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/Rab4S27N had the opposite effects. HRES-1/Rab4 inhibited surface expression of CD4 and targeted it for lysosomal degradation. HRES-1/Rab4S27N 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. 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/Rab4S27N had the opposite effects. HRES-1/Rab4 inhibited surface expression of CD4 and targeted it for lysosomal degradation. HRES-1/Rab4S27N 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. Endogenous retroviruses (ERV) 3The abbreviations used are: ERV, endogenous retroviruses; HERV, human ERV; HIV, human immunodeficiency virus; HIV-1, human immunodeficiency virus, type 1; PBL, peripheral blood lymphocytes; LTR, long terminal repeat; GST, glutathione S-transferase; GFP, green fluorescent protein; PDBu, phorbol 12,13-dibutyrate; HBSS, Hanks' balanced salt solution; IRES, internal ribosome entry site; PBS, primer-binding site; TFR, transferrin receptor; PE, phycoerythrin; CAT, chloramphenicol acetyltransferase; PBMC, peripheral blood mononuclear cells; Ab, antibody. 3The abbreviations used are: ERV, endogenous retroviruses; HERV, human ERV; HIV, human immunodeficiency virus; HIV-1, human immunodeficiency virus, type 1; PBL, peripheral blood lymphocytes; LTR, long terminal repeat; GST, glutathione S-transferase; GFP, green fluorescent protein; PDBu, phorbol 12,13-dibutyrate; HBSS, Hanks' balanced salt solution; IRES, internal ribosome entry site; PBS, primer-binding site; TFR, transferrin receptor; PE, phycoerythrin; CAT, chloramphenicol acetyltransferase; PBMC, peripheral blood mononuclear cells; Ab, antibody. belong to the larger family of retrotransposable elements that make up as much as 40% of the human genome (1Kazazian Jr., H.H. Science. 2000; 289: 1152-1153Crossref PubMed Scopus (134) Google Scholar). Human ERV (HERV) have the basic structures of the integrated proviral form of infectious retroviruses with long terminal repeats (LTRs) flanking sequences homologous to gag, pol, and env genes (2Coffin J.M. Hughes S.H. Varmus H.E. Coffin J.M. Hughes S.H. Varmus H.E. Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 343-435Google Scholar). Human ERV have generally been found to be defective proviruses having accumulated deletions or stop codons in gag, pol, and/or env open reading frames (3Wilkinson D.A. Mager D.L. Leong J.-A.C. Levy J.A. The Retroviridae. Plenum Publishing Corp., New York1994: 465-535Crossref Google Scholar). Human ERV are commonly designated as HERV followed by a single letter amino acid code corresponding to a tRNA. The 3′ terminus of tRNA is predicted to initiate reverse transcription by annealing to an 18-nucleotide-long primer-binding site (PBS) at the 5′-LTR. ERV copy numbers vary from one to several hundred per haploid genome (4Perl A. Rheum. Dis. Clin. N. Am. 2003; 29: 123-143Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). ERV may represent a key molecular link between the host genome and infectious viral particles. They constitute a large reservoir of viral genes that may be activated by mutations caused by radiation or chemicals or recombination with exogenous retroviruses. Although exogenous retroviruses are infectious, with a replication cycle that requires integration of proviral DNA into host cell DNA, ERV are transmitted genetically in a classical Mendelian fashion through the germ line as proviral DNA. Expression of ERV can influence the outcome of infections in different ways that are both beneficial and detrimental to the host (2Coffin J.M. Hughes S.H. Varmus H.E. Coffin J.M. Hughes S.H. Varmus H.E. Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 343-435Google Scholar). These include provision of genes for recombination with exogenous viruses, interference with virion assembly, modulation of immune responses to exogenous viruses, and blocking cellular receptors for viral entry (5Perl A. J. Rheumatol. 2001; 28: 461-464PubMed Google Scholar). Human immunodeficiency virus, type 1 (HIV-1), uses two receptors for cellular attachment and viral entry. Initial viral attachment occurs through the binding of the envelope protein gp120 to the CD4 molecule expressed on the surface of T lymphocytes and macrophages. Viral binding to CD4 is necessary but insufficient to mediate viral entry. Interaction between CD4 and gp120 increases the affinity of virions for coreceptor molecules CXCR4 and CCR5. Genetic polymorphisms or deletions within CCR5 diminish or abrogate viral binding to the receptor, which leads to a lower susceptibility to infection and slower disease progression in persons carrying these mutations (6Baban S. Freeman J.D. Mager D.L. Genomics. 1996; 33: 463-472Crossref PubMed Scopus (28) Google Scholar). CXCR4-using viruses are generally more pathogenic, via depletion of CD4 T cells, than are CCR5-using viruses. CD4 appears to play a role in HIV entry distinct from merely serving as the attachment protein for the virus. CD4 undergoes endocytosis following T cell activation via the activation of protein kinase C and subsequent of CD4 J.A. D.L. J. Google J. Full Text PDF PubMed Google Scholar). HIV binding was to of CD4 via a protein kinase of HIV endocytosis of CD4 S. Full Text PDF PubMed Scopus Google A. PubMed Scopus Google Scholar). interactions between a gene of the human type endogenous and HRES-1 was isolated based on homology to the long terminal and gag of human T cell type A. J.D. PubMed Scopus Google Scholar). with DNA of that HRES-1 was to the A. J.D. PubMed Scopus Google Scholar). HRES-1 is a single copy in the haploid genome that been to at the long of 1 A. Genomics. PubMed Scopus Google Scholar). A flanking to a a a tRNA primer-binding site and sequences at that are of a (2Coffin J.M. Hughes S.H. Varmus H.E. Coffin J.M. Hughes S.H. Varmus H.E. Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 343-435Google A. J.D. PubMed Scopus Google Scholar). HRES-1 is one of the human ERV that (3Wilkinson D.A. Mager D.L. Leong J.-A.C. Levy J.A. The Retroviridae. Plenum Publishing Corp., New York1994: 465-535Crossref Google A. J.D. PubMed Scopus Google Scholar). a novel transcript encoded by the antisense strand of the HRES-1 was isolated from human peripheral blood lymphocytes The of homology to the gene and is termed Antibody raised against recombinant HRES-1/Rab4 detected a native protein of identical molecular weight in and Jurkat and H9 T cell The exon of HRES-1/Rab4 is in the HRES-1 endogenous HRES-1 nucleotides 2151-1606, located upstream from HRES-1/Rab4 exon 1, promoter activity when oriented in the direction of HRES-1/Rab4 transcription. The tat gene of HIV-1 stimulates transcriptional activity of the HRES-1/Rab4 promoter via trans-activation of the HRES-1 and increases HRES-1/Rab4 protein levels. HRES-1/Rab4 recycling and surface expression of CD4 and susceptibility to infection by was from Jurkat cells, in to and to human J. PubMed Scopus Google or as A. J.D. PubMed Scopus Google Scholar). and of Expression and and of human in was with HRES-1 as A. J. Full Text PDF PubMed Google Scholar). into the site of and in both of the HRES-1/Rab4 was to Expression of HRES-1/Rab4 protein was expressed as a protein with glutathione as A. 1996; PubMed Scopus Google Scholar). and by of the and 3′ of the stop of and into and of expression of the recombinant protein was with 1 protein was through binding of to HRES-1/Rab4 protein was from by and was from the by and Transfection of Expression HRES-1/Rab4 was in Jurkat cells a expression PubMed Scopus Google Scholar). Jurkat cells in and by with by of S. Science. PubMed Scopus Google and for in the of 1 cells are Jurkat cells with and the reverse of with sequences in the of cells with and dominant-negative and cells in and of cells in an of the was by of with 1 which cell the fluorescent of cells was a and in the of and of and cells in cells to to in of and HIV-1 tat HeLa and Jurkat cells A. J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). and from the and of of the was from of H9 cells and infectious was by an in J. S. J. PubMed Google Scholar). with of infectious through a by and at with of p24 protein by an following the corresponding to per cells or a of infection of 1 of p24 protein to infectious in with J. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). infection was in 1 of for in the of cells in and in of and HIV-1 gag the gag protein Levy J.A. PubMed Scopus Google Scholar). the C at amino acid of and the terminus of viral HIV-1 gag S. A. PubMed Scopus Google and and of of CD4+ T from Human from peripheral blood N. A. J. Google and cells with of to CD4+ T cells with A and for by in with a and CD4+ T cells with HIV-1, as of by was by cell and by with in and as N. A. J. Google A. J. Full Text Full Text PDF PubMed Scopus Google Scholar). with was used to cell in with expression of and surface with CD4 and or transferrin of surface receptors was by with phorbol for 1 at J.A. D.L. J. Google J. Full Text PDF PubMed Google Scholar). cells and at to or to to recycling in the or of of recycling, cells on of surface expression by of for of by Jurkat cells in Hanks' balanced salt and for at cells in of with PubMed Scopus Google and and for at cells in of with and for of HIV-1 gag p24 or and for at in of with and and in of with and on up to to of HRES-1/Rab4, cells with or followed by and of cell protein in cells per on a to and with to HRES-1/Rab4 or to HIV-1 gag tat for or as A. J. Full Text PDF PubMed Google J. A. S. A. PubMed Scopus Google Scholar). CD4 was detected with and was detected with of was and detected with or followed by with Expression of HRES-1/Rab4, HIV-1 HIV-1 gag p24 was by enhanced followed by of and was used to the of protein expression a with cells for in at and in with transferrin for at and for and with Rab4 antibody. and cells with or on for in and was with for 1 at and on or to at and recycling, cells to with for at and in in Hanks' balanced salt with and in and with in and in for the cells in for and the in was on a with a of at and the with with the and to a an of 1 per and to The from the for the and and in the the a corresponding to the of the green green and was by in of of cells and the and from in as S. A. J. PubMed Scopus Google Scholar). with and and and and and and 1 or for and and and from These in and used to cells for and at the following 1 and was inhibited with and or and cells and CD4 and protein expression was from of by for expressed as the of at of and with HRES-1 of total from Jurkat cells detected and The transcript was isolated from a human peripheral blood based on to a HRES-1 A. J.D. PubMed Scopus Google Scholar). This novel corresponding to the transcript was found to be encoded by the antisense strand of the HRES-1 The of homology to the gene and was termed HRES-1/Rab4 codes for amino and two and The predicted molecular weight of HRES-1/Rab4 is whereas that of is The and in the HRES-1/Rab4 different from of HRES-1 was to human 1 A. Genomics. PubMed Scopus Google Scholar). of the HRES-1/Rab4 within to the The HRES-1 with corresponding to HRES-1/Rab4 exon 1, detected and that these encoded by the antisense The HRES-1 to a transcript detected by an A. J.D. PubMed Scopus Google Scholar). transcription of is the whereas the gene is in the direction of the at human of HRES-1/Rab4 The and an open reading of a protein; and stop codons are and of HRES-1/Rab4 with the HRES-1 endogenous of HRES-1/Rab4 is in of HRES-1/Rab4 The and an open reading of a protein; and stop codons are and of HRES-1/Rab4 with the HRES-1 endogenous of HRES-1/Rab4 is in of HRES-1/Rab4 and codons are in HRES-1/Rab4 and amino acid HRES-1/Rab4 codes for amino and two and in binding is of HRES-1/Rab4 13407 raised against recombinant HRES-1/Rab4 the recombinant in and detected the native protein of identical molecular weight in of two and Jurkat T cells Antibody raised against a acid of both HRES-1/Rab4 and with predicted molecular of and HRES-1/Rab4 in Jurkat line expression of the protein was by with 1 HRES-1/Rab4 was by in Jurkat line with the of HRES-1/Rab4 and codons are in HRES-1/Rab4 and amino acid HRES-1/Rab4 codes for amino and two and in binding is of HRES-1/Rab4 13407 raised against recombinant HRES-1/Rab4 the recombinant in and detected the native protein of identical molecular weight in of two and Jurkat T cells Antibody raised against a acid of both HRES-1/Rab4 and with predicted molecular of and HRES-1/Rab4 in Jurkat line expression of the protein was by with 1 HRES-1/Rab4 was by in Jurkat line with the for expression of native HRES-1/Rab4, an was raised in against recombinant protein expressed as a protein with in The and was used to 13407 This the protein in or Jurkat cells and detected the native protein of identical molecular weight in both and Jurkat cells. Antibody raised against a acid of HRES-1/Rab4 and of lower molecular The predicted molecular weight of HRES-1/Rab4 is whereas that of is the HRES-1 is a single copy in the haploid genome A. Genomics. PubMed Scopus Google the Rab4 may from or to an of the HRES-1/Rab4 The tat of HIV-1 the and Expression of exon of HRES-1/Rab4 is in the HRES-1 endogenous on with and transcription site of HRES-1/Rab4 was to HRES-1 gene the of HRES-1 promoter activity when oriented in the direction of HRES-1/Rab4 transcription of the HRES-1 to of the gene promoter activity in HeLa cells with HIV-1 tat whereas it promoter activity in HeLa cells activity of the HRES-1/Rab4 was enhanced in cells by Moreover, HRES-1/Rab4 protein in and H9 human T cells HRES-1/Rab4 protein increased in as with HeLa cells, by The that can expression of HRES-1/Rab4 via trans-activation of HRES-1 internal Although the HRES-1 was to an HIV-1 A. J.D. PubMed Scopus Google J. PubMed Scopus Google subsequent by and PubMed Scopus Google PubMed Scopus Google as a larger of the HIV-1 LTR, which is in up-regulation of HRES-1 expression by HIV-1 may through the PubMed Scopus Google PubMed Scopus Google Scholar). HRES-1/Rab4 p24 and HRES-1/Rab4 expression is by HIV-1 its role in viral was Jurkat cells a expression J. PubMed Google Scholar). Jurkat cells with the in the of 1 and as cells with the increased of HRES-1/Rab4 in the of 1 HRES-1/Rab4 expression was increased in cells in the of by of Jurkat cells HRES-1/Rab4 is in HRES-1/Rab4 reduced HIV gag p24 detected by and the of HIV-1 cells by of gag p24 and by and in the or of of HIV gag p24 detected by but by of cells of on infection by HIV-1, Jurkat cells a dominant-negative form of HRES-1/Rab4 in the of and of the as Rab4 A. J. Google of S. A. 2001; PubMed Scopus Google Scholar). was in the by The was into cells. cells by Expression of HRES-1/Rab4S27N was by and with to internal to native HRES-1/Rab4 protein of cells, HRES-1/Rab4S27N was expressed in cells at in the of and in the of based on to in of cells but of cells HRES-1/Rab4 or HRES-1/Rab4S27N or in with for cell type was with HRES-1/Rab4 abrogated of HIV-1 gag p24 as by the HRES-1/Rab4 reduced the of cells by of gag p24 and HRES-1/Rab4S27N enhanced gag p24 and apoptosis, and the was enhanced in cells with HRES-1/Rab4 Expression of CD4 via belong to the family of small that been to recycling of carrying the in cells Full Text PDF PubMed Scopus Google or in Full Text Full Text PDF PubMed Scopus Google Scholar). the of HRES-1/Rab4 on HIV infection was via recycling and expression of surface expression was in the of it was reduced by HRES-1/Rab4 in the of by transferrin and for of expression of CD4 was reduced on the surface of cells as with cells, in the of of reduced expression of CD4 on cells surface expression of CD4 was enhanced on cells CD4 expression was by increased of in cells Expression of HIV coreceptor and was by coordinate by HRES-1/Rab4 and up-regulation by HRES-1/Rab4S27N of CD4 expression a role for HRES-1/Rab4 in regulation of CD4 CD4 undergoes protein kinase endocytosis following T cell activation J.A. 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CD4 was by with for 1 at was by and cells at to or to to of and to the cell surface was in Jurkat cells HRES-1/Rab4 or HRES-1/Rab4S27N with to cells. expression of was reduced of HRES-1/Rab4 by for whereas the of recycling was by HRES-1/Rab4 or HRES-1/Rab4S27N expression of CD4 was reduced in cells HRES-1/Rab4, by and of recycling Although expression of CD4 was enhanced by and recycling for surface expression of CD4 by in the of and recycling, by on cells HRES-1/Rab4S27N in the of recycling of but TFR, was enhanced in cells of HRES-1/Rab4 with and for 1 and recycling of by with CD4 was by with for 1 at and to at for to and and Rab4 was by subsequent with and with HRES-1/Rab4 to of HRES-1/Rab4 or HRES-1/Rab4S27N expression CD4 with HRES-1/Rab4 to The of different CD4 to the of and cells and a CD4 to to the cell and to in cells HRES-1/Rab4 of CD4 was in cells HRES-1/Rab4 of HRES-1/Rab4 with and HRES-1/Rab4 and and dominant-negative HRES-1/Rab4S27N and Jurkat cells for with following cells with transferrin and with detected with transferrin and HRES-1/Rab4 of HRES-1/Rab4 and CD4 in cells. with CD4 with for 1 at and with followed by with antibody. HRES-1/Rab4 and CD4 recycling of CD4 of with CD4 and CD4 was by with for 1 at cells to for to recycling of CD4 and with followed by with antibody. of HRES-1/Rab4 and CD4 and cells peripheral of cells, CD4 with HRES-1/Rab4 in Overexpression of HRES-1/Rab4 of and that HRES-1/Rab4 may total CD4 protein levels. that HRES-1/Rab4 expression reduced CD4 protein to and of cells in the and of HRES-1/Rab4S27N increased CD4 protein and in the and of of with CD4 in the cell A. PubMed Scopus Google was with the and and or influence CD4 protein the lysosomal CD4 by HRES-1/Rab4 in a and lysosomal CD4 to a CD4 of cells and of cells HRES-1/Rab4S27N by or the of CD4 expression by HRES-1/Rab4 may have from of recycling and of CD4 for lysosomal degradation. of CD4 and HRES-1/Rab4 Expression in the of HIV-1 on expression of HRES-1/Rab4 in peripheral blood and CD4 T cells by a coordinate down-regulation of CD4 and up-regulation of HRES-1/Rab4 in cells Infection of CD4 T cells and with in down-regulation of CD4 expression with to cells or cells with or and ERV constitute a large reservoir of viral genes that can influence the outcome of infections by exogenous retroviruses via provision of genes for recombination with proviral DNA, interference with virion assembly, blocking cellular receptors for viral and modulation of immune responses to exogenous viruses (2Coffin J.M. Hughes S.H. Varmus H.E. Coffin J.M. Hughes S.H. Varmus H.E. Retrotransposons, Endogenous Retroviruses, and the Evolution of Retroelements. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997: 343-435Google A. J. Rheumatol. 2001; 28: 461-464PubMed Google Scholar). Although human ERV have and proviral DNA, of are (3Wilkinson D.A. Mager D.L. Leong J.-A.C. Levy J.A. The Retroviridae. Plenum Publishing Corp., New York1994: 465-535Crossref Google Scholar). The that both the and antisense of the human ERV HRES-1 can be in human cells. transcription been at several S.H. PubMed Scopus Google PubMed Scopus (28) Google ERV, (6Baban S. Freeman J.D. Mager D.L. Genomics. 1996; 33: 463-472Crossref PubMed Scopus (28) Google and the HRES-1 J.D. J. S. J. N. A. A. S. S. Levy S. J. J. N. S. J. A. J. A. J. S. S. S. A. A. A. A. S. S. S. N. A. J. S. J. J. S. A. S. S. J. S. S. J. A. A. A. N. S. S. S. A. J. J. A. S. S. A. J. S. J. J. J. A. J. J. S. N. Science. 2001; PubMed Scopus Google Scholar). Although the strand of HRES-1 a protein, expressed in T lymphocytes and cells (5Perl A. J. Rheumatol. 2001; 28: 461-464PubMed Google A. J.D. PubMed Scopus Google J. A. S. A. PubMed Scopus Google the antisense strand exon 1 and transcriptional elements of the HRES-1/Rab4 The tat gene of HIV-1 stimulates expression of HRES-1/Rab4 protein via trans-activation of the HRES-1 HRES-1/Rab4 surface expression of CD4 infection of T cells by The HRES-1/Rab4 as a of CD4 belong to the family of small that recycling S. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). been to influence recycling of the in cells Full Text PDF PubMed Scopus Google or in Full Text Full Text PDF PubMed Scopus Google Scholar). and surface expression of CD4 and was by Although HRES-1/Rab4 with both and surface expression of was reduced in cells HRES-1/Rab4 up CD4 by HRES-1/Rab4 and by CD4 by overexpression of of HRES-1/Rab4 expression was elicited by HIV infection or of that HIV-1 may HRES-1/Rab4 to CD4 of HIV-1 gag p24 and of cells reduced by HRES-1/Rab4 and enhanced by expression or recycling of was by HRES-1/Rab4, that infection by HIV-1 was via CD4 CD4 and by HRES-1/Rab4 or HRES-1/Rab4S27N that in surface expression on the protein CD4 appears to play a role in HIV entry merely serving as the attachment protein for the virus. CD4 undergoes endocytosis following T cell activation J.A. D.L. J. Google and HIV entry may on the of CD4 is on the activation of protein kinase C and subsequent of CD4 J. Full Text PDF PubMed Google Scholar). with PDBu, an of protein kinase reduced surface expression of kinase down-regulation of CD4 A. J. PubMed Scopus Google Scholar). CD4 is into and to the cell the of phorbol CD4 is from the recycling to the and as a is a in the recycling of of PDBu, CD4 expression of CD4 on the cell surface was by of protein with that CD4 was but to the cell Overexpression of HRES-1/Rab4 reduced surface expression of CD4 and targeted it for lysosomal degradation. CD4 by overexpression of HRES-1/Rab4 by lysosomal but surface expression, recycling, and total cellular CD4 was enhanced by HRES-1/Rab4 a role in CD4 expression in T cells by its between the recycling and The that HIV stimulates expression of HRES-1/Rab4 in recycling of CD4 to the cell down-regulation of CD4 expression on the surface of cells may be at in via of CD4 recycling by CD4 down-regulation been to and S. S. J. Full Text Full Text PDF PubMed Scopus Google lysosomal J. Full Text PDF PubMed Scopus Google J. PubMed Google and by the J. N. J. PubMed Google S. J. PubMed Google S. Full Text Full Text PDF PubMed Scopus Google Scholar). HIV expression J. D.L. Full Text Full Text PDF PubMed Scopus Google and of the N. A. A. Full Text Full Text PDF PubMed Scopus Google Scholar). This a role for HRES-1/Rab4 in lysosomal of HRES-1/Rab4 to the family of small that recycling S. 2003; Full Text Full Text PDF PubMed Scopus Google and may be in lysosomal of CD4 J. Full Text PDF PubMed Scopus Google J. PubMed Google Scholar). HRES-1/Rab4 inhibited whereas HRES-1/Rab4S27N enhanced HIV infection and virion production, that regulation of HRES-1/Rab4 expression may play an role in the cycle of This is by coordinate up-regulation of HRES-1/Rab4 and down-regulation of CD4 expression in CD4 T cells and HRES-1/Rab4 promoter and protein are increased in cells by HIV-1 or by enhanced expression of HRES-1/Rab4 may to down-regulation of CD4 recycling to the cell by HIV-1, for increased virion production, and cells against by T cells 2001; PubMed Scopus Google PubMed Scopus Google Scholar). of HRES-1/Rab4 expression by HIV-1 and regulation of HIV coreceptor CD4 recycling by HRES-1/Rab4 represent novel of coordinate between infectious viral and ERV of the human genome. for and

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