Host cyclophilin A (CypA) is essential for the replication of the human immunodeficiency virus type 1 (HIV-1) and thus represents an attractive target for new anti-viral therapies to combat AIDS pathogenesis. Despite intense interest in the involvement of CypA in HIV -replication, its precise role in the virus life cycle has yet to be elucidated. The investigators previous work suggests that CypA is exposed at the viral surface and is necessary for the initial step in HIV-1 infection - the virus attachment to target cells. They demonstrated that CypA-deficient viruses do not replicate because they fail to attach to target cells and showed that CypA is exposed at the viral membrane and mediates HIV-1 attachment. They have identified heparan sulphates (HS) as the exclusive cellular binding partner for CypA. Furthermore, they have found that CypA binds directly to heparan via a domain rich in basic residues similar to known heparin-binding motifs and have shown that this interaction between exposed CypA and cell surface heparans represents the initial step of HIV-1 attachment and is a necessary precursor to gpl20 binding to CD4. The goal of this proposal is to further understand the precise mechanistic role of CypA in the HIV-1 life cycle in order to develop novel anti-HIV-1 therapies. This proposal has three specific aims. First, they will identify and characterize the CypA-binding sites on the surface of target cells and determine their role in HIV- 1 attachment. Secondly, they will define the events that control both the release of CypA from Gag and its relocation to the viral surface. And third, they will determine whether CypA mediates HIV-1 attachment directly and/or whether other incorporates proteins participate in this process.
| Lim, Precious J; Gallay, Philippe A (2014) Hepatitis C NS5A protein: two drug targets within the same protein with different mechanisms of resistance. Curr Opin Virol 8:30-7 |
