A specific genetic mutation, known as CCR5-Δ32, renders some individuals resistant to common strains of HIV-1 by disabling a crucial immune cell receptor that the virus typically exploits for entry. This mutation, characterized by a 32-base-pair deletion in the CCR5 gene, prevents the expression of a functional CCR5 receptor on the surface of immune cells. Individuals who are homozygous for this mutation exhibit significant resistance to HIV-1 infection, while heterozygotes often experience delayed disease progression.
The current scientific hypothesis suggests that the relatively high prevalence of the CCR5-Δ32 allele, particularly among populations of European descent, reflects past selective pressure from historical epidemics. Research indicates that the mutation is evolutionarily young, estimated to have originated between 700 to 1,875 years ago. This timeline predates the emergence of HIV-1, leading scientists to propose that other devastating diseases, such as the Black Death (bubonic plague) or smallpox, drove its increased frequency in the population.
"Some humans are resistant to certain common HIV-1 strains due to a mutation called CCR5-Δ32, which disables a key immune cell receptor that HIV uses for entry into the cells. The current hypothesis is that its prevalence reflects past selective pressure from the black plague," stated a recent tweet by Hunter📈🌈📊.
While the Black Death hypothesis is widely discussed, some studies also point to smallpox as a strong selective agent, given its historical impact and the CCR5 receptor's role in immune responses to various pathogens. The mutation's highest frequencies are observed in Northern Europe, with approximately 10-15% of individuals in some regions carrying at least one copy. Conversely, it is largely absent in African, East Asian, and Amerindian populations.
Beyond HIV resistance, the CCR5-Δ32 mutation has been linked to both advantages and disadvantages. It may offer protection against certain autoimmune diseases and enteroviral cardiomyopathy. However, carrying the mutation has also been associated with increased susceptibility to other viral infections, such as West Nile virus and tick-borne encephalitis, and potentially a higher risk of fatal outcomes in influenza infections.
The understanding of CCR5-Δ32 has significantly influenced HIV research and therapeutic strategies. It has inspired the development of CCR5 antagonist drugs, which block the receptor, and gene-editing approaches, including CRISPR-Cas9 technology, aimed at mimicking this natural resistance to create HIV-resistant immune cells. The success of HIV cures in individuals who received bone marrow transplants from CCR5-Δ32 homozygous donors underscores the mutation's profound impact on the fight against HIV.