scholarly journals Major Histocompatibility Complex Class II Molecules Promote Human Immunodeficiency Virus Type 1 Assembly and Budding to Late Endosomal/Multivesicular Body Compartments

2006 ◽  
Vol 80 (19) ◽  
pp. 9789-9797 ◽  
Author(s):  
Andrés Finzi ◽  
Alexandre Brunet ◽  
Yong Xiao ◽  
Jacques Thibodeau ◽  
Éric A. Cohen
Keyword(s):  
Multivesicular Body ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Immunodeficiency Virus ◽  
Intracellular Compartments ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) assembly, budding, and release occur mostly at the plasma membrane in T lymphocytes as well as in established nonlymphoid cell lines, while in macrophages these processes occur primarily in intracellular compartments that harbor late endosomal/multivesicular body (LE/MVB) markers, including human leukocyte antigen DR (HLA-DR). Major histocompatibility complex class II molecules (MHC-II), which are expressed in macrophages and activated T cells, have been previously reported to induce the formation of multilaminar and multivesicular endocytic MHC-II-like structures analogous to MVB upon their expression in HEK 293 cells. Here, we have examined the role of MHC-II in HIV-1 Gag targeting as well as in virus assembly and release. Expression of HLA-DR in nonlymphoid cell lines induced a relocation of Gag to intracellular compartments that harbored LE/MVB markers and increased the accumulation of viral particles assembling intracellularly. Consequently, viral production and release from the cell surface was found to be substantially decreased in HLA-DR-expressing cells. This process was specific, since it was not observed with HLA-DR molecules lacking their cytoplasmic tails, nor with structurally related but functionally distinct MHC-II molecules such as HLA-DM or HLA-DO. Importantly, virus released intracellularly in HLA-DR-expressing cells retained infectivity. Overall, these results suggest a role of MHC-II molecules in promoting HIV-1 assembly and budding to LE/MVB and raise the possibility that this activity might be part of a normal pathway of virus production in cell types physiologically expressing MHC-II molecules, such as macrophages.

scholarly journals Human Immunodeficiency Virus Type 1 Vpu Protein Interacts with CD74 and Modulates Major Histocompatibility Complex Class II Presentation

2007 ◽  
Vol 82 (2) ◽  
pp. 893-902 ◽  
Author(s):  
Amjad Hussain ◽  
Clement Wesley ◽  
Mohammad Khalid ◽  
Ashutosh Chaudhry ◽  
Shahid Jameel
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
Complex Class ◽  
Yeast Two Hybrid ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Two Hybrid ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Vpu accessory protein is a transmembrane protein that down regulates CD4 expression and promotes the release of new virions. We screened a human leukocyte-specific yeast two-hybrid expression library to discover novel Vpu-interacting cellular proteins. The major histocompatibility complex class II (MHC II) invariant chain, also called Ii or CD74, was found to be one such protein. We show direct binding of Vpu and CD74 by using a yeast two-hybrid assay and coimmunoprecipitation from HIV-1-infected cells. The cytoplasmic region of Vpu was found to interact with the 30-amino-acid cytoplasmic tail of CD74. Human monocytic U937 cells infected with wild-type or Vpu-defective HIV-1 and transfected cells showed that Vpu down modulated the surface expression of mature MHC II molecules. The reduction in cell surface mature MHC II molecules correlated with decreased antigen presentation to T cells in culture. Thus, the Vpu protein also contributes to viral persistence by attenuating immune responses during HIV infection. This report further exemplifies the rich diversity and redundancy shown by HIV in immune evasion.

scholarly journals The Major Histocompatibility Complex Class II Alleles Mamu-DRB1*1003 and -DRB1*0306 Are Enriched in a Cohort of Simian Immunodeficiency Virus-Infected Rhesus Macaque Elite Controllers

2007 ◽  
Vol 82 (2) ◽  
pp. 859-870 ◽  
Author(s):  
Juan P. Giraldo-Vela ◽  
Richard Rudersdorf ◽  
Chungwon Chung ◽  
Ying Qi ◽  
Lyle T. Wallace ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Complex Class ◽  
Elite Controllers ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus

ABSTRACT The role of CD4+ T cells in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication is not well understood. Even though strong HIV- and SIV-specific CD4+ T-cell responses have been detected in individuals that control viral replication, major histocompatibility complex class II (MHC-II) molecules have not been definitively linked with slow disease progression. In a cohort of 196 SIVmac239-infected Indian rhesus macaques, a group of macaques controlled viral replication to less than 1,000 viral RNA copies/ml. These elite controllers (ECs) mounted a broad SIV-specific CD4+ T-cell response. Here, we describe five macaque MHC-II alleles (Mamu-DRB*w606, -DRB*w2104, -DRB1*0306, -DRB1*1003, and -DPB1*06) that restricted six SIV-specific CD4+ T-cell epitopes in ECs and report the first association between specific MHC-II alleles and elite control. Interestingly, the macaque MHC-II alleles, Mamu-DRB1*1003 and -DRB1*0306, were enriched in this EC group (P values of 0.02 and 0.05, respectively). Additionally, Mamu-B*17-positive SIV-infected rhesus macaques that also expressed these two MHC-II alleles had significantly lower viral loads than Mamu-B*17-positive animals that did not express Mamu-DRB1*1003 and -DRB1*0306 (P value of <0.0001). The study of MHC-II alleles in macaques that control viral replication could improve our understanding of the role of CD4+ T cells in suppressing HIV/SIV replication and further our understanding of HIV vaccine design.

scholarly journals Differential Incorporation of CD45, CD80 (B7-1), CD86 (B7-2), and Major Histocompatibility Complex Class I and II Molecules into Human Immunodeficiency Virus Type 1 Virions and Microvesicles: Implications for Viral Pathogenesis and Immune Regulation

2001 ◽  
Vol 75 (13) ◽  
pp. 6173-6182 ◽  
Author(s):  
Mark T. Esser ◽  
David R. Graham ◽  
Lori V. Coren ◽  
Charles M. Trubey ◽  
Julian W. Bess ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Hiv Infection ◽  
Host Cell ◽  
Mhc Ii ◽  
Host Cell Proteins ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus (HIV) infection results in a functional impairment of CD4+ T cells long before a quantitative decline in circulating CD4+ T cells is evident. The mechanism(s) responsible for this functional unresponsiveness and eventual depletion of CD4+ T cells remains unclear. Both direct effects of cytopathic infection of CD4+ cells and indirect effects in which uninfected “bystander” cells are functionally compromised or killed have been implicated as contributing to the immunopathogenesis of HIV infection. Because T-cell receptor engagement of major histocompatibility complex (MHC) molecules in the absence of costimulation mediated via CD28 binding to CD80 (B7-1) or CD86 (B7-2) can lead to anergy or apoptosis, we determined whether HIV type 1 (HIV-1) virions incorporated MHC class I (MHC-I), MHC-II, CD80, or CD86. Microvesicles produced from matched uninfected cells were also evaluated. HIV infection increased MHC-II expression on T- and B-cell lines, macrophages, and peripheral blood mononclear cells (PBMC) but did not significantly alter the expression of CD80 or CD86. HIV virions derived from all MHC-II-positive cell types incorporated high levels of MHC-II, and both virions and microvesicles preferentially incorporated CD86 compared to CD80. CD45, expressed at high levels on cells, was identified as a protein present at high levels on microvesicles but was not detected on HIV-1 virions. Virion-associated, host cell-derived molecules impacted the ability of noninfectious HIV virions to trigger death in freshly isolated PBMC. These results demonstrate the preferential incorporation or exclusion of host cell proteins by budding HIV-1 virions and suggest that host cell proteins present on HIV-1 virions may contribute to the overall pathogenesis of HIV-1 infection.

scholarly journals Nef-Mediated Resistance of Human Immunodeficiency Virus Type 1 to Antiviral Cytotoxic T Lymphocytes

2002 ◽  
Vol 76 (4) ◽  
pp. 1626-1631 ◽  
Author(s):  
Otto O. Yang ◽  
Phuong Thi Nguyen ◽  
Spyros A. Kalams ◽  
Tanya Dorfman ◽  
Heinrich G. Göttlinger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Cytotoxic T Lymphocytes ◽  
Complex Class ◽  
Accessory Gene ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Although Nef has been proposed to effect the escape of human immunodeficiency virus type 1 (HIV-1) from cytotoxic T lymphocytes (CTL) through downmodulation of major histocompatibility complex class I molecules, little direct data have been presented previously to support this hypothesis. By comparing nef-competent and nef-deleted HIV-1 strains in an in vitro coculture system, we demonstrate that the presence of this viral accessory gene leads to impairment of the ability of HIV-1-specific CTL clones to suppress viral replication. Furthermore, inhibition by genetically modified CTL that do not require major histocompatibility complex class I-presented antigen (expressing the CD4 T-cell receptor [TCR] ζ-chain hybrid receptor) is similar for both nef-competent and -deleted strains, indicating that Nef does not impair the effector functions of CTL but acts at the level of TCR triggering. In contrast, we note that another accessory gene, vpr, does not induce resistance of HIV-1 to suppression by CTL clones. We conclude that Nef (and not Vpr) contributes to functional HIV-1 immune evasion and that this effect is mediated by diminished antigen presentation to CTL.

scholarly journals CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

2003 ◽  
Vol 77 (21) ◽  
pp. 11536-11545 ◽  
Author(s):  
Nicoletta Casartelli ◽  
Gigliola Di Matteo ◽  
Marina Potestà ◽  
Paolo Rossi ◽  
Margherita Doria
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) nef gene is a crucial determinant in AIDS disease progression. Although several in vitro activities have been attributed to the Nef protein, identifying the one critical for in vivo pathogenicity remains elusive. In this study, we examined a large number of nef alleles derived at various time points from 13 perinatally infected children showing different progression rates: six nonprogressors (NPs), three slow progressors (SPs), and four rapid progressors (RPs). The patient-derived nef alleles were analyzed for their steady-state expression of a Nef protein, for their relative ability to downregulate cell surface expression of CD4 and major histocompatibility complex class I (MHC-I) and for their capacity to bind the clathrin adaptor AP-1 complex. We found that NP-derived nef alleles, compared to nef alleles isolated from SPs and RPs, had reduced CD4 and MHC-I downregulation activities. In contrast, SP- and RP-derived nef alleles did not differ and efficiently downregulated both CD4 and MHC-I. AP-1 binding was a conserved function of primary nef alleles not correlated with clinical progression. Defective Nef proteins from NPs, rather than sharing common specific changes in their sequences, accumulated various amino acid substitutions, mainly located outside the conserved domains previously associated with Nef biological properties. Our data indicate that Nef-mediated downregulation of cell surface CD4 and MHC-I significantly contributes to the expression of the pathogenic potential of HIV-1.

scholarly journals Substitutions in a Major Histocompatibility Complex Class II-Restricted Human Immunodeficiency Virus Type 1 gp120 Epitope Can Affect CD4+ T-Helper-Cell Function

1998 ◽  
Vol 72 (7) ◽  
pp. 5840-5844 ◽  
Author(s):  
Christine Lekutis ◽  
Norman L. Letvin
Keyword(s):  
Rhesus Monkey ◽  
Cell Function ◽  
Immune Recognition ◽  
Complex Class ◽  
T Helper ◽  
Histocompatibility Complex ◽  
Th Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT It has been suggested that the inability of the immune response to control human immunodeficiency virus type 1 (HIV-1) replication may be due, at least in part, to the capacity of this virus to escape from immune recognition through mutation. While there is increasing evidence for the importance of HIV-1-specific CD4+ T cells in containing HIV-1 spread in the infected individual, little is known about the consequences of HIV-1 mutation on virus-specific CD4+ T-cell function. The impact of HIV-1 sequence variation on CD4+ T-helper (Th)- cell function was assessed with a rhesus monkey model for immune recognition of the HIV-1 envelope (Env) glycoprotein. A series of HIV-1 Env(484-496) variant peptides were shown to retain the ability to bind to the appropriate rhesus monkey major histocompatibility complex class II DR molecule. Peptides bearing substitutions at position 490, however, failed to drive the proliferation or cytokine secretion of two well-characterized HXBc2 Env-specific rhesus monkey CD4+ Th-cell lines. Exogenous costimulation was ineffective in complementing the ability of the nonstimulatory peptides to induce [3H]thymidine incorporation by these cells. Finally, HIV-1 Env(484-496) variant peptides with substitutions at position 490 antagonized the HXBc2 Env peptide-induced proliferative response of the CD4+ Th-cell lines. Thus, HIV-1 variants appear to have the capacity to neutralize the function of virus-specific CD4+ T lymphocytes.

scholarly journals Competition Model for Upregulation of the Major Histocompatibility Complex Class II-Associated Invariant Chain by Human Immunodeficiency Virus Type 1 Nef

2008 ◽  
Vol 82 (16) ◽  
pp. 7758-7767 ◽  
Author(s):  
Richard S. Mitchell ◽  
Rittik Chaudhuri ◽  
O. Wolf Lindwasser ◽  
Kristie A. Tanaka ◽  
David Lau ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Plasma Membrane ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Invariant Chain ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Nef protein upregulates the expression of the invariant chain (Ii)/major histocompatibility complex class II (MHC-II) complex at the cell surface. This complex appears to reach the antigen-loading endosomal compartment at least in part via an indirect pathway in which it is internalized from the cell surface via the adaptor protein 2 (AP-2) complex. Here we provide evidence for a competition model to explain how Nef upregulates the expression of Ii at the cell surface. In this model, Nef and Ii compete for binding to AP-2. In support of this model, Nef decreased the rate of internalization of Ii from the cell surface. The AP-binding dileucine motif in Nef, ENTSLL165, was necessary and sufficient for the upregulation of Ii. In addition, two leucine-based AP-binding motifs in the Ii cytoplasmic tail, DDQRDLI8 and EQLPML17, were critical for the efficient upregulation of Ii by Nef. Experiments using Nef variants in which the native dileucine-based sorting motif was replaced with similar motifs from cellular transmembrane proteins allowed modulation of AP-binding specificity. Analysis of these variants suggested that the binding of Nef to AP-2 is sufficient to upregulate Ii at the plasma membrane. Finally, interference with the expression of AP-2 caused an upregulation of Ii at the plasma membrane, and this decreased the effect of Nef. These data indicate that Nef usurps AP-2 complexes to dysregulate Ii trafficking and potentially interfere with antigen presentation in the context of MHC-II.

scholarly journals Down-Modulation of Mature Major Histocompatibility Complex Class II and Up-Regulation of Invariant Chain Cell Surface Expression Are Well-Conserved Functions of Human and Simian Immunodeficiency Virus nef Alleles

2003 ◽  
Vol 77 (19) ◽  
pp. 10548-10556 ◽  
Author(s):  
Michael Schindler ◽  
Stephanie Würfl ◽  
Philippe Benaroch ◽  
Thomas C. Greenough ◽  
Rod Daniels ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Progressive Disease ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Invariant Chain ◽  
Complex Class ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Recently, it has been demonstrated that the human immunodeficiency virus type 1 (HIV-1) Nef from laboratory strains down-modulates cell surface expression of mature major histocompatibility complex class II (MHC-II) molecules, while up-regulating surface expression of the invariant chain (Ii) associated with immature MHC-II (P. Stumptner-Cuvelette, S. Morchoisne, M. Dugast, S. Le Gall, G. Raposo, O. Schwartz, and P. Benaroch, Proc. Natl. Acad. Sci. USA 98:12144-12149, 2001). These Nef functions could contribute to impaired CD4+-T-helper-cell responses found in HIV-1-infected patients with progressive disease. However, it is currently unknown whether nef alleles derived from HIV-1-infected individuals or from other primate lentiviruses also modulate MHC-II and Ii. In the present study, we demonstrate that both activities are conserved among primary HIV-1 nef alleles, as well as among HIV-2 and simian immunodeficiency virus (SIV) nef alleles. Down-modulation of mature MHC-II required high levels of Nef expression. In contrast, surface expression of Ii was already strongly increased at low to medium levels of Nef expression. Notably, nef genes derived from two of four HIV-1-infected long-term nonprogressors did not up-regulate Ii, whereas nef alleles derived from 10 individuals with progressive disease were active in this assay. Unlike other in vitro Nef functions, the average activity of Nef in modulating MHC-II and Ii surface expression did not change significantly during the course of infection. Mutational analysis confirmed that MHC-II down- and Ii up-regulation are functionally separable from each other and from other Nef functions and identified acidic residues, located at the base of the flexible C-proximal loop of Nef, that are critical for increased Ii expression. Overall, our results suggest that the ability of Nef to interfere with MHC-II antigen presentation might play a role in AIDS pathogenesis.

scholarly journals Human Immunodeficiency Virus Type 1 Nef Expression Prevents AP-2-Mediated Internalization of the Major Histocompatibility Complex Class II-Associated Invariant Chain

2008 ◽  
Vol 82 (17) ◽  
pp. 8373-8382 ◽  
Author(s):  
Hélène Toussaint ◽  
François-Xavier Gobert ◽  
Michael Schindler ◽  
Carina Banning ◽  
Patrycja Kozik ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Human Immunodeficiency Virus Type ◽  
Complex Class ◽  
Histocompatibility Complex ◽  
Chain Complexes ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The lentiviral Nef protein has been studied extensively for its ability to induce the downregulation of several immunoreceptors on the surfaces of infected cells. However, Nef expression is unique in inducing highly effective upregulation of the major histocompatibility complex class II-associated chaperone invariant (Ii) chain complexes in different cell types. Under normal conditions, endocytosis of the Ii chain and other molecules, like the transferrin receptor and CD4, is rapid and AP-2 dependent. Human immunodeficiency virus type 1 (HIV-1) Nef expression strongly reduces the internalization of the Ii chain, enhances that of CD4, and does not modify transferrin uptake. The mutation of AP-2 binding motifs LL164 and DD174 in Nef leads to the inhibition of Ii chain upregulation. In AP-2-depleted cells, surface levels of the Ii chain are high and remain unmodified by Nef expression, further indicating that Nef regulates Ii chain internalization via the AP-2 pathway. Immunoprecipitation experiments revealed that the Ii chain can interact with Nef in a dileucine-dependent manner. Importantly, we have shown that Nef-induced CD4 downregulation and Ii chain upregulation are genetically distinguishable. We have identified natural nef alleles that have lost one of the two functions but not the other one. Moreover, we have characterized Nef mutant forms possessing a similar phenotype in the context of HIV-1 infection. Therefore, the Nef-induced accumulation of Ii chain complexes at the cell surface probably results from a complex mechanism leading to the impairment of AP-2-mediated endocytosis rather than from direct competition between Nef and the Ii chain for binding AP-2.

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