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Journal of Virology, January 2002, p. 569-581, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.569-581.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Soluble Factor(s) Secreted from CD8+ T Lymphocytes Inhibits Human Immunodeficiency Virus Type 1 Replication through STAT1 Activation

Theresa Li-Yun Chang,1 Arevik Mosoian,2 Richard Pine,3 Mary E. Klotman,2,4* and John P. Moore1*

Weill Medical College of Cornell University,1 Departments of Medicine,2 Mount Sinai School of Medicine, Public Health Research Institute, New York, New York,3 Microbiology4

Received 14 May 2001/ Accepted 9 October 2001

CD8+ T lymphocytes can suppress human immunodeficiency virus type 1 (HIV-1) replication by secreting a soluble factor(s) known as CD8+ T-lymphocyte antiviral factor (CAF). One site of CAF action is inhibition of HIV-1 RNA transcription, particularly at the step of long terminal repeat (LTR)-driven gene expression. However, the mechanism by which CAF inhibits LTR activation is not understood. Here, we show that conditioned media from several herpesvirus saimari-transformed CD8+ T lymphocytes inhibit, in a time- and dose-dependent manner, the replication of HIV-1 pseudotype viruses that express the envelope glycoproteins of vesicular stomatitis virus (HIV-1VSV). The same conditioned media also inhibit phorbol myristate acetate-induced activation of the HIV-1 LTR and activate the signal transducer and activator of transcription 1 (STAT1) protein. We have obtained direct evidence that STAT1 is necessary for CAF-mediated inhibition of LTR activation and HIV-1 replication. Thus, the inhibitory effect of CAF on HIV-1VSV replication was abolished in STAT1-deficient cells. Moreover, CAF inhibition of LTR activation was diminished both in STAT1-deficient cells and in cells expressing a STAT1 dominant negative mutant but was restored when STAT1 was reintroduced into the STAT1-deficient cells. We also observed that CAF induced the expression of interferon regulatory factor 1 (IRF-1), and that IRF-1 gene induction was STAT-1 dependent. Taken together, our results suggest that CAF activates STAT1, leading to IRF-1 induction and inhibition of gene expression regulated by the HIV-1 LTR. This study therefore helps clarify one molecular mechanism of host defense against HIV-1.

* Mailing address for Mary E. Klotman: Box 1090, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10024.

* Corresponding author. Mailing address for John P. Moore: Weill Medical College of Cornell University, Department of Microbiology and Immunology, 1300 York Ave., W-805, New York, NY 10021. Phone: (212) 746-4462. Fax: (212) 746-8340. E-mail: jpm2003{at}mail.med.cornell.edu.

Journal of Virology, January 2002, p. 569-581, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.569-581.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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