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Journal of Virology, September 2005, p. 11742-11751, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11742-11751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Rab9 GTPase Is Required for Replication of Human Immunodeficiency Virus Type 1, Filoviruses, and Measles Virus

James L. Murray,1,§ Manos Mavrakis,2 Natalie J. McDonald,3 Mamadi Yilla,3 Jinsong Sheng,4,5 William J. Bellini,3 Lijun Zhao,6 Joseph M. Le Doux,7 Michael W. Shaw,3 Chi-Cheng Luo,1 Jennifer Lippincott-Schwartz,2 Anthony Sanchez,3,{dagger} Donald H. Rubin,4,5,8,{dagger} and Thomas W. Hodge1,9,{dagger}*

National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,1 Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892,2 National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333,3 Departments of Medicine, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee 37232,4 Avatar BioSci, Inc., Nashville, Tennessee,5 Department of Infectious Diseases, University of Georgia, Athens, Georgia 30602,6 Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, Georgia 30332,7 Department of Research Medicine, VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212,8 Hudson-Alpha Institute for Biotechnology, Huntsville, Alabama9

Received 17 September 2004/ Accepted 10 June 2005

Rab proteins and their effectors facilitate vesicular transport by tethering donor vesicles to their respective target membranes. By using gene trap insertional mutagenesis, we identified Rab9, which mediates late-endosome-to-trans-Golgi-network trafficking, among several candidate host genes whose disruption allowed the survival of Marburg virus-infected cells, suggesting that Rab9 is utilized in Marburg replication. Although Rab9 has not been implicated in human immunodeficiency virus (HIV) replication, previous reports suggested that the late endosome is an initiation site for HIV assembly and that TIP47-dependent trafficking out of the late endosome to the trans-Golgi network facilitates the sorting of HIV Env into virions budding at the plasma membrane. We examined the role of Rab9 in the life cycles of HIV and several unrelated viruses, using small interfering RNA (siRNA) to silence Rab9 expression before viral infection. Silencing Rab9 expression dramatically inhibited HIV replication, as did silencing the host genes encoding TIP47, p40, and PIKfyve, which also facilitate late-endosome-to-trans-Golgi vesicular transport. In addition, silencing studies revealed that HIV replication was dependent on the expression of Rab11A, which mediates trans-Golgi-to-plasma-membrane transport, and that increased HIV Gag was sequestered in a CD63+ endocytic compartment in a cell line stably expressing Rab9 siRNA. Replication of the enveloped Ebola, Marburg, and measles viruses was inhibited with Rab9 siRNA, although the nonenveloped reovirus was insensitive to Rab9 silencing. These results suggest that Rab9 is an important cellular target for inhibiting diverse viruses and help to define a late-endosome-to-plasma-membrane vesicular transport pathway important in viral assembly.

* Corresponding author. Present address: University of Georgia, College of Veterinary Medicine, Department of Infectious Diseases, 220 Riverbend Rd., Room 112, Athens, GA 30602. Phone: (706) 542-9882. Fax: (706) 583-0176. E-mail: thodge{at}vet.uga.edu.

§ Present address: Department of Infectious Diseases, University of Georgia, Athens, GA 30602.

{dagger} These authors contributed equally to this work.

Journal of Virology, September 2005, p. 11742-11751, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11742-11751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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