CCR5-Delta 32 Mutation
Research demonstrates that a human mutation designated CCR5-delta 32 confers immunity to AIDS if inherited from both parents. Scientists have known for some time that these individuals carry a genetic mutation (known as CCR5-delta 32) that prevents the virus from entering the cells. Vikings seeded the mutation in Normandy and England. A genetic mutation that arose in just one person
who was probably living in the lost Kingdom of Khazars in southern Russia more
than 1200 years ago.
Studies on beneficial/protective mutations
Marc M. Buhler, Anne Proos, Viive Howell, Bruce H. Bennetts, Leslie Burnett, and Graeme J. Stewart.
"Could Admixture of the CCR5-D32 Allele into Ashkenazi Jews and Vikings be Explained by an Origin in the Kingdom of the Khazars?"
Papers of the XIX International Congress of Genetics (Melbourne, Australia, July 2003); also scheduled for publication in a journal. The D in D32 represents the Greek letter Delta both in the presentation title above and in the abstract below.
Abstract: "CCR5 is the major co-receptor for viral entry used by macrophage-tropic HIV strains and protection from infection is seen in homozygotes for the 32-basepair deletion mutation CCR5-D32. Global surveys of the CCR5--D32 allele have confirmed a single mutation event in a Northeastern European population as the source of this allele. While the initial population survey of CCR5--D32 showed the highest frequency in Ashkenazi Jews and another study did support this, other reports including Ashkenazi samples have not shown such increase. Here, Australian Ashkenazi Jews (n = 807) were found to have a CCR5--D32 allele frequency of 14.6% while Australian Sephardic Jews (n = 35) had a frequency of 5.7% and non-Jewish Australian controls (n = 311) had an allele frequency of 11.25%. Homozygotes (n = 23) for CCR5--D32 were genotyped with 3p21 region microsatellites including D3S4579, D3S4580, D3S3559, D3S663, D3S1578, afmb362wb9 and chlc.gaat12d11. This defined an ancestral haplotype on which the mutation first occurred and helped to date this event to about 50 generations, or just over a thousand years ago. Data on birthplace of grandparents showed a gradient with highest CCR5--D32 frequencies from Eastern European Ashkenazim (~19.5% for those whose four grandparents come only from Russia, Poland, Hungary, Austria and Czechoslovakia; n = 197) which differs significantly from the frequency seen in Ashkenazi Jews from Western Europe (n = 101, p = 0.001). This gradient, combined with the dating of the mutation by microsatellite allele frequencies, suggests an origin for the CCR5--D32 allele in the kingdom of Khazaria with subsequent admixture into both Swedish Vikings and Ashkenazi Jews." Deborah Smith. "From an ancient kingdom, the mutant that can fight off AIDS." The Sydney Morning Herald (July 12, 2003). Excerpts:
"It's a story about ... a genetic mutation that arose in just one person who was probably living in the lost Kingdom of Khazars in southern Russia more than 1200 years ago. Today the mutation is widespread among Caucasians and helps protect carriers against infection with the AIDS virus. Marc Buhler, a Sydney geneticist, has pieced together this colourful history of the mutation's origins to explain its particularly high prevalence in populations as disparate as Jewish people in Australia and people living in Iceland. The mutation, in a gene known as CCR5, was discovered in 1996. People with one copy usually take several years to become ill if they acquire HIV. People with two copies rarely become infected. Mr Buhler ... tested DNA from about 1400 Australians and found about 15 per cent of Ashkenazi Jews (from Germany and Eastern Europe) were carriers, but only 6 per cent of Sephardic Jews (from southern Europe and Africa). ... he found about 20 per cent of Ashkenazi Jews had the mutation if their grandparents had come from Russia, Poland, Hungary or Czechoslovakia. ... But how to explain its prevalence in Iceland and other Nordic countries? ... If a person in Khazar had developed the CCR5 mutation it would have spread back to Scandinavia with the Vikings [suggested Buhler]." Observations: Marc Buhler indicates that the article contains erroneous statistics: "the values in the article are given for individuals where I was describing alleles (so there are twice the value cited, so to speak). What the writer of that article did was take 'allele frequencies' and put them in terms of individuals. Each person has two alleles, so to speak, but that was not corrected for." Buhler also provides the following specific data about his study: "Of 807 Australian Ashkenazi Jews, 216 individuals (26.6%, i.e. about 1 in 4) carried the deletion. 197 were 'heterozygoytes', that is carriers with one wild-type allele and one allele with the deletion. 19 were 'homozygotes' for the allele. In terms of allele frequency, these 807 individuals have 1614 alleles in total and the allele frequency of the deletion was 14.6% ( (38+197) / 1416 ) since all homozygotes have two of the alleles and heterozygotes have one. The general frequency found for European caucasian groups is an allele frequency of about 10% (or about one in five individuals). This frequency is slightly greater in countries to the north and east of Europe. An allele frequency of ~15% was reported for Iceland, and Sweden has three reports of about 14%. The allele frequency I reported for the Sephardic Jews was 5.7% or just over 1 in 10 individuals. When the grandparents of the individuals we tested came from a group of countries (Russia, Poland, Austria, Czechoslovakia, or Hungary) the frequency was seen to be 19.5%. (197 individuals with 30% carriers and 4.6% homozygotes, or 1 out of 3 individuals.) Note that 'Austria' somehow dropped from the SMH report. Elevated frequency of Ashkenazi Jews from Eastern Europe was initally reported by Martinson in 1997 (~21% allele frequency for 43 Ashkenazi) and also reported by Lucotte, but our numbers are quite large. The Australian Ashkenazi Jews with grandparents from Western Europe had an allele frequency more in line with the general caucasian frequency. Of 123 Western Europe Ashkenazi, an allele frequency of 11.8% was seen (about one in five individuals). Our non-Jewish Australian sample was of 311 individuals and the allele frequency was 11.3%. ...[I]n general, the Middle East groups, while often not zero, are still just a few percent and not as high as the ~10% seen in European caucasians and certainly not above that. One group that has been pointed out with an elevated frequency are the Mordvinians (reported allele frequency of ~17%)." Other studies have shown that the CCR5-D32 allele appears to have a protective effect not only against HIV infection, but also rheumatoid arthritis and smallpox, and possibly also multiple sclerosis, Crohn's Disease, and type 1 diabetes.
See also the July 25, 2003 news release from the University of Sydney by Alison Handmer.
Laura Spinney. "HIV protection via the Vikings?" BioMedNet News (July 23, 2003). Excerpts:
"A common genetic mutation that confers protection against HIV and possibly also multiple sclerosis and type 1 diabetes may have arisen over 1000 years ago in a lost kingdom in what is now Russia, according to an Australian geneticist. Marc Buhler of the Institute for Immunology and Allergy Research at the University of Sydney thinks that the delta32 deletion mutation in the CCR5 gene is now a target for selection because it protects against certain strains of HIV, but that initially it may have been selected for because carriers survived small pox... The CCR5-delta32 mutation is particularly common among Ashkenazi Jews... among Ashkenazis from Western Europe, for instance, it occurs with the same frequency as in Caucasian non-Jews... He then genotyped the 26 Ashkenazi Jewish individuals who turned out to be homozygous for the mutation, and measured the degree of recombination that had taken place in the region in which the mutation occurs to come up with an estimate of when the mutation first arose. To his surprise, his calculations generated an age of 50 generations, or just over 1000 years. The Ashkenazi Jews left Israel around 2000 years ago... Since the mutation is not common among the Sephardic Jews who stayed in the Middle East, and since it appears to be older than the Ashkenazis' Germanic period - the last time they were concentrated as a population - Buhler surmises that it had its origins elsewhere [other than Germany]. There were several other pieces to fit into the jigsaw: for instance, the incidence of CCR5-delta32 is relatively high among Scandinavians... When he gathered information about his Ashkenazi volunteers' forebears, he found that the frequency of the mutation leapt to 20% in a subgroup whose grandparents came from Russia or Eastern Europe - almost 10% higher than the frequency among Western European Ashkenazis... Since small pox kills around one third to a half of its untreated victims, Buhler says selection would have been very strong for CCR5-delta32 if heterozygotes did indeed avoid death... [U]pper class Khazars adopted Judaism in the mid-10th century... 'The Jewish Khazars had the main block of the mutation,' says Buhler, 'But a few [Khazar] slaves kidnapped by the Vikings would have been enough for them to take it away as a souvenir.' Khazaria ceased to exist around the 13th century, when it was absorbed by Russia, and from then on the Khazar Jews would have blended with the Ashkenazi ancestors of Buhler's Australian volunteers." "Geneticist finds Ashkenazi immunity." Australian Jewish News (August 22, 2003). Excerpts:
"...In a study of 1400 subjects, Marc Buhler found that Jews originating from Austria, Hungary, Czechoslovakia, Poland and Russia are prone to carry CCRS-delta 32 - a gene modifier that alters the immune system. ...Buhler said that the gene modifier fends off the symptoms of HIV/AIDS for anywhere between four years and a lifetime. ... Presented in Melbourne at the International Congress of Genetics, the study found CCRS-delta 32 in as many as 35 per cent of Jewish subjects originating from Austria, Hungary, Czechoslovakia, Poland and Russia. The proportion for non-Jewish subjects hailing from that part of the world was around 25 per cent. However, Jews from other parts of Europe, Asia and the Middle East are no more likely to carry the gene modifier than their non-Jewish counterparts from the same region, he said. CCRS-delta 32 was also discovered in nearly 30 per cent of subjects from Iceland - an observation that prompted Buhler to speculate that the mutation first emerged among medieval Russian Jewish communities and was spread to Northern Europe by the Vikings. Buhler believes that the first carrier of the gene mutation was probably born in Khazaria (in Southern Russia) between 800 and 1000AD. ... Buhler said that CCRS-delta 32 may have also protected Jews against the smallpox. The gene modifier has thrived, he said, because it can ward off adverse symptoms and keep carriers alive long enough to procreate." http://www.khazaria.com/genetics/abstracts-diseases.html
http://en.wikipedia.org/wiki/CCR5
Plagues are not all bad, and the Black Death (bubonic plague) that swept into Europe from Asia in 1346 was no exception.
It is now common knowledge that bacteria, insects, plants, and even humans can build up resistances to poisons, diseases, and antibiotics.
Mutations are always occurring; some good, some neutral, some bad. It has been found that a human mutation designated CCR5-delta 32 confers immunity to AIDS if inherited from both parents. People carrying the CCR5-delta 32 mutation lack the receptors to which the AIDS virus must attach itself if it is to infect the person.
What has all this to do with the Black Death?
"Although the origin of the mutation is obscure, it appears to have suddenly become relatively common among white Europeans about 700 years ago. That increase suggests that something must have occurred about that time to greatly favor the survival of people carrying the mutation." What biological catastrophe decimated Europe 700 years ago? The Black Death. One-quarter to one-third of the Europeans succumbed between 1347 and 1350. The Black Death strongly modified the European gene pool, increasing the frequency of CCR5-delta 32. This mutation may not have had any direct effect on the plague itself. It may just be a quirk of fate that the survivors of the Black Death had a higher frequency of the CCR5-delta 32 mutation, and it is doubly quirky that the mutation confers a resistance to AIDS, which is a recent human affliction.
About 10% of whites of European origin now carry the CCR5-delta 32 mutation. The incidence is only 2% in central Asia. The mutation is completely absent among East Asians, Africans, and American Indians.
(Brown, David; "AIDS Resistance Might Be a Legacy of Plague Survival," Dallas Morning News, May 18, 1998. Cr. D. Phelps)
There is apparently a human gene mutation, "CCR-5-delta-32", which makes its holders immune to AIDS
The Secrets of the Dead episode begins not with HIV but by investigating why so many residents of Eyam, England, survived the Black Death when it hit the remote village in 1665. Research by geneticist Stephen O'Brien has traced Crohn's DELTA 32 mutation back hundreds of years to towns like Eyam, where the defensive genetic mutation held off the Black Death in much the same way it now protects Steve Crohn from HIV. Today, about 10% of people of European heritage are estimated to be "DELTA 32-homozygous," having inherited the genetic mutation from both parents.
There is apparently a human gene mutation,
"Mutation CCR-5-delta-32",
which makes its holders nearly immune to AIDS,
since this gene has no receptor for AIDS-similar viruses.
Whoever has inherited this gene from BOTH parents
is fairly immune to AIDS. Whoever has inherited this gene
from only ONE parent also has a good deal of immunity.
(The immunity is not perfect in either case, since rare strains
of AIDS can use the receptor CXCR 4).
A gene mutation is generally a matter of chance
and its distribution among the population, according to O'Brien,
reaches only 1 percent at the most.
As the researchers have discovered, however,
"Mutation CCR-5-delta-32" not only is immense in its distribution,
but it also has a distinct north to south distribution,
and, on the evidence of Australia, an "Indo-European" touch.
Sweden (13.7 percent of all Swedes), Russia (13.6 of all Russians),
Estonia - [near Latvia] (13.3), Poland (13.3), Slovakia (13.3),
Australia (11.8), Great Britain (11.7), Ireland (11.3), Germany (10.8),
Czechoslovakia (10.2), Spain (9.8), Finland (9.1); France (8.9),
Austria (8.9), Denmark (8.3), Albania (8.2), Slovenia (7.7),
Turkey (6.3), Italy (5.5), Azerbaijan - southeast Caucasus (5.0),
Greece (4.4), Uzbekistan (3.4), Mexico (2.4).
As the Chicago researchers note, this gene mutation
is found only in white Europeans of Caucasian origin
- but not in persons of African, East-Asian or Indian origin.
Anthropologists think that the Caucasians were isolated
circa 200,000 years ago and that the mutation
must have occurred after this time.
According to O'Brien, by tracing the chemical evolution
of this gene back in terms of time, the mutation must be
around 127,500 years old [surely too high].
This is also the period at which some researchers place
the "origin" of "modern" man. Were these the first "Indo-Europeans"??
LexiLine predicts the presence of Mutation CCR-5-delta-32
among the oldest existing Pharaonic mummies
and the remains of royal rulers buried in shaft-tombs.
What is the frequency of this gene among the Hebrews??
What is the frequency among the Cohens - the priests?
There was a study done some time ago that these had
definable genetic similarities differing from the normal
Hebrew population.
LexiLine predicts the frequency will be high.
This genetic finding in Chicago also supports
the Nostratic theory of proto-Indo-European migrations,
north to south as alleged by Bomhard.
http://www.lexiline.com/lexiline/lexi76.htm
“Geneticist finds Ashkenazi immunity.” Australian Jewish News
(8/22/2003). Excerpts: ” Study of 1400 subjects, Marc Buhler found Jews
originating from Austria, Hungary, Czechoslovakia, Poland & Russia
are prone to carry CCRS-delta 32-a gene modifier that alters the immune
system. …it fends off the symptoms of HIV/AIDS for anywhere between four
years & a lifetime. … Presented in Melbourne at the Int’l Congress
of Genetics, the study found CCRS-delta 32 in as many as 35% of Jewish
subjects originating from Austria, Hungary, Czechoslovakia, Poland &
Russia. CCRS-delta 32 was also discovered in nearly 30% of subjects
from Iceland – prompted speculation that the mutation 1st emerged among
medieval Russian Jewish communities & spread to N. Europe by the
Vikings. The first carrier of the gene mutation was probably born in
Khazaria (S. Russia) between 800-1000AD. He said the CCRS-delta 32 may
have also protected Jews against the smallpox. The gene modifier has
thrived, he said, because it can ward off adverse symptoms & keep
carriers alive long enough to procreate.” http://www.khazaria.com/genetics/abstracts-diseases.html
Biologists Discover Why 10 Percent Of Europeans Are Safe From HIV Infection ScienceDaily (Apr. 3, 2005) — Biologists at the University of Liverpool have discovered how the plagues of the Middle Ages have made around 10% of Europeans resistant to HIV.
See Also:Health & Medicine Reference Scientists have known for some time that these individuals carry a genetic mutation (known as CCR5-delta 32) that prevents the virus from entering the cells of the immune system but have been unable to account for the high levels of the gene in Scandinavia and relatively low levels in areas bordering the Mediterranean.
They have also been puzzled by the fact that HIV emerged only recently and could not have played a role in raising the frequency of the mutation to the high levels found in some Europeans today.
Professor Christopher Duncan and Dr Susan Scott from the University’s School of Biological Sciences, whose research is published in the March edition of Journal of Medical Genetics, attribute the frequency of the CCR5-delta 32 mutation to its protection from another deadly viral disease, acting over a sustained period in bygone historic times.
Some scientists have suggested this disease could have been smallpox or even bubonic plague but bubonic plague is a bacterial disease rather than a virus and is not blocked by the CCR5-delta 32 mutation.
Professor Duncan commented: “The fact that the CCR5-delta 32 mutation is restricted to Europe suggests that the plagues of the Middle Ages played a big part in raising the frequency of the mutation. These plagues were also confined to Europe, persisted for more than 300 years and had a 100% case mortality.”
Around 1900, historians spread the idea that the plagues of Europe were not a directly infectious disease but were outbreaks of bubonic plague, overturning an accepted belief that had stood for 550 years. Professor Duncan and Dr Scott illustrated in their book, Return of the Black Death (2004, Wiley), that this idea was incorrect and the plagues of Europe (1347-1660) were in fact a continuing series of epidemics of a lethal, viral, haemorrhagic fever that used the CCR5 as an entry port into the immune system.
Using computer modeling, they demonstrated how this disease provided the selection pressure that forced up the frequency of the mutation from 1 in 20,000 at the time of the Black Death to values today of 1 in 10.
Lethal, viral haemorrhagic fevers were recorded in the Nile valley from 1500 BC and were followed by the plagues of Mesopotamia (700-450BC), the plague of Athens (430BC), the plague of Justinian (AD541-700) and the plagues of the early Islamic empire (AD627-744). These continuing epidemics slowly raised the frequency from the original single mutation to about 1 in 20,000 in the 14th century simply by conferring protection from an otherwise certain death.
Professor Duncan added: “Haemorrhagic plague did not disappear after the Great Plague of London in 1665-66 but continued in Sweden, Copenhagen, Russia, Poland and Hungary until 1800. This maintenance of haemorrhagic plague provided continuing selection pressure on the CCR5-delta 32 mutation and explains why it occurs today at its highest frequency in Scandinavia and Russia.”
C-C chemokine receptor type 5 also known as CCR5 is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins.[1][2]
In Humans, the CCR5 gene location is on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[3]
The CCR5 protein has also recently been designated CD195 (signifying a cluster of differentiation of cell surface molecules present on White blood cells). The CCR5 protein is a G protein-coupled receptor[1] which functions as a chemokine receptor in the CC chemokine group. The natural chemokineligands that bind to this receptor are RANTES (a chemotacticcytokine protein also known as CCL5) and macrophage inflammatory protein (MIP) 1α and 1β (also known as CCL3 and CCL4). CCR5 is predominantly expressed on T cells, macrophages, dendritic cells and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.
HIV most commonly uses CCR5 or CXCR4 as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[4] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
A number of new experimental HIV drugs, called entry inhibitors, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140Progenics), Vicriviroc (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.[6][7]
CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cells. CCR5-Δ32 is widely dispersed throughout Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.[8] Smallpox may be another candidate for the high level of the mutation in the European population.[6]
The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,[9] indicating that not all of the functions of CCR5 may be compensated by other receptors.
While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection.[10] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.[11] Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS by about 2 years. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.[12]
In 2007, an AIDS patient who had also developed myeloid leukemia, was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However transplant was performed from a donor with the CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[13][14] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[14] However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[15] After three years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[16]
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.
In Humans, the CCR5 gene location is on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32mutation resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.[3]
The CCR5 protein has also recently been designated CD195 (signifying a cluster of differentiation of cell surface molecules present on White blood cells). The CCR5 protein is a G protein-coupled receptor[1] which functions as a chemokine receptor in the CC chemokine group. The natural chemokineligands that bind to this receptor are RANTES (a chemotacticcytokine protein also known as CCL5) and macrophage inflammatory protein (MIP) 1α and 1β (also known as CCL3 and CCL4). CCR5 is predominantly expressed on T cells, macrophages, dendritic cells and microglia. It is likely that CCR5 plays a role in inflammatory responses to infection, though its exact role in normal immune function is unclear.
HIV most commonly uses CCR5 or CXCR4 as a co-receptor to enter its target cells. Several chemokine receptors can function as viral coreceptors, but CCR5 is likely the most physiologically important coreceptor during natural infection. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection,[4] suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.
A number of new experimental HIV drugs, called entry inhibitors, have been designed to interfere with the interaction between CCR5 and HIV, including PRO140Progenics), Vicriviroc (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer). A potential problem of this approach is that, while CCR5 is the major co-receptor by which HIV infects cells, it is not the only such co-receptor. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, examination of viral resistance to AD101, molecular antagonist of CCR5, indicated that resistant viruses did not switch to another coreceptor (CXCR4) but persisted in using CCR5, either through binding to alternative domains of CCR5, or by binding to the receptor at a higher affinity. Development of Aplaviroc has been terminated due to safety concerns (potential liver toxicity).
CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.[6][7]
CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cells. CCR5-Δ32 is widely dispersed throughout Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.[8] Smallpox may be another candidate for the high level of the mutation in the European population.[6]
The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,[9] indicating that not all of the functions of CCR5 may be compensated by other receptors.
While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection.[10] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.[11] Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS by about 2 years. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.[12]
In 2007, an AIDS patient who had also developed myeloid leukemia, was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However transplant was performed from a donor with the CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[13][14] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[14] However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[15] After three years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[16]
Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.
