Host cyclophilin A (CypA) is essential for the replication of the human immunodeficiency virus type 1 (HIV- I) and thus represents an attractive target for the elaboration of new anti-viral therapeutic agents to combat AIDS pathogenesis. Despite intense interest in the involvement of CypA in HIV- I replication, its precise role in the virus life cycle has yet to be elucidated. Our recent work suggests that CypA is exposed at the viral surface and is necessary for the initial step in HIV- I infection - the virus attachment to target cells. We demonstrated that CypA-deficient viruses do not replicate because they fail to attach to target cells. We showed that CypA is exposed at the viral membrane and mediates HIV- I attachment. We identified heparan suiphates (HS) as the exclusive cellular binding partner for CypA. Furthermore, we found that CypA binds directly to heparan via a domain rich in basic residues similar to known heparin-binding motifs. Finally, we showed that this interaction between exposed CypA and cell surface heparans represents the initial step of HIV- I attachment and is a necessary precursor to gp12O-binding to CD4. Our objective is to further understand the precise mechanistic role of CypA in the HIV-l life cycle in order to develop novel anti-HIV-l therapies. We propose to pursue the following aims: 1) to identify and characterize cell surface heparan sulfate proteoglycans necessary for CypA-mediated HIV- I attachment to target cells; 2) to define the events that control both the release of CypA from Gag and its relocation to the viral surface; and 3) to determine the direct participation of exposed CypA and/or other virus-associated proteins in HIV- I attachment.
