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

Abstract

SummaryThe 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.

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

“…Consistent with these activities, rapamycin effectively inhibited the replication of R5, but not X4, HIV in primary PBLs (11,13,15). Nicoletti et al have shown that rapamycin inhibits R5 HIV replication in a mouse model (41). In a recent human study, HIV-infected kidney transplant recipients treated with rapamycin had lower frequencies of lymphocytes containing HIV DNA than those treated with other immunosuppressive drugs, suggesting an anti-HIV effect of rapamycin (42).…”

mTOR as a multifunctional therapeutic target in HIV infection

“…Beclin-1 mRNA expression and autophagosomes were also reduced in HIV-1-infected cells [27,28]. The in vivo evidence indicating that the blockade of mTOR with rapamycin neither prevents CD4 + -T-cell decline in HIV-1-infected SCID mice [13] nor fails to influence their numbers in HIV-infected individuals receiving liver transplantation [14] seems to suggest that promotion of autophagy via mTOR blockade does not influence HIV-1-induced CD4 + -T-cell death in vivo.…”

“…In addition, rapamycin synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro [12]. Rapamycin also inhibits HIV-1 infection in human peripheral blood leukocyte reconstituted SCID mice [13], and a recent prospective trial of liver-transplanted HIV patients indicated significantly better control of HIV and hepatitis C virus replication in those receiving rapamycin monotherapy [14].…”

New Perspectives in HCV Therapy: Entry Inhibitors

“…It should be further noted that the antiviral action of alpha IFN has been linked alongside other effects to a decrease in the expression levels of SR-BI on the cell surface, thereby restricting virus attachment and entry into hepatocytes [154]. Likewise, drugs that downregulate expression of HCV receptors at the surface of hepatocytes may be used to block HCV cell entry, as this has already been demonstrated for other viruses like HIV [155]. However, given the physiological role of SR-BI in reverse cholesterol transport [156], agents interfering with its expression and/or function may have unpredictable effects for long term therapy in humans.…”