Novel interfering bifunctional molecules against the CCR5 coreceptor are efficient inhibitors of HIV-1 infection.
CCR5 is the major coreceptor for the HIV-1 strains responsible for primary infection. Individuals homozygous for a 32-bp deletion in the CCR5 coding region are resistant to HIV-1 infection. Strategies to delete CCR5 functionally could thus be of substantial benefit in preventing HIV-1 infection or delaying disease. We evaluated new molecules for their ability to inhibit cell membrane CCR5 expression and to prevent HIV-1 infection. These inhibitors include several truncated forms of CCR5 that may act as negative transdominants, as well as bifunctional molecules resulting from the combination of a previously described anti-CCR5 ribozyme or a truncated CCR5 variant with an intracellular chemokine (RANTES-KDEL). These constructs efficiently blocked membrane CCR5 expression when cotransfected into HEK 293 cells. When expressed by retroviral transduction, some of these molecules significantly inhibited CCR5-dependent chemotaxis in the MCF-7 cell line and reduced CCR5 expression and HIV-1 infection in human T cells. Analysis of inhibitors with different efficiencies showed a strong linear correlation between CCR5 expression inhibition and prevention of HIV-1 infection. This study indicates the potential clinical application of several new CCR5 inhibitory molecules for HIV-1 gene therapy.
Luis Abad
José
J
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma Cantoblanco, E-28049, Madrid, Spain.
González
Manuel A
MA
del Real
Gustavo
G
Mira
Emilia
E
Mañes
Santos
S
Serrano
Fernando
F
Bernad
Antonio
A
D019380:Anti-HIV Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010455:Peptides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010455:Peptides