Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin

• Published in: Clinical and experimental immunology Vol. 155; no. 1; pp. 28 - 34
• Main Authors: Nicoletti, F, Lamenta, C, Donati, S, Spada, M, Ranazzi, A, Cacopardo, B, Mangano, K, Belardelli, F, Perno, C, Aquaro, S
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.01.2009; Blackwell Publishing Ltd; Blackwell; Blackwell Science Inc
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD4/CD8; CD8-Positive T-Lymphocytes - immunology; Coculture Techniques; DNA, Viral - analysis; Fundamental and applied biological sciences. Psychology; HIV; HIV Infections - drug therapy; HIV-1; hu-PBL-SCID; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunosuppressive Agents - therapeutic use; immunotherapy; Infectious diseases; Lymph Nodes - virology; Medical sciences; Mice; Mice, SCID; Models, Animal; Peritoneum - virology; RAPA; RNA, Viral - blood; Sirolimus - therapeutic use; Spleen - virology; Translational Studies; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Animal model; CD4 T lymphocyte; Sirolimus; HIV-1 virus; Leukocyte; RAPA; Biochemistry; Blood; Macrocycle; Immunotherapy; T-Lymphocyte; Protein synthesis inhibitor; Inhibition; CD8 T lymphocyte; Human; Immunopathology; CD4/CD8; Retroviridae; Lactone; AIDS; Severe combined immunodeficient mouse; Immune deficiency; Lentivirus; Macrolide; Infection; Virus; Treatment; HIV; hu-PBL-SCID; Viral disease; Animal; Suppressive cell; Human immunodeficiency virus
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2008.03780.x

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.