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J. Biol. Chem., Vol. 281, Issue 45, 34574-34591, November 10, 2006

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Regulation of CD4 Expression via Recycling by HRES-1/RAB4 Controls Susceptibility to HIV Infection^*

Gyorgy Nagy¹, Jeffrey Ward¹, Dick D. Mosser^¶, Agnes Koncz, Peter Gergely, Jr., Christina Stancato, Yueming Qian, David Fernandez, Brian Niland, Craig E. Grossman, Tiffany Telarico, Katalin Banki^||, and Andras Perl²

From the Departments of Medicine, Microbiology and Immunology, and ^||Pathology, State University of New York, College of Medicine, Syracuse, New York 13210 and the ^¶Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada

A novel 2986-base transcript encoded by the antisense strand of the HRES-1 human endogenous retrovirus was isolated from peripheral blood lymphocytes. This transcript codes for a 218-amino acid protein, termed HRES-1/Rab4, based on homology to the Rab4 family of small GTPases. Antibody 13407 raised against recombinant HRES-1/Rab4 detected a native protein of identical molecular weight in human T cells. HRES-1 nucleotides 2151-1606, located upstream of HRES-1/Rab4 exon 1, have promoter activity when oriented in the direction of HRES-1/Rab4 transcription. The human immunodeficiency virus, type 1 (HIV-1), tat gene stimulates transcriptional activity of the HRES-1/Rab4 promoter via trans-activation of the HRES-1 long terminal repeat. Transfection of HIV-1 tat into HeLa cells or infection of H9 and Jurkat cells by HIV-1 increased HRES-1/Rab4 protein levels. Overexpression of HRES-1/Rab4 in Jurkat cells abrogated HIV infection, gag p24 production, and apoptosis, whereas dominant-negative HRES-1/Rab4^S27N had the opposite effects. HRES-1/Rab4 inhibited surface expression of CD4 and targeted it for lysosomal degradation. HRES-1/Rab4^S27N enhanced surface expression, recycling, and total cellular CD4 content. Infection by HIV elicited a coordinate down-regulation of CD4 and up-regulation of HRES-1/Rab4 in PBL. Moreover, overexpression of HRES-1/Rab4 reduced CD4 expression on peripheral blood CD4+ T cells. Stimulation by HIV-1 of HRES-1/Rab4 expression and its regulation of CD4 recycling reveal novel coordinate interactions between an infectious retrovirus and the human genome.

Received for publication, June 30, 2006 , and in revised form, August 21, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY585832 [GenBank] , M28211 [GenBank] , X16660. [GenBank]

^* This work was supported in part by Grants AI 48079, AI 61066, and F05 TW05421 from the National Institutes of Health and the Central New York Community Foundation. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Medicine, State University of New York, 750 East Adams St., Syracuse, NY 13210. E-mail: perla{at}upstate.edu.

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