Functional deletion of the CCR5 receptor by intracellular immunization produces cells that are refractory to CCR5-dependent HIV-1 infection and cell fusion

Studies of naturally occurring polymorphisms of the CCR5 gene have shown th at deletion of the functional receptor or reduced expression of the gene ca n have beneficial effects in preventing HIV-1 infection or delaying disease . Because these polymorphisms are found in otherwise healthy people, strate gies that aim to prevent or limit expression of CCR5 should be beneficial i n the treatment of HIV-1 disease. To test this approach we have developed a CCR5-specific single-chain antibody that was expressed intracellularly and retained in the endoplasmic reticulum. This CCR5-intrabody efficiently blo cked surface expression of human and rhesus CCR5 and thus prevented cellula r interactions with CCR5-dependent HIV-1 and simian immunodeficiency virus envelope glycoprotein, Intrabody-expressing cells were shown to be highly r efractory to challenge with R5 HIV-1 viruses or infected cells. These resul ts suggest that gene therapy approaches that deliver this intracellular ant ibody could be of benefit to infected individuals, Because the antibody rea cts with a conserved primate epitope on CCR5 this strategy can be tested in nonhuman lentivirus models of HIV-1 disease.