scholarly journals Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1

2006 ◽  
Vol 396 (2) ◽  
pp. 371-380 ◽  
Author(s):  
Anna L. Remoli ◽  
Giulia Marsili ◽  
Edvige Perrotti ◽  
Eleonora Gallerani ◽  
Ramona Ilari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mhc Class I ◽  
Consensus Sequence ◽  
Class I ◽  
Tat Protein ◽  
Cellular Functions ◽  
Infected Cells ◽  
Cryptic Epitopes ◽  
Hiv 1

The Tat protein is the transcriptional activator of HIV-1 gene expression, which is not only essential for viral replication, but also important in the complex HIV-induced pathogenesis of AIDS, as both an intracellular and an extracellular released protein. Accordingly, Tat is able to profoundly affect cellular gene expression, regulating several cellular functions, also in non-infected cells. We showed recently that Tat induces modification of immunoproteasomes in that it up-regulates LMP7 (low-molecular-mass polypeptide 7) and MECL1 (multicatalytic endopeptidase complex-like 1) subunits and down-modulates the LMP2 subunit, resulting in a change in the generation and presentation of epitopes in the context of MHC class I. In particular, Tat increases presentation of subdominant and cryptic epitopes. In the present study, we investigated the molecular mechanism responsible for the Tat-induced LMP2 down-regulation and show that intracellular Tat represses transcription of the LMP2 gene by competing with STAT1 (signal transducer and activator of transcription 1) for binding to IRF-1 (interferon-regulatory factor-1) on the overlapping ICS-2 (interferon consensus sequence-2)–GAS (γ-interferon-activated sequence) present in the LMP2 promoter. This element is constitutively occupied in vivo by the unphosphorylated STAT1–IRF-1 complex, which is responsible for the basal transcription of the gene. Sequestration of IRF-1 by intracellular Tat impairs the formation of the complex resulting in lower LMP2 gene transcription and LMP2 protein expression, which is associated with increased proteolytic activity. On the other hand, extracellular Tat induces the expression of LMP2. These effects of Tat provide another effective mechanism by which HIV-1 affects antigen presentation in the context of the MHC class I complex and may have important implications in the use of Tat for vaccination strategies.

scholarly journals The Human Immunodeficiency Virus Type 1 (HIV-1) Vpu Protein Interferes with an Early Step in the Biosynthesis of Major Histocompatibility Complex (MHC) Class I Molecules

1997 ◽  
Vol 185 (7) ◽  
pp. 1295-1306 ◽  
Author(s):  
Thomas Kerkau ◽  
Igor Bacik ◽  
Jack R. Bennink ◽  
Jonathan W. Yewdell ◽  
Thomas Hünig ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Heavy Chains ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1 ◽  
Mhc Class I Molecules

The human immunodeficiency virus type 1 (HIV-1) vpu gene encodes a small integral membrane phosphoprotein with two established functions: degradation of the viral coreceptor CD4 in the endoplasmic reticulum (ER) and augmentation of virus particle release from the plasma membrane of HIV-1–infected cells. We show here that Vpu is also largely responsible for the previously observed decrease in the expression of major histocompatibility complex (MHC) class I molecules on the surface of HIV-1–infected cells. Cells infected with HIV-1 isolates that fail to express Vpu, or that express genetically modified forms of Vpu that no longer induce CD4 degradation, exhibit little downregulation of MHC class I molecules. The effect of Vpu on class I biogenesis was analyzed in more detail using a Vpu-expressing recombinant vaccinia virus (VV). VV-expressed Vpu induces the rapid loss of newly synthesized endogenous or VV-expressed class I heavy chains in the ER, detectable either biochemically or by reduced cell surface expression. This effect is of similar rapidity and magnitude as the VV-expressed Vpu-induced degradation of CD4. Vpu had no discernible effects on cell surface expression of VV-expressed mouse CD54, demonstrating the selectivity of its effects on CD4 and class I heavy chains. VVexpressed Vpu does not detectably affect class I molecules that have been exported from the ER. The detrimental effects of Vpu on class I molecules could be distinguished from those caused by VV-expressed herpes virus protein ICP47, which acts by decreasing the supply of cytosolic peptides to class I molecules, indicating that Vpu functions in a distinct manner from ICP47. Based on these findings, we propose that Vpu-induced downregulation of class I molecules may be an important factor in the evolutionary selection of the HIV-1–specific vpu gene by contributing to the inability of CD8+ T cells to eradicate HIV-1 from infected individuals.

On the Role of the Second Coding Exon of the HIV-1 Tat Protein in Virus Replication and MHC Class I Downregulation

1998 ◽  
Vol 14 (17) ◽  
pp. 1553-1559 ◽  
Author(s):  
KOEN VERHOEF ◽  
MONICA BAUER ◽  
ANDREAS MEYERHANS ◽  
BEN BERKHOUT
Keyword(s):  
Mhc Class I ◽  
Virus Replication ◽  
Class I ◽  
Tat Protein ◽  
Hiv 1

scholarly journals Nef from a primary isolate of human immunodeficiency virus type 1 lacking the EE155 region shows decreased ability to down-regulate CD4

2004 ◽  
Vol 85 (6) ◽  
pp. 1451-1461 ◽  
Author(s):  
Young-Soon Na ◽  
Keejung Yoon ◽  
Jeong-Gu Nam ◽  
Byeongsun Choi ◽  
Joo-Shil Lee ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mhc Class I ◽  
Infected Individual ◽  
Laboratory Strain ◽  
Class I ◽  
Target Cells ◽  
Down Regulation ◽  
Immunodeficiency Virus ◽  
Infected Cells

The human immunodeficiency virus (HIV) nef gene encodes a 27 kDa myristoylated cytosolic protein that has an important role in the pathogenesis of AIDS. One function of Nef is the down-regulation of CD4 and MHC class I surface molecules in HIV-infected cells. Nef directly isolated from an infected individual (KS2), who could be defined as a long-term non-progressor, was compared with Nef from a standard laboratory strain, HIV-1 NL4-3. KS2 Nef protein was characterized by its lowered ability to down-regulate CD4, while still maintaining the ability to down-regulate MHC class I. The ability of KS2 Nef to down-regulate CD4 was more prominent when CD4 was measured 2–3 days after transfer of the nef gene to the target cells, and also when the effect was measured in CD4+-enriched primary T cells. The amino acid sequence analysis indicated that the most notable feature of KS2 Nef was lack of the two glutamic acids: the EE155 region. When the EE155 region was added to KS2 Nef, the CD4 down-regulation ability was increased almost to the level of NL4-3 Nef. Conversely, when the EE155 region was deleted from NL4-3, its CD4 down-regulation ability was dramatically impaired. These data suggested that the EE155 region plays an important role(s) in the down-regulation of CD4 by Nef protein and also that primary nef sequences could be very useful in identifying the original biological functions of Nef in vivo.

scholarly journals Human Immunodeficiency Virus Type 1 Nef-Mediated Downregulation of CD4 Correlates with Nef Enhancement of Viral Pathogenesis

2003 ◽  
Vol 77 (3) ◽  
pp. 2124-2133 ◽  
Author(s):  
Cheryl A. Stoddart ◽  
Romas Geleziunas ◽  
Sharon Ferrell ◽  
Valerie Linquist-Stepps ◽  
Mary E. Moreno ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mhc Class I ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Class I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The nef gene products encoded by human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus type 1 (SIV-1) increase viral loads in infected hosts and accelerate clinical progression to AIDS. Nef exhibits a spectrum of biological activities, including the ability to downregulate surface expression of CD4 and major histocompatibility complex (MHC) class I antigens, to alter the state of T-cell activation, and to enhance the infectivity of viral particles. To determine which of these in vitro functions most closely correlates with the pathogenic effects of Nef in vivo, we constructed recombinant HIV-1 NL4-3 viruses carrying mutations within the nef gene that selectively impair these functions. These mutant viruses were evaluated for pathogenic potential in severe combined immunodeficiency (SCID) mice implanted with human fetal thymus and liver (SCID-hu Thy/Liv mice), in which virus-mediated depletion of thymocytes is known to be Nef dependent. Disruption of the polyproline type II helix (Pxx)4 within Nef (required for binding of Hck and p21-activated kinase-like kinases, downregulation of MHC class I, and enhancement of HIV-1 infectivity in vitro but dispensable for CD4 downregulation) did not impair thymocyte depletion in virus-infected Thy/Liv human thymus implants. Conversely, three separate point mutations in Nef that compromised its ability to downregulate CD4 attenuated thymocyte depletion while not diminishing viral replication. These findings indicate that the functional ability of Nef to downregulate CD4 and not MHC class I downregulation, Hck or PAK binding, or (Pxx)4-associated enhancement of infectivity most closely correlates with Nef-mediated enhancement of HIV-1 pathogenicity in vivo. Nef-mediated CD4 downregulation merits consideration as a new target for the development of small-molecule inhibitors.

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