The HIV Type 1 Coreceptor CCR5 and Its Role in Viral Transmission and Disease Progression

The purified CD4 ⁺ lymphocytes of a group of highly exposed but HIV-1-uninfected individuals were deter-mined to be less susceptible to infection with multiple non-syncytium-inducing (NSI) primary isolates of HIV-1 than were CD4 ⁺ lymphocytes from nonexposed control individuals. This relative resistance to HIV-1 in-fection did not extend to T cell line-adapted or syncytium-inducing (SI) primary viral isolates, was restrictedby the envelope glycoprotein, and was associated with an increased production of the C-C chemokinesRANTES, MIP-1α, and MIP-1β. The block to replication in CD4 ⁺ lymphocytes from two exposed-uninfectedsubjects was at the point of entry, as was the block imposed by the recombinant C-C chemokines RANTES, MIP-1α, and MIP-1β. Resistance to infection and the high production of β chemokines were characteristicof every CD4 ⁺ lymphocyte clone from the exposed-uninfected subjects. We have now identified the mecha-nism underlying this in vitro and in vivo resistance to infection: These individuals have inherited a homozy-gous 32-bp nucleotide deletion (Δ32) within the gene encoding the coreceptor for primary NSI isolates of HIV-1 (CCR5). This deletion encodes a severely truncated and unstable protein that is not expressed on the cellsurface. This allele is common in the Caucasian population, with a frequency of 0.0808, but is not found inpeople of African or Asian ancestry. To determine its role in HIV-1 transmission and disease progression, weanalyzed the CCR5 genotype of 1252 homosexual men enrolled in the Chicago component of the MulticenterAIDS Cohort Study (MACS). No infected participant was found to be homozygous for the Δ32 allele whereas3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective roleof this genotype against sexual acquisition of HIV-1. No evidence was found to suggest that heterozygotes wereprotected against HIV-1 infection, but a limited protective role against disease progression was noted. The Δ32 allele of CCR5 is therefore an important host factor in HIV-1 transmission and pathogenesis.