Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the <i>CKR5</i> Structural Gene

TLDR

CKR5 is a secondary receptor for certain HIV‑1 strains and a 32‑bp deletion allele (CKR5Δ32) occurs at ~10 % frequency in Caucasians. The authors examined 1,955 participants from six AIDS cohorts, finding that CKR5Δ32 homozygotes were present only among HIV‑negative exposed individuals and absent in infected patients. The deletion acts as a recessive restriction gene against HIV‑1 infection and, in heterozygotes, confers a dominant delay in AIDS progression, as evidenced by higher heterozygote frequency in long‑term survivors and slower disease progression in these individuals.

Abstract

The chemokine receptor 5 (CKR5) protein serves as a secondary receptor on CD4 + T lymphocytes for certain strains of human immunodeficiency virus-type 1 (HIV-1). The CKR5 structural gene was mapped to human chromosome 3p21, and a 32-base pair deletion allele ( CKR5Δ32 ) was identified that is present at a frequency of ∼0.10 in the Caucasian population of the United States. An examination of 1955 patients included among six well-characterized acquired immunodeficiency syndrome (AIDS) cohort studies revealed that 17 deletion homozygotes occurred exclusively among 612 exposed HIV-1 antibody-negative individuals (2.8 percent) and not at all in 1343 HIV-1-infected individuals. The frequency of CKR5 deletion heterozygotes was significantly elevated in groups of individuals that had survived HIV-1 infection for more than 10 years, and, in some risk groups, twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes than in individuals homozygous for the normal CKR5 gene. The CKR5Δ32 deletion may act as a recessive restriction gene against HIV-1 infection and may exert a dominant phenotype of delaying progression to AIDS among infected individuals.