Regulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection.
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.
Nagy
Gyorgy
G
Department of Medicine, State University of New York, College of Medicine, Syracuse, New York 13210, USA.
Ward
Jeffrey
J
Mosser
Dick D
DD
Koncz
Agnes
A
Gergely
Peter
P
Stancato
Christina
C
Qian
Yueming
Y
Fernandez
David
D
Niland
Brian
B
Grossman
Craig E
CE
Telarico
Tiffany
T
Banki
Katalin
K
Perl
Andras
A
D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics; D004198:Disease Susceptibility; D005091:Exons / Q000235:genetics; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000235:genetics* / Q000494:pharmacology; D005799:Genes, Dominant; D016655:HIV Core Protein p24 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D019169:Jurkat Cells; D008247:Lysosomes; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D011990:Receptors, Transferrin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D020695:rab4 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015703:Antigens, CD; D015704:CD4 Antigens; C068126:CD71 antigen; D015696:Gene Products, tat; D016655:HIV Core Protein p24; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D015500:Chloramphenicol O-Acetyltransferase; D020695:rab4 GTP-Binding Proteins