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Journal of Virology, November 2002, p. 11440-11446, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11440-11446.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of Endosomal/Lysosomal Degradation Increases the Infectivity of Human Immunodeficiency Virus

Brenda L. Fredericksen,1,{dagger} Bangdong L. Wei,1 Jian Yao,1 Tianci Luo,2 and J. Victor Garcia1*

Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390,1 Genetic Therapy, Inc., Gaithersburg, Maryland 208782

Received 11 March 2002/ Accepted 9 August 2002

Productive entry of human immunodeficiency virus type 1 (HIV-1) into a host cell is believed to proceed via fusion of the viral envelope with the host cell's plasma membrane. Interestingly, the majority of HIV-1 particles that bind to the cell surface are taken up by the host cell via endocytosis; however, this mode of internalization generally does not result in infection. Presumably, virus particles remain trapped in the endocytic pathway and are eventually degraded. Here, we demonstrate that treatment of cells with various pharmacological agents known to elevate the pH of endosomes and lysosomes allows HIV-1 to efficiently enter and infect the host cell. Pretreatment of cells with bafilomycin A1 results in up to a 50-fold increase in the infectivity of HIV-1SF2. Similarly, pretreatment of target cells with amantadine, concanamycin A, concanamycin B, chloroquine, and ammonium chloride resulted in increases in HIV-1 infectivity ranging between 2- and 15-fold. Analysis of receptor and coreceptor expression, HIV-long terminal repeat (LTR) transactivation, and transduction with amphotropic-pseudotyped murine leukemia virus (MLV)-based vectors suggests that the increase in infectivity is not artifactual. The increased infectivity under these conditions appears to be due to the ability of HIV-1 and MLV particles to enter via the endocytic pathway when spared from degradation in the late endosomes and lysosomes. These results could have significant implications for the administration of current and future lysosmotropic agents to patients with HIV disease.

* Corresponding author. Mailing address: Department of Internal Medicine, Division of Infectious Diseases, Y9.206, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9113. Phone: (214) 648-9970. Fax: (214) 648-0231. E-mail: victor.garcia{at}utsouthwestern.edu.

{dagger} Present address: Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9113.

Journal of Virology, November 2002, p. 11440-11446, Vol. 76, No. 22
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.22.11440-11446.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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