Host resistance to HIV-1

HIV-1 infects immune cells through a multistep process. Viral entry begins with binding of the HIV envelope protein to the CD4 receptor on T lymphocytes and other immune cells. The virus then requires a co-receptor—most commonly CCR5—to complete membrane fusion and gain access to the host cell. Most newly transmitted HIV strains are CCR5-tropic (R5-tropic) and depend on this receptor for infection.

Some HIV variants may later evolve to use an alternative co-receptor, CXCR4, particularly during advanced stages of infection. Nevertheless, CCR5 remains the principal co-receptor involved in the initial establishment of HIV infection.

The prevalence of CCR5-Δ32 varies considerably among populations. The mutation is most frequently observed in individuals of Northern European ancestry, whereas it is rare in African, East Asian, Middle Eastern, and many Indigenous populations. Homozygous individuals represent only a small fraction of the population, making identification of suitable stem cell donors challenging.

Because of this low frequency, targeted CCR5 genotyping can play an important role during donor selection for transplantation candidates living with HIV.

For most people, genetic testing for CCR5-Δ32 is not used to predict HIV risk, as behavioural, epidemiological, and clinical factors remain far more important determinants of HIV acquisition. However, CCR5 testing has a highly specialised and clinically meaningful role in transplantation medicine.

In HIV-positive patients requiring allogeneic stem cell transplantation for conditions such as:

• Acute myeloid leukemia (AML)
• Certain lymphomas

The identification of a CCR5-Δ32 homozygous donor may offer a unique opportunity to replace the patient’s HIV-susceptible immune system with donor-derived immune cells that are resistant to CCR5-tropic HIV infection.

Following successful engraftment, donor-derived immune cells lacking functional CCR5 receptors may substantially reduce the ability of residual HIV to infect newly formed immune cells. Together with conditioning regimens and immune-mediated elimination of infected host cells, this strategy has led to a small number of cases of long-term HIV remission worldwide.

The clinical importance of CCR5 testing was first demonstrated in the case of Timothy Ray Brown, known worldwide as the Berlin Patient. Brown was living with HIV and developed acute myeloid leukemia. Physicians at Charité – Universitätsmedizin Berlin deliberately searched for an HLA-matched stem cell donor who was homozygous for the CCR5-Δ32 mutation.

After undergoing allogeneic stem cell transplantation, Brown discontinued antiretroviral therapy and remarkably showed no evidence of viral rebound. Long-term follow-up studies confirmed sustained HIV remission, making him the first individual widely recognised as having been cured of HIV.

This landmark case provided compelling evidence that CCR5 plays a central role in maintaining HIV infection and established a scientific foundation for future curative approaches targeting CCR5.

Subsequent cases, including the London Patient and additional transplant recipients, have reinforced the concept that CCR5-deficient donor cells can contribute to durable HIV remission under carefully selected clinical circumstances.

The discovery of CCR5-mediated HIV resistance has influenced HIV treatment strategies more broadly. It directly contributed to the development of CCR5 antagonists, such as maraviroc, which block CCR5-mediated viral entry into target cells. These therapies require confirmation that the patient’s virus is CCR5-tropic before treatment initiation.

Furthermore, modern gene-editing strategies are seeking to replicate the protective effect of CCR5-Δ32 by disrupting CCR5 expression in a patient’s own immune cells. Although these approaches remain under investigation, they are inspired by the biological principle first demonstrated by naturally resistant CCR5-Δ32 carriers and later validated through the Berlin Patient.

While CCR5-Δ32 remains the most impactful host genetic factor identified to date, several additional variants have been associated with HIV control and disease progression. These include:

• CCR2 p.Val64Ile (CCR2-64I)
• CXCL12/SDF1 3′A
• Protective HLA alleles such as HLA-B57 and HLA-B27

However, their effects are generally smaller and less consistent than those observed for CCR5-Δ32. Consequently, they are not routinely used in donor selection or HIV resistance assessment.

The CCR5-Δ32 mutation represents the most clinically significant genetic determinant of natural resistance to HIV-1. By preventing normal CCR5-mediated viral entry, the mutation provides strong protection against infection by CCR5-tropic HIV strains. While routine CCR5 screening has limited value in predicting HIV susceptibility, CCR5 genotyping plays an important role in the selection of stem cell donors for HIV-positive patients requiring transplantation.

The success of the Berlin Patient established a landmark proof of concept that transplantation with CCR5-Δ32 homozygous donor cells can contribute to long-term HIV remission and potentially cure. As a result, CCR5 testing remains a valuable component of specialised transplant programs and continues to inform the development of next-generation HIV therapies, including gene-editing and CCR5-targeted treatment strategies.

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