Being “immune to HIV” typically refers to individuals who either resist infection or naturally control the virus after infection. Absolute immunity is exceptionally rare. Instead, scientific observations highlight genetic factors that confer resistance or unique immune responses enabling long-term viral control without medication. These mechanisms offer insights into new strategies for HIV prevention and treatment.
Genetic Factors for HIV Resistance
A well-documented genetic mutation, CCR5-delta 32 (CCR5-Δ32), plays a significant role in natural resistance to HIV infection. HIV primarily enters host CD4+ T cells by binding to the CD4 receptor and a co-receptor, most commonly CCR5. The CCR5-Δ32 mutation involves a 32-base pair deletion in the CCR5 gene, which results in a truncated, non-functional CCR5 protein that is not expressed on the cell surface.
Individuals inheriting two copies of this mutation (homozygous CCR5-Δ32) lack functional CCR5 receptors, making them highly resistant to infection by CCR5-tropic HIV strains responsible for most initial transmissions. This resistance is substantial but not absolute, as rare infections have occurred even in homozygous individuals. Those with one copy (heterozygous) can be infected but often experience slower progression to AIDS.
The CCR5-Δ32 mutation is found predominantly in populations of European descent, with approximately 1% homozygous and up to 20% heterozygous in Western European populations. Its prevalence varies geographically, with higher frequencies in Northern Europe.
Natural Control of HIV
Beyond genetic resistance, some individuals living with HIV demonstrate a remarkable ability to control the virus naturally without antiretroviral therapy (ART). These “elite controllers” or “elite suppressors” maintain undetectable viral loads, typically below 50 copies/mL, for extended periods without medication. This natural control is distinct from genetic resistance, as elite controllers are infected but their immune systems effectively suppress viral replication.
Natural control involves robust immune responses. Elite controllers often exhibit strong cytotoxic T-lymphocyte (CTL) responses that target HIV-infected cells. Certain human leukocyte antigen (HLA) alleles, such as HLA B57 and B27, are overrepresented in these individuals and associated with a greater ability to recognize and attack HIV-infected cells.
Innate immune responses, involving cells like natural killer (NK) cells and dendritic cells, also contribute to viral control. Elite controllers often have a smaller viral reservoir, meaning fewer latently infected cells, which aids in maintaining low viral levels. While a powerful demonstration of the body’s potential to manage HIV, elite control is rare, occurring in less than 1% of people living with HIV worldwide.
Key Discoveries in HIV Resistance and Cure
Significant breakthroughs in understanding HIV resistance and cure have emerged from specific patient cases, offering proof-of-concept for eradicating the virus. The “Berlin Patient,” Timothy Ray Brown, became the first person considered cured of HIV in 2008. Brown, who was living with HIV and also diagnosed with acute myeloid leukemia, underwent an allogeneic hematopoietic stem cell transplant. His doctors intentionally selected a donor with the homozygous CCR5-Δ32 mutation, replacing Brown’s immune system with naturally resistant cells, demonstrating a cure was achievable through medical intervention. After the transplant and discontinuing ART, HIV was undetectable in his body, a remission that lasted until his passing from leukemia in 2020.
Following Brown’s case, Adam Castillejo, the “London Patient,” became the second person to achieve long-term HIV remission after a similar procedure. Castillejo, also diagnosed with HIV and Hodgkin’s lymphoma, received a stem cell transplant from a donor with the CCR5-Δ32 mutation in 2016. He has remained free of detectable HIV for an extended period after stopping ART. These cases, while not natural immunity, underscore the CCR5 co-receptor’s importance in HIV infection and provide a blueprint for gene therapy and other curative strategies.
Impact on Future HIV Prevention and Treatment
Knowledge from studying genetic resistance, natural controllers, and functional cures profoundly influences current and future HIV research. Understanding the CCR5-Δ32 mutation has spurred gene therapy efforts to mimic this natural protection. Researchers are exploring gene editing techniques, such as CRISPR, to modify immune cells to remove or inactivate the CCR5 gene, making them resistant to HIV infection.
Insights from elite controllers guide the development of therapeutic vaccines. By studying their strong immune responses, scientists aim to design vaccines that elicit similar protective immunity. The goal is to “teach” the immune system of HIV-positive individuals to control the virus without daily medication or to prevent infection in HIV-negative individuals.
Efforts to achieve a broader cure also draw heavily from these discoveries. Strategies like “shock and kill” aim to activate latent HIV reservoirs, making infected cells visible to the immune system or targeted therapies for eradication. The ultimate goals include developing effective vaccines, gene therapies, and treatments for widespread prevention and, eventually, a cure for HIV, moving beyond lifelong ART.