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J. Biol. Chem., Vol. 281, Issue 2, 1241-1250, January 13, 2006

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Altered HIV-1 Gag Protein Interactions with Cyclophilin A (CypA) on the Acquisition of H219Q and H219P Substitutions in the CypA Binding Loop^*

Hiroyuki Gatanaga1, Debananda Das, Yasuhiro Suzuki, Damaris D. Yeh, Khaja A. Hussain¶, Arun K. Ghosh¶, and Hiroaki Mitsuya2

From the Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, theDepartments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860, Japan, and the^¶Department of Chemistry, University of Illinois, Chicago, Illinois 60607

HIV-1 Gag protein interaction with cyclophilin A (CypA) is critical for viral fitness. Among the amino acid substitutions identified in Gag noncleavage sites in HIV-1 variants resistant to protease inhibitors, H219Q (Gatanaga, H., Suzuki, Y., Tsang, H., Yoshimura, K., Kavlick, M. F., Nagashima, K., Gorelick, R. J., Mardy, S., Tang, C., Summers, M. F., and Mitsuya, H. (2002) J. Biol. Chem. 277, 5952-5961) and H219P substitutions in the viral CypA binding loop confer the greatest replication advantage to HIV-1. These substitutions represent polymorphic amino acid residues. We found that the replication advantage conferred by these substitutions was far greater in CypA-rich MT-2 and H9 cells than in Jurkat cells and peripheral blood mononuclear cells (PBM), both of which contained less CypA. High intracellular CypA content in H9 and MT-2 cells, resulting in excessive CypA levels in virions, limited wild-type HIV-1 (HIV-1_WT) replication and H219Q introduction into HIV-1 (HIV-1_H219Q), reduced CypA incorporation of HIV-1, and potentiated viral replication. H219Q introduction also restored the otherwise compromised replication of HIV-1_P222A in PBM, although the CypA content in HIV-1_H219Q/P222A was comparable with that in HIV-1_P222A, suggesting that H219Q affected the conformation of the CypA-binding motif, rendering HIV-1 replicative in a low CypA environment. Structural modeling analyses revealed that although hydrogen bonds are lost with H219Q and H219P substitutions, no significant distortion of the CypA binding loop of Gag occurred. The loop conformation of HIV-1_P222A was found highly distorted, although H219Q introduction to HIV-1 restored the conformation of the loop close to that of HIV-1 _P222A. The present data suggested that the effect of CypA on HIV-1 replicative _WT ability is bimodal (both high and low CypA content limits HIV-1 replication), that the conformation of the CypA binding region of Gag is important for viral fitness, and that the function of CypA is to maintain the conformation.

Received for publication, May 31, 2005 , and in revised form, November 7, 2005.

^* This work was supported in part by the Intramural Research Program of the NCI, Center for Cancer Research, National Institutes of Health, in part by National Institutes of Health Grant GM 53386 (to A. K. G.), in part by Research for the Future Program Grant JSPS-RFTF 97L00705 from the Japan Society for the Promotion of Science (to H. M.), a grant-in-aid for scientific research (priority areas) from the Ministry of Education (to H. M.), a grant from the Culture, Sports, Sciences, and Technology of Japan (Monbu-Kagakusho) (to H. M.), and a grant for the promotion of AIDS research from the Ministry of Health Welfare and Labor of Japan (Kosei-Rohdosho) (to H. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: AIDS Clinical Center, International Medical Center of Japan, Tokyo162-8655, Japan.

² To whom correspondence should be addressed: Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bldg. 10, Rm. 5A11, 9000 Rockville Pike, Bethesda, MD 20892. Tel.: 301-496-9238; Fax: 301-402-0709; E-mail: hmitsuya{at}helix.nih.gov.

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