|Keywords:||Aids; Disease diagnostics (human); Drugs (human).|
|Correct citation:||Jurriaans, S. (1997), "Biomedical Developments in AIDS Research." Biotechnology and Development Monitor, No. 30, p. 25.|
Huge scientific efforts aim at understanding AIDS and its subsequent prevention and treatment. However, the high cost of diagnostics and therapies prevent their worldwide use. Moreover, differences in HIV variants make some technologies less applicable to people in developing countries.
In 1981 the first reports on Acquired Immunodeficiency Syndrome
(AIDS) appeared. Three years later, Human Immunodeficiency Virus
(HIV) was identified as the cause of AIDS. Until then no human life threatening
diseases were linked to a virus. The route of HIV infections differs between
industrialized and developing countries. HIV infection in the developed
countries spreads mainly by anal intercourse among homosexual men and by
contaminated blood among intravenous drug users. In the days prior to heat
treatment of blood products and donor screening, many haemophiliacs were
infected. For example, between 1979 and 1985, over 10,000 haemophiliacs
were infected in Europe and North America. In addition, infections occur
among children born to HIVinfected mothers. In Africa and Asia, the
main route of HIV transmission is heterosexual intercourse. Central and
East African countries are suffering from an AIDS epidemic; it is estimated
that 20 per cent of sexually active adults are infected.
While the rate of developing AIDS upon infection is very high, its clinical manifestation is slow to develop. Over 95 per cent of HIVinfected individuals develop AIDS. Of this group, only one per cent may develop AIDS after one to two years. Another one to two per cent do not develop AIDS even after 15 years, while the majority of HIVinfected persons develop clinical manifestations of AIDS within 10 to 12 years. This implies that people who carry HIV may look and feel healthy for a number of years, but meanwhile they can transmit the virus to others.
With AIDS, virology has become an important field in the management of prevalent infectious diseases. Most of the research is performed in the industrialized countries such as USA, Canada, United Kingdom, France, Italy, the Netherlands and Belgium. The research is largely funded by pharmaceutical industries. Governments, universities and nongovernmental organizations (NGOs) are also funding a number of research projects. The budget for AIDS research in Western countries far exceeds the total budget for medical care in developing countries.
Diagnosis of HIV infection
There are different methods to detect the HIV infection:
|The HIV particle and the viral life cycle
The HIV is a very small sphere, which contains the viral genetic material
surrounded by viral proteins (the socalled core). The outside of the
virus consists of a lipid bilayer (which is derived from the infected cell)
spiked with viral proteins (together called the envelope). HIV attacks
cells of the immune system called lymphocytes, specifically its
subset known as a helper Tcell. Present on the outside of these
Tcells is a protein called CD4. These CD4+ lymphocytes have
an important role in almost all immune responses. The loss of these cells
causes a severe defect in the host defense mechanism against pathogens.
This renders a person susceptible to all kinds of infections.
During the acute phase of infection, HIV replicates at high levels in the blood. Following the emergence of an immune response to the virus, there is a decline in the level of viral nucleic acids in the blood. In most individuals, a further reduction in the number of HIV particles is observed during the asymptomatic phase of infection. Two distinct groups of HIVinfected people have been identified. The first group seems to be able to reduce the number of circulating virus particles to a very low level for a prolonged period. These individuals were found to be longterm asymptomatic. The second group are those HIVinfected persons who lack the capacity to further reduce the number of circulating virus particles. These individuals could be stratified as being rapid progressors. This is based on the HIV RNA count in the blood. This occurs before the presence of any symptoms or other markers (CD4+ cell count, presence of p24 antigen) direct towards disease progression. The stratification of patients on the basis of viral RNA levels in the blood is predictive of their progression to AIDS or death.
Besides developments in diagnostics, there is also progress in antiretroviral therapies and their evaluation. HIV RNA is a good surrogate marker to evaluate the effectiveness of antiretroviral therapy. The first clinically available compound with antiHIV activity was zidovudine (AZT). It was developed and is sold exclusively by UK GlaxoWellcome. The therapy aims to disrupt the HIV reproduction. AZT chemically resembles one component of the DNA. Hence, AZT can 'trick' the virus into incorporating AZT into the DNA molecule during the conversion of RNA into DNA. However, the other components necessary to build the DNA cannot be attached to the AZT molecule. This impairs the reverse transcriptase of RNA to DNA. A number of trials demonstrated that zidovudine monotherapy had a beneficial effect to people who had already developed AIDS. It has been shown to postpone death by one to two years. However, the drug failed significantly to benefit asymptomatic HIVinfected people.
Recently far more potent drug regimens have been introduced consisting of three or more antiviral components. These protease inhibitors work in a similar way to AZT. However, the combination therapy does not only arrest the reverse transcription of the virus. These drugs further block the HIV protease, an enzyme needed to produce the viral proteins. In some cases, it has been shown that under combination therapy, HIV RNA levels are dramatically reduced by as much as 100 to 1000 times within one to two weeks after the start of treatment. However, if there is no significant decline in this period, this indicates that the drug regimen is not effective for the individuals involved.
The recent regimens have significantly decreased the levels of HIV RNA in the blood of most infected people. In addition, it is most probable that these individuals now have a good clinical prognosis. However, time will prove whether this assumption is true, and whether these individuals will still progress to AIDS despite the low HIV RNA level.
These combination regimens are commercially available. Examples of protease inhibitors are: Ritonavir produced by US Abbott; Indinavir produced by US Merck, Sharpe and Dohme; and Saquinavir, produced by Roche Molecular Systems. Examples of reverse transcriptase inhibitor are: 3TC produced by GlaxoWellcome; D4T produced by US Bristol Meyers Squibb; and Nevirapine produced by Boehringer Ingelheim of Germany. However, the high cost of these drugs and tests greatly limits their usage. For example, even for a developed country like the Netherlands, funding for the evaluation of the therapy, such as HIV RNA load testing is already difficult. Moreover, the efficacy of antiviral treatment on different HIV variants remains to be established. Due to the recent introduction of combination therapies and the limited availability of antiviral drugs in developing countries little is known about this subject.
In a relatively short period of time (about 15 years), the world has learned a lot about AIDS: the cause, the pathogenesis, and even (in part) the treatment. At present there is reason believe that AIDS may eventually become a treatable disease. However, due to the cost and intensity of medical care (i.e. treatment regimens must be tuned to each individual) this hope remains mainly restricted in the industrialised world. Therefore, research must continue to develop a vaccine against HIV, which can be supplied to the developing countries on a large scale and at much lower cost. V
Department of Human Retrovirology Academic Medical Centre, University
Meibergdreef 15, 1105 AZ Amsterdam, the NetherlandsFax (+31) 20 691 6531.
F. BarréSinoussi, J.C. Chermann, et. al. (1983), "Isolation of a Tlymphotropic Retrovirus from a Patient at Risk for Acquired Immune Deficiency Syndrome (AIDS)". Science, Vol, 220 pp.868871.
E. Hogervorst, S. Jurriaans, et. al. (1995), "Predictors for None and Slow Progression in Human Immunodeficiency Virus (HIV) Type 1 Infection: Low viral RNA copy numbers in serum and maintenance of high HIV1 p24specific but not V3specific antibody levels". Journal of Infectious Disease, Vol. 171, pp.811821.
S. Jurriaans, B. van Gemen, et. al. (1994), "The Natural History of HIV1 Infection: Virus load and virus phenotype independent determinants of clinical course?". Virology, Vol. 204, pp.223233.
S. Jurriaans, G. J. Weverling, et. al. (1995), "Distinct Changes in HIV type 1 RNA Versus p24 Antigen Levels in Serum During Short Term Zidovudine Therapy in Asymptomatic Individuals With and Without Progression to AIDS". AIDS Res Hum Retroviruses, Vol. 11, pp. 473479.
D.D. Ho, A.U. Neumann, et. al. (1995), "Rapid Turnover of Plasma Virions and CD4 Lymphocytes in HIV1 Infection". Nature, Vol. 373, pp.123126.
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