title: Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin.
abstract: The capacity of the immunomodulatory drug rapamycin (RAPA) to inhibit replication of the CCR5 strain of human immunodeficiency virus (HIV) in vitro prompted us to test its effects in a murine preclinical model of HIV infection. RAPA (0.6 or 6 mg/kg body weight) or its vehicle were administered daily, per os, to SCID mice reconstituted with human peripheral blood leucocytes (hu-PBL) starting 2 days before the intraperitoneal challenge with the R5 tropic SF162 strain of HIV-1 (1000 50% tissue culture infective dose/ml). Relative to hu-PBL-SCID mice that received no treatment, HIV-infected hu-PBL-SCID mice treated with the vehicle control for 3 weeks exhibited a severe depletion of CD4(+) cells (90%), an increase in CD8(+) cells and an inversion of the CD4(+)/CD8(+) cell ratio. In contrast, treatment of HIV-infected mice with RAPA prevented a decrease in CD4(+) cells and the increase of CD8(+) cells, thereby preserving the original CD4(+):CD8(+) cell ratio. Viral infection also resulted in the detection of HIV-DNA within peritoneal cells and spleen, and lymph node tissues of the vehicle-treated mice within 3 weeks of the viral challenge. In contrast, treatment with RAPA decreased cellular provirus integration and reduced HIV-RNA levels in the blood. Furthermore, in co-cultivation assays, spleens from RAPA-treated mice exhibited a reduced capacity for infecting allogeneic T cells which was dose-dependent. These data show that RAPA possesses powerful anti-viral activity against R5 strains of HIV in vivo and support the use of additional studies to evaluate the potential application of this drug in the management of HIV patients.
authors.affiliation: Department of Biomedical Sciences, Section of Clinical Pathology and Molecular Oncology, University of Catania, Catania, Italy. ferdinic@unict.it
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.forename: C
authors.initials: C
authors.lastname: Lapenta
authors.forename: C
authors.initials: C
authors.lastname: Lamenta
authors.forename: S
authors.initials: S
authors.lastname: Donati
authors.forename: M
authors.initials: M
authors.lastname: Spada
authors.forename: A
authors.initials: A
authors.lastname: Ranazzi
authors.forename: B
authors.initials: B
authors.lastname: Cacopardo
authors.forename: K
authors.initials: K
authors.lastname: Mangano
authors.forename: F
authors.initials: F
authors.lastname: Belardelli
authors.forename: C
authors.initials: C
authors.lastname: Perno
authors.forename: S
authors.initials: S
authors.lastname: Aquaro
mesh_terms: D000818:Animals; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D004279:DNA, Viral / Q000032:analysis; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D023421:Models, Animal; D010537:Peritoneum / Q000821:virology; D012367:RNA, Viral / Q000097:blood; D020123:Sirolimus / Q000627:therapeutic use*; D013154:Spleen / Q000821:virology
chemical_list: D004279:DNA, Viral; D007166:Immunosuppressive Agents; D012367:RNA, Viral; D020123:Sirolimus