The Influence of <i>CCL3L1</i> Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility

TLDR

Segmental duplications in the human genome are enriched for immune genes, but their impact on host defense remains unclear. Lower CCL3L1 copy number, especially when combined with disease‑accelerating CCR5 genotypes, markedly increases HIV‑1/AIDS susceptibility, underscoring the gene’s central role in disease pathogenesis and genetic variability in immune responses.

Abstract

Segmental duplications in the human genome are selectively enriched for genes involved in immunity, although the phenotypic consequences for host defense are unknown. We show that there are significant interindividual and interpopulation differences in the copy number of a segmental duplication encompassing the gene encoding CCL3L1 (MIP-1alphaP), a potent human immunodeficiency virus-1 (HIV-1)-suppressive chemokine and ligand for the HIV coreceptor CCR5. Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) susceptibility. This susceptibility is even greater in individuals who also possess disease-accelerating CCR5 genotypes. This relationship between CCL3L1 dose and altered HIV/AIDS susceptibility points to a central role for CCL3L1 in HIV/AIDS pathogenesis and indicates that differences in the dose of immune response genes may constitute a genetic basis for variable responses to infectious diseases.