Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimer's disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of HIV(+) European and African American subjects, we found that the APOE epsilon 4/epsilon 4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE epsilon 3/epsilon 3 genotype. However, an association between the epsilon 4/epsilon 4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimer's disease, was not detected. Consistent with the genotype-phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HlVfusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an apoE3-like molecule to treat Alzheimer's disease might also have clinical applicability in HIV disease.