Human immunodeficiency virus (HIV) continues to pose a substantial global health challenge, affecting millions worldwide. This persistent viral infection can progress to acquired immunodeficiency syndrome (AIDS), weakening the immune system and making individuals susceptible to various opportunistic infections and cancers. While advancements in antiretroviral therapies have transformed HIV into a manageable chronic condition for many, a complete cure remains a significant scientific pursuit. Some individuals naturally exhibit resistance to HIV infection, even after repeated exposures, due to specific genetic differences.
The Genetic Shield Against HIV
A particular genetic alteration provides a natural defense against HIV. This genetic factor involves the C-C chemokine receptor type 5, commonly known as CCR5. Under normal circumstances, CCR5 is a protein found on the surface of certain immune cells, including CD4+ T cells, which are primary targets for HIV. Its usual role involves guiding immune cells to sites of inflammation and infection by binding to specific chemical signals.
A specific mutation within the CCR5 gene, called delta 32 (Δ32), fundamentally alters this receptor. This mutation is a deletion of 32 base pairs in the gene’s coding region. Individuals who inherit two copies of this mutated gene, one from each parent, do not produce functional CCR5 proteins on their cell surfaces. This absence of the normal receptor means that the cells are naturally protected from infection by the most common strains of HIV.
Heterozygous carriers, who possess one normal and one mutated copy of the gene, also show some protection, experiencing a delayed progression to AIDS if they become infected.
How the Resistance Works
The resistance conferred by the delta 32 mutation operates at the molecular level, directly interfering with how HIV typically enters human cells. HIV first attaches to a primary receptor called CD4 on the surface of immune cells. Following this initial attachment, the virus requires a co-receptor to complete its entry into the host cell. The CCR5 protein serves as this primary co-receptor for the majority of HIV strains, known as R5-tropic HIV.
When an individual carries two copies of the CCR5-delta32 mutation, the 32 base-pair deletion causes the CCR5 gene to produce a truncated, non-functional protein. This altered protein is not correctly transported to the cell surface, effectively rendering the cell devoid of accessible CCR5 receptors. Without a functional CCR5 co-receptor, R5-tropic HIV strains cannot bind to the cell and fuse with its membrane, preventing the virus from entering and establishing an infection.
While this mutation provides strong resistance against R5-tropic HIV, it does not protect against less common strains that utilize a different co-receptor, CXCR4, for cell entry. However, R5-tropic viruses are responsible for nearly all initial HIV transmissions, making this genetic resistance a significant factor in preventing infection.
Origin and Distribution of the Gene
The CCR5-delta32 mutation is found predominantly in populations of European and West Asian descent, with its frequency generally increasing towards northern Europe. Studies suggest the allele is virtually absent in African, Asian, and American Indian populations. Its age has been estimated to be between 700 and 3,500 years, indicating a relatively recent origin in human evolutionary history.
A prominent theory links the mutation’s prevalence to historical disease pressures, particularly the bubonic plague, or “Black Death,” which devastated Europe in the mid-14th century. The hypothesis suggests individuals carrying the CCR5-delta32 mutation may have had a survival advantage during plague epidemics, leading to a higher frequency of the allele in subsequent generations. However, some historical analyses question this direct link, proposing that plague mortality’s geographical distribution does not perfectly align with the CCR5-delta32 allele’s current distribution.
Alternative theories suggest other historical pathogens, such as smallpox, might have exerted selective pressure on the CCR5-delta32 mutation. The allele’s greater prevalence in Scandinavian countries, for instance, aligns more closely with regions that experienced severe smallpox epidemics. Regardless of the exact historical disease, the allele’s current distribution, with frequencies ranging from around 0% in some populations to about 14% in parts of Northern Europe, suggests it was under intense natural selection.
Impact on HIV Treatment and Prevention
Understanding the CCR5 resistance gene has significantly influenced the development of strategies to combat HIV. This knowledge led to the creation of CCR5 inhibitor drugs, such as maraviroc, which block the CCR5 co-receptor on host cells. By preventing R5-tropic HIV from binding to CCR5, these drugs effectively stop the virus from entering immune cells, reducing viral load and improving patient health. Maraviroc is a targeted therapy used for individuals whose HIV strain is confirmed to be R5-tropic.
Beyond pharmaceutical interventions, the CCR5-delta32 mutation has inspired more advanced therapeutic approaches, particularly in gene therapy and stem cell transplantation. The “Berlin Patient” and the “London Patient” are publicized examples of individuals who received stem cell transplants to treat cancers. Their HIV was functionally cured because the stem cell donors possessed the CCR5-delta32 mutation. This procedure replaced their own immune systems with HIV-resistant cells, allowing them to stop antiretroviral therapy without viral rebound.
While stem cell transplantation is a high-risk procedure typically reserved for cancer patients, these cases demonstrate the potential for replicating natural resistance. Research continues into gene-editing techniques like CRISPR/Cas9, which aim to modify an individual’s own CCR5 gene to mimic the delta 32 mutation, offering a pathway toward a more widely applicable functional cure for HIV.