Natural resistance to infection is a subject of intense scientific interest. For the human immunodeficiency virus (HIV), a specific genetic variation provides a powerful form of natural immunity, preventing the virus from establishing infection in some individuals. This genetic difference influences how the virus interacts with immune cells, effectively blocking the infection process. Understanding this natural resistance has been instrumental in shaping modern research into HIV infection mechanisms and the development of new therapeutic strategies.
Identifying the Primary Resistance Gene
The gene responsible for this resistance is the C-C chemokine receptor type 5, or CCR5. CCR5 normally functions as a receptor on the surface of immune cells, including CD4+ T-cells and macrophages. Its role is to bind to signaling proteins called chemokines, guiding immune cells to sites of inflammation. However, the most common strain of HIV-1, known as R5-tropic virus, exploits this receptor, using it as a gateway to infect these cells.
The specific variation conferring resistance is the CCR5-delta 32 (\(Delta 32\)) mutation, characterized by a 32-base-pair deletion in the gene sequence. This deletion causes a frameshift, resulting in the premature termination of protein synthesis. The resulting protein is truncated, non-functional, and never correctly expressed on the cell surface. Individuals who inherit this mutation from both parents (homozygous \(Delta 32\)/\(Delta 32\)) are highly resistant to infection by the R5-tropic strain of HIV-1. Those with one copy (heterozygous) have reduced susceptibility and, if infected, experience slower progression to AIDS.
Molecular Mechanism of HIV Entry Blockade
HIV infection begins when the viral surface protein, gp120, binds to the primary receptor, CD4, on the target T-cell. This binding causes a change in the viral envelope protein, exposing a site for the co-receptor, which is the CCR5 molecule. The virus must bind to CCR5 to complete the second, necessary step of the entry process.
The CCR5-delta 32 mutation disrupts this sequence by preventing the functional receptor from reaching the cell surface. The deletion introduces an early stop signal, causing the cell to produce a shortened, misfolded protein. This faulty protein is recognized by the cell’s quality control mechanisms and is trapped inside the cell or degraded.
Because functional CCR5 is absent from the cell membrane, the HIV-1 virus cannot find the secondary docking site required for fusion, even after binding to CD4. Without successful binding to both receptors, the viral envelope cannot fuse with the host cell membrane. This mechanism effectively blocks infection by R5-tropic strains, which cause most initial HIV transmission events.
Geographic Distribution and Evolutionary Origin
The CCR5-delta 32 mutation is not uniformly distributed across the global population. The highest frequencies of the \(Delta 32\) allele are observed in populations of Northern European descent, averaging about 10% across Europe. This frequency exhibits a north-to-south gradient, with the highest prevalence in the Baltic regions and Scandinavia, and a near-absence in African and Asian populations.
This distinct geographic pattern suggests the mutation conferred a strong selective advantage in European history, well before the emergence of HIV. The leading theory posits that the selective pressure was a historical epidemic disease that used the CCR5 receptor for entry. Pathogens such as the bubonic plague or smallpox have been proposed as likely evolutionary drivers, as surviving these epidemics would have rapidly increased the frequency of the protective \(Delta 32\) allele. The mutation is estimated to be relatively young, having arisen within the last millennium.
Gene Therapy and Therapeutic Applications
The discovery of the CCR5-delta 32 mutation has provided a functional blueprint for developing curative strategies for HIV. The primary application has involved allogeneic hematopoietic stem cell transplantation, a procedure used to treat blood cancers. In a small number of cases, including the “Berlin Patient” and the “London Patient,” HIV-positive individuals with concurrent blood cancers received stem cell transplants from donors who carried the homozygous \(Delta 32\)/\(Delta 32\) mutation. The transplant replaced the patient’s susceptible immune system with cells inherently resistant to HIV, resulting in the eradication of the virus and a functional cure.
The high risk and complexity of stem cell transplantation limit its use to patients who also require the procedure for cancer treatment. This limitation has driven research into gene editing technologies, such as CRISPR/Cas9, to artificially replicate the \(Delta 32\) mutation. Researchers can harvest a patient’s own immune or blood stem cells, use CRISPR to edit the CCR5 gene to disable it, and then infuse the engineered, resistant cells back into the patient. While this approach is feasible and can introduce a population of resistant cells, challenges remain in achieving a high enough proportion of edited cells to completely control the virus without anti-retroviral drugs.