Human immunodeficiency virus (HIV) weakens the immune system, leading to acquired immunodeficiency syndrome (AIDS) if untreated. A small percentage of individuals possess natural genetic resistance to the virus. This protection stems from an alteration in a protein on the surface of immune cells, known as the CCR5 receptor. Understanding this genetic variation provides insights into how some individuals resist HIV infection.
How HIV Infects Cells
HIV primarily targets CD4+ T cells, a type of white blood cell integral to the body’s immune response. The infection process begins with the virus attaching to and entering these cells. HIV first binds to the CD4 receptor, a protein on the surface of CD4+ T cells. This initial attachment positions the virus for entry.
Following binding to the CD4 receptor, the virus requires a second binding event to a co-receptor for full entry. The most common co-receptor utilized by R5 HIV strains is the CCR5 receptor. These R5 strains account for the vast majority of new HIV infections. Without binding to both the CD4 receptor and a co-receptor like CCR5, the virus cannot fuse its outer membrane with the host cell’s membrane, preventing infection.
The CCR5 Receptor and Its Mutation
The CCR5 receptor is a protein present on the outer surface of various immune cells, including CD4+ T-cells, macrophages, and dendritic cells. Under normal conditions, CCR5 functions as a chemokine receptor. Chemokines are small proteins that guide immune cells to specific locations, such as sites of inflammation or infection.
A specific genetic alteration, the CCR5-delta 32 (Δ32) mutation, impacts this receptor. This mutation involves a deletion of 32 base pairs within the CCR5 gene. This genetic change results in a truncated CCR5 protein, which is significantly shorter than its normal counterpart. Due to its altered structure, this non-functional protein fails to correctly fold and is unable to reach the cell surface, remaining trapped inside the cell. Individuals can inherit two copies of this mutated gene, one from each parent, making them homozygous for the Δ32 mutation. Alternatively, they can inherit one mutated copy and one normal copy, resulting in a heterozygous genetic makeup.
Mechanism of HIV Resistance
Individuals who inherit two copies of the CCR5-delta 32 mutation, making them homozygous for Δ32, do not produce functional CCR5 receptors on the surface of their immune cells. Without these receptors, R5 strains of HIV cannot enter and infect these cells. The absence of the CCR5 co-receptor physically blocks the virus from fusing with the cell membrane, conferring strong natural resistance to infection by common HIV strains. This mechanism represents a direct disruption of the viral entry pathway.
People who are heterozygous for the CCR5-delta 32 mutation possess one normal copy of the gene and one mutated copy. Their cells produce some functional CCR5 receptors on their surface, though typically fewer than individuals without the mutation. While not fully resistant to R5 strains of HIV, these individuals often experience a delayed progression to AIDS if infected. The reduced number of available CCR5 co-receptors makes it more challenging for the virus to establish a widespread infection, slowing disease advancement.
Implications for HIV and Beyond
The discovery of the CCR5-delta 32 mutation and its protective effect has influenced HIV research and treatment strategies. This natural resistance mechanism provided insights into HIV pathogenesis, highlighting the receptor’s role in viral entry. These insights led to the development of anti-HIV medications known as CCR5 inhibitors, such as maraviroc, that work by blocking the CCR5 receptor on host cells. By occupying the receptor site, these drugs prevent R5 strains of HIV from binding and entering cells, halting viral replication.
The understanding derived from this mutation has also spurred advancements in gene therapy research aimed at achieving similar resistance in HIV-infected individuals. HIV-positive individuals have undergone bone marrow transplants from donors homozygous for the CCR5-delta 32 mutation. These procedures have led to functional cures in some instances, as the transplanted immune cells, lacking functional CCR5 receptors, are resistant to HIV infection. This approach offers a proof-of-concept for eradicating the virus by modifying the host’s susceptibility. The CCR5-delta 32 mutation primarily offers protection against R5 HIV strains. It does not provide resistance against X4 HIV strains, which use a different co-receptor called CXCR4 for cellular entry.