Functional association of cyclophilin A with HIV-1 virions

Abstract

Cyclophilins are a family of proteins that bind the immunosuppressant cyclosporin A, possess peptidyl-prolyl cis-trans isomerase activity, and assist in the folding of proteins. Human cyclophilins A and B are host cell proteins that bind specifically to the HIV-1 Gag polyprotein p55gag in vitro. Here we report that viral particles formed by p55gag, in contrast to particles formed by the Gag polyproteins of other retroviruses, contain significant amounts of cyclophilin A. Sequences in the capsid domain of p55gag are both required and sufficient for the virion-association of cyclophilin A. The association of cyclophilin A with HIV-1 virions was inhibited in a dose-dependent manner by cyclosporin A as well as by SDZ NIM811 ([Melle-4]cyclosporin), a non-immunosuppressive analogue of cyclosporin A. Drug-induced reductions in virion-associated cyclophilin A levels were accompanied by reductions in virion infectivity, indicating that the association is functionally relevant. Moreover, SDZ NIM811 inhibited the replication of HIV-1 but was inactive against SIVMAC, a primate immunodeficiency virus closely related to HIV-1, which does not incorporate cyclophilin A.

Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

“…The degree of this enhancement was inversely related to the basal level of infectivity of the mutant virus in the absence of CspA treatment. CspA treatment of the target cells did not influence the infectivity of the HIV(SCA) control virus in all three cell lines, as expected, because the virus is unrestricted in monkey cells and the SIV mac CA protein does not bind CypA (7,43). These results confirm that CypA-CA interactions can influence the degree of HIV-1 restriction in monkey cells and demonstrate that the enhancing effect of CspA on HIV-1 infectivity in these cells is dependent upon the ability of restriction factors to bind and negatively modulate HIV-1 CA.…”

“…The Gag precursor protein is synthesized as a 55-kDa polyprotein which is myristylated and subsequently localized to the plasma membrane, where it recruits other viral components that are important for infectivity (26). In addition, a number of host factors appropriated by the virus (Tsg101, ubiquitin, ERK2, cyclophilin A [CypA], and topoisomerase I) interact specifically with elements of the HIV-1 Gag polyprotein and contribute to assembly, release, and subsequent postentry events in the viral life cycle (11,19,24,27,(41)(42)(43)47). After the release of viral particles, virions undergo a maturation process during which the viral protease cleaves the HIV-1 Gag polyprotein into four mature proteins: p17 matrix (MA), p24 capsid (CA), p7 nucleocapsid (NC), and p6 (20).…”

Extended binding sites of cyclophilin as revealed by the interaction with HIV‐1 Gag polyprotein derived oligopeptides

“…CsA enables complex dissociation by its high affinity to cyclophilins. Obviously, the antiviral effect of CsA has to be due to a pathway distinct from irnmunosuppression because CsA derivatives with negligible immunosuppressive activity but high affinities for the active site of Cypl8 retain potent anti-HIV activity [6][7][8][9][10][11][12].…”

“…Similarly, protein variants P217A and P231A retain Cypl8 binding. Analogously, small in-frame deletions in the capsid domain of Pr55 gag drastically decrease Cypl8 packaging into viral particles [7].…”

CD147 stimulates HIV-1 infection in a signal-independent fashion

“…This notion has been supported in a number of subsequent publications [14][15][16]. CypA is incorporated into HIV-1 particles during virus morphogenesis through a specific interaction with the CA domain of the Gag precursor polyprotein [17][18][19][20] and plays an essential role in the early steps of the HIV-1 life cycle [21;22]. Biochemical studies indicate that CypA is exposed on the viral surface [23;24] and thus may signal through CD147.…”