Download Resistenz der Wirtszelle gegen eine Infektion mit HIV

1
Evolution in fast motion – Resistance to HIV (Information)
Information material:
Resistance to HIV
HIV (Human immunodeficiency virus) came into being as a human pathogen at the beginning
of the 20th century. It is characterized by a high evolutionary rate. This is due to the high
frequency of mutations, which is a consequence of the lack of error correction during DNAreplication, short generation times and high reproduction rates. Thus the virus can change
radically in a short period of time and, as a consequence, eventually escape the host’s immune
system.
In contrast to the high evolutionary rate of the virus, its hosts, i.e. human beings, show a
comparatively low evolutionary rate. Mutations are relatively rare in humans because DNA
replication underlies an effective control mechanism responsible for repairing most of the
replication errors. Furthermore, mutations are permanently established in the genome at a
slow rate because of the longer generation time of humans and their lower reproduction rate.
Nevertheless, mutations still appear and like in viruses, positive mutations become fixed in
the genome through selection, while at the same time disadvantageous mutations become
purged out of the human genome through selection. Many mutations, however, are initially
neutral and often have no relevance for the survival of the organism.
Because HIV is a relatively ‘young’ virus and because there is a relatively long period of time
between one generation of human beings and the next, the human immune system so far could
not adapt to the HIV epidemic through natural selection and develop resistance to HIV as a
reaction to the impact of infection. However, researchers have repeatedly observed both
human beings with high risk of infection with HIV who did not become infected and HIVpositive persons who show an unusually slow onset of AIDS. These observations were made
between 1978 and 1984. Blood donations were not tested for HIV at that time (the virus was
first discovered in 1981) and many patients received contaminated blood. However, around
10-25% of the recipients did not become virus carriers (O’Brien & Dean, 1997). Research
shows that over 10% of the people in Europe are resistant to an infection with HIV. The
resistance is due to a special gene, which is located on the third chromosome. This gene
encodes the surface protein CCR5, which is located on the surface of both T-cells (CD4 cells)
and macrophages and is used, in addition to the CD4 receptor, as co-receptor for virus
adhesion.
www.evolution-of-life.com
Janina Jördens (corresponding author)
2
Evolution in fast motion – Resistance to HIV (Information)
CCR5
The CCR5 receptor is a transmembrane protein on CD4 cells and macrophages. In an immune
reaction, it is essential for signal transmission with chemokine. The receptor induces the
migration of neutrophiles, basophiles, eosinophiles, lymphocytes and macrophages to the place
of infection and initiates the defense of the infection.
The mutation of the CCR5 gene results in a change in the amino acid sequence and causes a
shortening of the resulting protein. This change obviously does not have any negative effect on
the efficiency of the immune system. Other chemokine receptors seem to compensate for the
modification of the CCR5 receptor.
The two copies (alleles) of the gene encoding the co-receptor CCR5 are located on the third
human pair of chromosomes. In July 1996 Marry Carrington discovered that a major variant
of the ‘unmutated’ CCR5 allele occurred in about one out of five persons: “Comparison of the
nucleotide sequences of the two CCR5 alleles revealed that the less common one was missing
32 nucleotides. Because of the way the genetic code works, we knew that the loss would
result in the premature creation of a ’stop’ code in the gene and would, in turn, cause the cell
to manufacture a severely foreshortened version of the CCR5 protein.“ ( O’Brien & Dean,
1997)
Since then different research groups started to investigate the DNA-sequences of this gene
and analyzed the consequences of the mutation. One of these research groups (Samson et al.,
1998) analyzed more than 700 samples from HIV-infected patients and compared them with
the CCR5-sequences from more than 700 healthy persons. The results of the DNA-sequencing
revealed mutations in the CCR5-gene in HIV-infected persons whose course of disease was
delayed as well as in some samples of healthy persons (but not in HIV-patients with normal
courses of disease).
If a person is homozygous for the “standard“-allele CCR5 (CCR5/CCR5), he or she is not
resistant to HIV. If, however, persons are homozygous for the “mutant”-allele (CCR5Δ32/
CCR5Δ32), they are resistant to an infection with HIV. The deletion of 32 nucleotides causes
a deficient CCR5 protein, to which the virus cannot adhere anymore and therefore an
infection of the cell is not possible. If a person is heterozygous for the alleles, which means he
or she has both a “standard”-allele CCR5 and a “mutant”-allele CCR5Δ32 (CCR5/CCR5Δ32),
the onset of the disease will be delayed and protection against the infection is only partial. The
standard receptor CCR5 is expressed in a strongly reduced amount and so the course of
disease is slowed down for many years (Galvani & Slatkin, 2003) (Figure 1).
www.evolution-of-life.com
Janina Jördens (corresponding author)
3
% of HIV-infected patients, who have not
progressed to AIDS
Evolution in fast motion – Resistance to HIV (Information)
100
Patients carrying
only standard
alleles of CCR5
90
80
70
Patients carrying one
mutant allele and one
standard allele of CCR5
60
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
Years since infection
Figure 1: Course of disease of patients being heterozygous or homozygous for the standard allele of CCR5
(O’Brien & Dean, 1997; with kind permission from Laurie Grace)
Literature & links:
O'Brien, S. and M. Dean (1997). "In Search of AIDS-Resistance Genes." Scientific American
9: 28-35.
Galvani, A. P. and M. Slatkin (2003). "Evaluating plague and smallpox as historical selective
pressures for the CCR5-Δ32 HIV-resistance allele." Proceedings of the National
Academy of sciences of the USA 100(25): 15276-15279.
Samson, M., F. Libert, et al. (1996). "Resistance to HIV-1 infections in caucasian individuals
bearing mutant alleles of the CCR-5 chemokine receptor gene." Nature 382: 722-725.
HIV: the ultimate evolver (www.evolution.berkeley.edu/evolibrary/article/_0_0/medicine_04)
(Last access: July 2009)
Ghost of epidemic past (www.evolution.berkeley.edu/evolibrary/news/081001_hivmalaria)
(Last access: July 2009)
HIV immunity (www.pbs.org/wgbh/evolution/library/10/4/l_104_06.html)
(Last access: July 2009)
www.evolution-of-life.com
Janina Jördens (corresponding author)
18