Some individuals possess a remarkable natural resistance to HIV, the virus that causes AIDS. This inherent protection is quite rare, affecting only a very small percentage of the global population. The existence of such individuals has long fascinated scientists, prompting extensive research into the biological mechanisms behind this unusual immunity. Understanding these natural defenses offers valuable insights into potential strategies for preventing and treating HIV infection in a broader context.
The CCR5-delta32 Mutation
The primary factor contributing to natural HIV resistance is the CCR5-delta32 mutation. This genetic alteration affects the CCR5 gene, which provides instructions for a protein on the surface of immune cells (T-cells and macrophages). HIV uses this protein as a co-receptor to enter cells. The delta32 mutation involves a deletion of 32 base pairs in the CCR5 gene, resulting in a non-functional receptor not expressed on the cell surface.
This genetic variation is not uniformly distributed. It is observed most frequently in people of European descent, with 5% to 15% prevalence in some Northern European populations. In contrast, it is largely absent among East Asian, American Indian, Tamil Indian, and African ethnic groups. Its discovery in the mid-1990s explained why some individuals remained uninfected despite repeated HIV exposure.
How HIV Entry is Blocked
The CCR5-delta32 mutation blocks entry of common R5-tropic HIV strains into host cells. These strains primarily establish infection in newly infected individuals. HIV initiates infection by binding to a primary receptor, CD4, on the host cell surface. It then requires a co-receptor, usually CCR5, for its envelope protein to bind and facilitate cell membrane fusion.
Individuals inheriting two copies of this mutated gene (one from each parent) produce no functional CCR5 receptors on their immune cells. Without these receptors, R5-tropic HIV cannot complete the binding and fusion steps to enter the cell. This absence prevents the virus from establishing infection.
Those with one mutated and one normal gene copy still produce some functional CCR5 receptors. While not completely immune, they often exhibit a slower progression to AIDS once infected. This partial protection highlights the CCR5 receptor’s role in the viral life cycle, showing how even a reduced number of functional receptors can impact disease progression.
Other Protective Genetic Variations
While the CCR5-delta32 mutation is the most understood genetic factor for HIV resistance, other genetic variations also contribute to natural protection or better viral control. Variations in genes like TRIM5alpha can interfere with early viral replication after cell entry. This protein acts as an intrinsic retroviral restriction factor, disabling viral capsids before integration into the host genome.
APOBEC3G, a cellular enzyme, introduces mutations into viral DNA during reverse transcription, rendering the virus non-functional. Variations enhancing APOBEC3G activity or expression can offer protection. Similarly, certain Human Leukocyte Antigen (HLA) alleles, involved in presenting viral fragments, are associated with better immune control and slower disease progression. These other genetic factors generally provide less complete protection than the CCR5-delta32 mutation.
Impact on HIV Prevention and Treatment Research
Studying naturally HIV-resistant individuals has influenced HIV prevention and treatment research. Understanding how the CCR5-delta32 mutation prevents viral entry led to the development of CCR5 inhibitors, a new class of antiretroviral drugs. Maraviroc, an approved CCR5 inhibitor, works by binding to the CCR5 receptor on host cells, blocking interaction with the HIV gp120 protein and preventing R5-tropic HIV entry.
Beyond drug development, natural immunity insights have inspired gene therapy approaches mimicking the CCR5-delta32 mutation. Researchers are exploring ways to genetically modify a patient’s immune cells to remove or inactivate the CCR5 receptor, making them HIV-resistant. The “Berlin Patient” case, where viral eradication occurred after a stem cell transplant from a CCR5-delta32 donor, provided compelling evidence for this strategy.
Knowledge from these individuals also informs the design of effective HIV vaccines, guiding efforts to prevent initial infection or control viral replication. These individuals offer blueprints for developing broader public health solutions against HIV.