CCR5-Δ32
CCR5-Δ32 is a genetic variant of the CCR5 gene characterized by a 32-base-pair deletion that produces a nonfunctional receptor on the surface of immune cells, conferring strong resistance to HIV-1 infection in individuals who inherit two copies of the mutation.
CCR5 Δ32 is a 32-base-pair deletion that introduces a premature stop codon into the CCR5 receptor locus, resulting in a nonfunctional receptor. CCR5 is required for M-tropic HIV-1 virus entry. Individuals homozygous for CCR5 Δ32 do not express functional CCR5 receptors on their cell surfaces and are resistant to HIV-1 infection, despite multiple high-risk exposures. Individuals heterozygous for the mutant allele have a greater than 50% reduction in functional CCR5 receptors on their cell surfaces due to dimerization between mutant and wild-type receptors that interferes with transport of CCR5 to the cell surface. Heterozygote carriers are resistant to HIV-1 infection relative to wild types and when infected, heterozygotes exhibit reduced viral loads and a 2-3-year-slower progression to AIDS relative to wild types. Heterozygosity for this mutant allele also has shown to improve one's virological response to anti-retroviral treatment. CCR5 Δ32 has a heterozygote frequency of 9% in Europe, and a homozygote frequency of 1%.
Recent research indicates that CCR5 Δ32 enhances cognition and memory. In 2016, researchers showed that removing the CCR5 gene from mice significantly improved their memory. CCR5 is a powerful suppressor for neuronal plasticity, learning, and memory; CCR5 over-activation by viral proteins may contribute to HIV-associated cognitive deficits.
HIV
uses CCR5 receptor to target and infect host T-cells in humans. It weakens the immune system by destroying the CD4+ T-helper cells, making the body more susceptible to other infections. CCR5-Δ32 is an allelic variant of CCR5 gene with a 32 base pair deletion that results in a truncated receptor. People with this allele are resistant to AIDS as HIV cannot bind to the non-functional CCR5 receptor. An unusually high frequency of this allele is found in European Caucasian population, with an observed cline towards the north. Most researchers have attributed the current frequency of this allele to two major epidemics of human history: plague and smallpox. Although this allele originated much earlier, its frequency rose dramatically about 700 years ago. This led scientists to believe that bubonic plague acted as a selective pressure that drove CCR5-Δ32 to high frequency. It was speculated that allele may have provided protection against the Yersinia pestis, which is the causative agent for plague. Many in vivo mouse studies have refuted this claim by showing no protective effects of CCR5-Δ32 allele in mice infected with Y. pestis. Another theory that has gained more scientific support links the current frequency of the allele to smallpox epidemic. Although plague has killed a greater number people in a given time period, smallpox has collectively taken more lives. As smallpox has been dated back to 2000 years, a longer time period would have given smallpox enough time to exert selective pressure given an earlier origin of CCR5-Δ32. Population genetic models that analyzed geographic and temporal distribution of both plague and smallpox provide a much stronger evidence for smallpox as the driving factor of CCR5-Δ32. Smallpox has a higher mortality rate than plague, and it mostly affects children under the age of ten. From an evolutionary viewpoint, this results in greater loss of reproductive potential from a population which may explain increased selective pressure by smallpox. Smallpox was more prevalent in regions where higher CCR5-Δ32 frequencies are seen. Myxoma and variola major belong to the same family of viruses and myxoma has been shown to use CCR5 receptor to enter its host. Moreover, Yersinia is a bacterium which is biologically distinct from viruses and is unlikely to have similar mechanism of transmission. Recent evidence provides a strong support for smallpox as the selective agent for CCR5-Δ32.Haplotype and architecture
Genetic studies published in 2025 revealed that the CCR5Δ32 deletion is part of a specific haplotype, termed Haplotype A, which includes 86 linked variants in high linkage disequilibrium. Within this haplotype, two single nucleotide polymorphisms, rs113341849 and rs113010081, are in perfect LD with CCR5Δ32 and thus statistically indistinguishable in genotype data. This haplotype is located on chromosome 3, spans approximately 0.19 megabases, and encompasses several chemokine receptor genes, including CCR3, CCR2, CCR5, and CCRL2. Although two additional haplotypes, B and C, were identified in the region, only Haplotype A carries the CCR5Δ32 deletion. The configuration of the three haplotypes—A, B, and C—was illustrated in Figure 1A of the study.Evolutionary history
The CCR5 Δ32 allele is notable for its recent origin, unexpectedly high frequency, and distinct geographic distribution, which together suggest that it arose from a single mutation, and it was historically subject to positive selection.Two studies have used linkage analysis to estimate the age of the CCR5 Δ32 deletion, assuming that the amount of recombination and mutation observed on genomic regions surrounding the CCR5 Δ32 deletion would be proportional to the age of the deletion. Using a sample of 4000 individuals from 38 ethnic populations, Stephens et al. estimated that the CCR5-Δ32 deletion occurred 700 years ago. Another group, Libert et al., used microsatellite mutations to estimate the age of the CCR5 Δ32 mutation to be 2100 years. On the basis of observed recombination events, they estimated the age of the mutation to be 2250 years. A third hypothesis relies on the north-to-south gradient of allele frequency in Europe, which shows that the highest allele frequency occurred in the Nordic countries and lowest allele frequency in southern Europe. Because the Vikings historically occupied these countries, it may be possible that the allele spread throughout Europe due to the Viking dispersal in the 8th to 10th centuries. Vikings were later replaced by the Varangians in Russia, which may have contributed to the observed east-to-west cline of allele frequency.
HIV-1 was initially transmitted from chimpanzees to humans in the early 1900s in Southeast Cameroon, Africa, through exposure to infected blood and body fluids while butchering bushmeat. However, HIV-1 was effectively absent from Europe until the 1980s. Therefore, given the average age of roughly 1000 years for the CCR5-Δ32 allele, it can be established that HIV-1 did not exert selection pressure on the human population for long enough to achieve the current frequencies. Hence, other pathogens have been suggested as agents of positive selection for CCR5 Δ32, including bubonic plague and smallpox.
Other data suggest that the allele frequency experienced negative selection pressure as a result of pathogens that became more widespread during Roman expansion. The idea that negative selection played a role in the allele's low frequency is also supported by experiments using knockout mice and Influenza A, which demonstrated that the presence of the CCR5 receptor is important for efficient response to a pathogen.
Evidence for a single mutation
Several lines of evidence suggest that the CCR5 Δ32 allele evolved only once. First, CCR5 Δ32 has a relatively high frequency in several different European populations but is comparatively absent in Asian, Middle Eastern and American Indian populations, suggesting that a single mutation occurred after divergence of Europeans from their African ancestor. Second, genetic linkage analysis indicates that the mutation occurs on a homogeneous genetic background, implying that inheritance of the mutation occurred from a common ancestor. This was demonstrated by showing that the CCR5 Δ32 allele is in strong linkage disequilibrium with highly polymorphic microsatellites. More than 95% of CCR5 Δ32 chromosomes also carried the IRI3.1-0 allele, while 88% carried the IRI3.2 allele. By contrast, the microsatellite markers IRI3.1-0 and IRI3.2-0 were found in only 2 or 1.5% of chromosomes carrying a wild-type CCR5 allele. This evidence of linkage disequilibrium supports the hypothesis that most, if not all, CCR5 Δ32 alleles arose from a single mutational event. Finally, the CCR5 Δ32 allele has a unique geographical distribution indicating a single Northern origin followed by migration. A study measuring allele frequencies in 18 European populations found a North-to-South gradient, with the highest allele frequencies in Finnish and Mordvinian populations, and the lowest in Sardinia.Positive selection
In the absence of selection, a single mutation would take an estimated 127,500 years to rise to a population frequency of 10%. Estimates based on genetic recombination and mutation rates place the age of the allele between 1000 and 2000 years. This discrepancy is a signature of positive selection.It is estimated that HIV-1 entered the human population in Africa in the early 1900s, but symptomatic infections were not reported until the 1980s. The HIV-1 epidemic is therefore far too young to be the source of positive selection that drove the frequency of CCR5 Δ32 from zero to 10% in 2000 years.