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J. Biol. Chem., Vol. 282, Issue 6, 3539-3546, February 9, 2007

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Distinct Patterns of Cytokine Regulation of APOBEC3G Expression and Activity in Primary Lymphocytes, Macrophages, and Dendritic Cells^*

Kim S. Stopak^¶1, Ya-Lin Chiu, Jerry Kropp, Robert M. Grant^||, and Warner C. Greene^¶||2

From the Gladstone Institute of Virology and Immunology and the Departments of Physiology, ^||Medicine, and ^¶Microbiology & Immunology, University of California, San Francisco, California 94158

Human APOBEC3G (A3G), a deoxycytidine deaminase, is a broadly acting antiretroviral factor expressed in a variety of cells. Mitogen activation of CD4 T cells enhances A3G expression and leads to recruitment of low molecular mass (LMM) A3G, which functions as a post-entry human immunodeficiency virus (HIV) restriction factor, into enzymatically inactive, high molecular mass (HMM) RNA-protein complexes that include Staufen RNA-transporting granules. We now report that interleukin-2 (IL-2), IL-15 and, to a lesser extent, IL-7 enhance the expression of A3G in peripheral blood lymphocytes and that this effect is blocked by inhibitors of the JAK and MAPK signaling pathways. In mixed cultures of CD4+ T cells containing either HMM or LMM A3G, HIV preferentially infected cells containing HMM A3G. A3G shifted into a HMM complex when IL-2, -7, or -15 was added to resting T cells, likely explaining how cytokine treatment renders resting CD4+ T cells permissive to HIV infection. Similarly, poly(I:C)/tumor necrosis factor--induced maturation of dendritic cells was associated with a sharp increase in A3G expression; however, this induction led to the accumulation of LMM A3G. Together, these results highlight the distinct inductive effects of select cytokines on A3G gene expression and A3G complex assembly that occur in natural cellular targets of HIV infection.

Received for publication, October 30, 2006 , and in revised form, November 16, 2006.

^* 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 Supported by Grant D05-GI-413 from the Universitywide AIDS Research Program.

² Supported by Grants PO1 HD40543 and RO1 AI065329 from the National Institutes of Health. To whom correspondence should be addressed: Gladstone Inst. of Virology and Immunology, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-4805; Fax: 415-355-0153; E-mail: wgreene{at}gladstone.ucsf.edu.

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