Cyclosporine Blocks Incorporation of HIV-1 Envelope Glycoprotein into Virions

Abstract

Cyclosporine (CsA) decreases HIV-1 infectivity by blocking HIV-1 capsid (CA) interaction with target cell cyclophilin A (CypA). Yet, HIV-1 virions produced in the presence of CsA also exhibit decreased infectivity that was previously shown to be independent of the well-characterized HIV-1 CA-CypA interaction. Here, we demonstrate that CsA decreases gp120 and gp41 incorporation into HIV-1 virions and that the fusion of these virions with susceptible target cells is impaired. This effect was not observed with HIV-1 virions pseudotyped with the vesicular stomatitis virus glycoprotein or with the amphotropic envelope protein of murine leukemia virus. It was independent of calcineurin signaling, the endoplasmic reticulum luminal protein cyclophilin B, and the long cytoplasmic tail of gp41. Thus, cyclosporine blocks HIV-1 infectivity via two independent mechanisms, the first involving HIV-1 CA in target cells and the second involving HIV-1 Env in producer cells.

CD8 + Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy

“…However, these clinical instances are different from CD8 depletion as they may involve depletion of all T cells, as in the case of aggressive chemotherapy regimens, or markedly reduce CD4 + T cell activation, as in the case of several commonly used immunomodulators. For instance, cyclosporine and Tacrolimus (FK506) are calcineurin inhibitors that inhibit NFAT-mediated CD4 + T cell activation and have a well-characterized direct antiviral effect via inhibition of cyclophilin (Bartz et al, 1995; Braaten et al, 1996; Emmel et al, 1989; Franke and Luban, 1996; Franke et al, 1994; Schaller et al, 2011; Sokolskaja et al, 2010; Streblow et al, 1998). Similarly, mycophenolate induces apoptosis of activated CD4 + T lymphocytes and, in a time-dependent manner and inhibits HIV replication (Chapuis et al, 2000; Margolis et al, 2002) while rapamycin (sirolimus) decreases LTR-driven transcription of HIV (Roy et al, 2002) and reduces expression of the main HIV co-receptor CCR5 (Gilliam et al, 2007).…”

Mitochondrial Glutaminase Release Contributes to Glutamate-Mediated Neurotoxicity during Human Immunodeficiency Virus-1 Infection

“…Cyclosporine (CsA) is a very potent immunosuppressive agent that has an apparent selective action on T lymphocyte-dependent immune responses and has been used extensively in clinical transplantation to prevent solid organ allograft rejection and graft-versus-host disease (GVHD) (Borel 1976; Borel et al 1976; Hess et al 1986). In addition, hyperactivation of the immune system has emerged as an important clinical marker of HIV disease progression to AIDS, and CsA, an immune response suppressor, also blocks HIV-1 infectivity via two independent mechanisms, the first involving HIV-1 capsid (CA) interaction with target cell cyclophilin A (CypA) and the second involving HIV-1 envelope glycoprotein (Env) in producer cells (Argyropoulos and Mouzaki 2006; Sokolskaja et al 2010). Thus the treatment with CsA in macrophages during HIV-1 infection attenuates the HIV-1 replication (Fig.…”

Cyclophilin A: A Key Factor in Virus Replication and Potential Target for Anti-viral Therapy

“…CsA and Cs can also disrupt CA-CypA interaction in HeLa cells, (Hatziioannou et al, 2005;Ylinen at al., 2009). All these reports demonstrate that targeting cellular CypA is quite helpful to overcome HIV-1 CA-mediated infections (Sokolskaja et al, 2010). Cyclosporine A and other nonimmunosuppressive CypA inhibitors (CsA analogues) such as Debio 025, NIM811, and SCY-635 disrupt the HCV-CypA complex and block HCV replication by defusing the enzymatic functions of CypA both in vitro (Mathy et al, 2008;Chatterji et al, 2009;Kaul et al, 2009;Lee, 2013) and in vivo (Flisiak et al, 2009;Hopkins et al, 2009), as CsA can abrogate the CypA stimulated domain II RNA binding activity (Foster et al, 2011).…”

“…CsA also decreases gp120 and gp41 incorporation into HIV-1 virions, which weakens the fusion of these virions to susceptible target cells (Sokolskaja et al, 2010). CsA and Cs can also disrupt CA-CypA interaction in HeLa cells, (Hatziioannou et al, 2005;Ylinen at al., 2009).…”

“…In the last few decades, substantial studies have focused on the development of CypA inhibitors since CypA is associated with the regulation of disease and viral infections (Sokolskaja et al, 2010;Yang et al, 2015). The development of host CypA inhibitors has been regarded as an alternative approach for viral infection because it is selective, effective and safe (Yang et al, 2015).…”