may provide false positive and false negative results. False positive results often occur with women that have had many pregnancies, with people infected with other viral diseases or with people who have had prolonged contact to animals - animal trainers and veterinarians can harbour otherwise harmless virae which may interfere with the HIV-tests. False negative tests occur, when the infected person has not seroconverted, or, less often, when the person is infected with an HIV variant (mutants or HIV-2), which is not being tested for (most tests in the US and in Europe are designed to detect HIV-1 Group M Subtype B). The false-negative rate for people infected with HIV-1 mutants is low compared to the false-negative rate for people infected with HIV-211. Combinations of tests are quite reliable. Hence the general advice to take multiple tests if one suspects HIV infection.
The most common test is called ELISA. ELISA is an acronym for enzyme linked immuno-sorbent assay; it detects the antibodies produced by the human body. In this test a blood sample is dropped on a plate which has HIV-antigens bound to it. Only antibodies stick (or adsorb) to antigens, the rest is rinsed away from the plate. The antibodies can be selectively stained after the rinsing, so if the plate contains antibodies it will become stained. As mentioned above, other antibodies (which may originate from other viral infections which are not necessarily harmful) can interact with the test. Additionally, ELISA tests give false-negative results if the person is not seroconverted. Apart from these false negatives, false-positive tests occur more often than false-negatives. In other words, if an ELISA tests gives a negative result, the person is most probably either really negative or has not seroconverted. Latter can be detected if another test is carried out after some months time.
In most cases a test called 'western blot' is performed in addition to the ELISA as a confirmatory test. This test also produces more false positives, because the western blot also detects HIV-antibodies by binding them to antigens. As a general guideline, both tests, ELISA and the western blot, must yield the same result or else the test is considered indeterminate and should be repeated. The combination of both tests yields quite reliable results for the absence of viral antibodies, that is, for true negative and non-seroconverted individuals.
The most accurate test is the viral PCR test, which is (when possible) performed when the other tests (ELISA, western Blot) yield indeterminate or positive results. PCR stands for polymerase chain reaction. PCR tests detect viral genome, or the virus directly. The big problem with the PCR is that it is expensive and somewhat complicated to perform.
The number of false-positives and false-negatives is very small if all these tests are performed. However improbable, even so false results do occur. Hence the advice to take more than one test, preferably with some months time in between, if an HIV infection is suspected.