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Increased frequency of CCR-5 Δ32 heterozygotes among long-term non-progressors with HIV-1 infection

1997; Lippincott Williams & Wilkins; Volume: 11; Issue: 15 Linguagem: Inglês

10.1097/00002030-199715000-00007

1473-5571

Graeme J. Stewart, Lesley J. Ashton, Robyn A. Biti, Rosemary Ffrench, Bruce Bennetts, Nicole R. Newcombe, Elizabeth M. Benson, Andrew Carr, David A. Cooper, John M. Kaldor,

HIV/AIDS drug development and treatment

Background: The β-chemokine receptor CCR-5 is used as a coreceptor by macrophage-tropic strains of HIV-1 to gain entry into CD4+ cells. Objective: To determine the effect of a common 32 base-pair deletion mutation in the CCR-5 gene (CCR-5 Δ32) on progression of HIV infection to AIDS, and to assess the level of heterozygosity for this mutation in a well-defined group of long-term non-progressors (LTNP). Participants: Sixty-four HIV-1-infected LTNP (CD4+ T lymphocyte count > 500 × 106/l after 8 years) were compared with 95 individuals infected within a similar period (1983–1986) but who had rapidly progressed to AIDS and death, and with a further 120 HIV-positive individuals with CD4+ counts < 500 × 106/l. Methods: The presence of the CCR-5 Δ32 mutation was assessed using polymerase chain reaction with primers spanning the 32 base-pair deletion. CD4+ and CD8+ counts, plasma HIV-1 RNA, p24 antigen and β2-microglobulin levels in LTNP carrying the CCR-5 Δ32 mutation were compared with LTNP lacking the mutation. Results: A marked increase in the frequency of CCR-5 Δ32 heterozygosity was found among LTNP (35.9%) compared with rapid progressors (12.6%; P = 0.0005) and patients selected on the basis of a CD4+ T-cell count < 500 × 106/l (12.5%; P = 0.0004). LTNP heterozygous for CCR-5 Δ32 had a significantly higher CD8+ T-cell count than those without the mutation (1218 versus 972 × 106/l; P = 0.044). No significant correlation was observed between heterozygosity and CD4 count, viral load, p24 antigen or β2-microglobulin within the LTNP group. Conclusions: This study provides the strongest evidence to date for the importance of a single copy of the CCR-5 Δ32 mutation in long-term non-progression of HIV infection, which may involve, in part, CD8+ T lymphocytes. To determine the effect of a common 32 base-pair deletion mutation in the CCR-5gene (CCR-5 Δ32) on progression of HIV infection to AIDS, and to assess the level of heterozygosity for this mutation in a well-defined group of long-term non-progressors (LTNP).