Inhibitors of HIV-1 Nef-Mediated Activation of the Myeloid Src-Family Kinase Hck Block HIV-1 Replication in Macrophages and Disrupt MHC-I Downregulation

2022 ◽  
Author(s):  
Lori A. Emert-Sedlak ◽  
Omar Moukha-Chafiq ◽  
Haibin Shi ◽  
Shoucheng Du ◽  
John J. Alvarado ◽  
...  
Keyword(s):  
Src Family Kinase ◽  
Mhc I ◽  
Hiv 1

scholarly journals HIV-1 Nef Assembles a Src Family Kinase-ZAP-70/Syk-PI3K Cascade to Downregulate Cell-Surface MHC-I

2007 ◽  
Vol 1 (2) ◽  
pp. 121-133 ◽  
Author(s):  
Chien-Hui Hung ◽  
Laurel Thomas ◽  
Carl E. Ruby ◽  
Katelyn M. Atkins ◽  
Nicholas P. Morris ◽  
...  
Keyword(s):  
Cell Surface ◽  
Src Family Kinase ◽  
Mhc I ◽  
Hiv 1

scholarly journals HIV-1 Nef sequesters MHC-I intracellularly by targeting early stages of endocytosis and recycling

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Brennan S. Dirk ◽  
Emily N. Pawlak ◽  
Aaron L. Johnson ◽  
Logan R. Van Nynatten ◽  
Rajesh A. Jacob ◽  
...  
Keyword(s):  
Mhc I ◽  
Early Stages ◽  
Hiv 1

scholarly journals Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Yushen Du ◽  
Tian-Hao Zhang ◽  
Lei Dai ◽  
Xiaojuan Zheng ◽  
Aleksandr M. Gorin ◽  
...  
Keyword(s):  
Binding Affinity ◽  
High Throughput ◽  
Peptide Binding ◽  
Virus Evolution ◽  
Mhc I ◽  
Hla Alleles ◽  
Ctl Escape ◽  
Peptide Binding Affinity ◽  
Hiv 1

ABSTRACT Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.

scholarly journals Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes

Viruses ◽  
2017 ◽  
Vol 9 (8) ◽  
pp. 222 ◽  
Author(s):  
Christian Setz ◽  
Melanie Friedrich ◽  
Pia Rauch ◽  
Kirsten Fraedrich ◽  
Alina Matthaei ◽  
...  
Keyword(s):  
Deubiquitinating Enzymes ◽  
Mhc I ◽  
Hiv 1

scholarly journals Structure of HIV-2 Nef reveals unique features distinct from HIV-1 involved in immune regulation

2019 ◽  
Author(s):  
Kengo Hirao ◽  
Sophie Andrews ◽  
Kimiko Kuroki ◽  
Hiroki Kusaka ◽  
Takashi Tadokoro ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Immune Regulation ◽  
Titration Calorimetry ◽  
Viral Control ◽  
Mhc I ◽  
Infected People ◽  
Sorting Motif ◽  
Α Helix ◽  
Hiv 1

SummaryThe HIV accessory protein Nef plays a major role in establishing and maintaining infection, particularly through immune evasion. Many HIV-2 infected people experience long-term viral control and survival, resembling HIV-1 elite control. HIV-2 Nef has overlapping but also distinct functions from HIV-1 Nef. Here we report the crystal structure of HIV-2 Nef core. The dileucine sorting motif forms a helix bound to neighboring molecules, and moreover, isothermal titration calorimetry demonstrated that the CD3 endocytosis motif can directly bind to HIV-2 Nef, ensuring AP-2 mediated endocytosis for CD3. The highly-conserved C-terminal region forms a α-helix, absent from HIV-1. We further determined the structure of SIV Nef harboring this region, demonstrating similar C-terminal α-helix, which may contribute to AP-1 binding for MHC-I downregulation. These results provide new insights into the distinct pathogenesis of HIV-2 infection.

scholarly journals Expression of Nef Downregulates CXCR4, the Major Coreceptor of Human Immunodeficiency Virus, from the Surfaces of Target Cells and Thereby Enhances Resistance to Superinfection

2006 ◽  
Vol 80 (22) ◽  
pp. 11141-11152 ◽  
Author(s):  
Stephanie Venzke ◽  
Nico Michel ◽  
Ina Allespach ◽  
Oliver T. Fackler ◽  
Oliver T. Keppler
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Maximum Level ◽  
Target Cells ◽  
Class I Mhc ◽  
Mhc I ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Stromal Cell Derived Factor ◽  
Hiv 1

ABSTRACT Lentiviral Nef proteins are key factors for pathogenesis and are known to downregulate functionally important molecules, including CD4 and major histocompatibility complex class I (MHC-I), from the surfaces of infected cells. Recently, we demonstrated that Nef reduces cell surface levels of the human immunodeficiency virus type 1 (HIV-1) entry coreceptor CCR5 (N. Michel, I. Allespach, S. Venzke, O. T. Fackler, and O. T. Keppler, Curr. Biol. 15:714-723, 2005). Here, we report that Nef downregulates the second major HIV-1 coreceptor, CXCR4, from the surfaces of HIV-infected primary CD4 T lymphocytes with efficiencies comparable to those of the natural CXCR4 ligand, stromal cell-derived factor-1 alpha. Analysis of a panel of mutants of HIV-1SF2 Nef revealed that the viral protein utilized the same signature motifs for downmodulation of CXCR4 and MHC-I, including the proline-rich motif P73P76P79P82 and the acidic cluster motif E66E67E68E69. Expression of wild-type Nef, but not of specific Nef mutants, resulted in a perinuclear accumulation of the coreceptor. Remarkably, the carboxy terminus of CXCR4, which harbors the classical motifs critical for basal and ligand-induced receptor endocytosis, was dispensable for the Nef-mediated reduction of surface exposure. Functionally, the ability of Nef to simultaneously downmodulate CXCR4 and CD4 correlated with maximum-level protection of Nef-expressing target cells from fusion with cells exposing X4 HIV-1 envelopes. Furthermore, the Nef-mediated downregulation of CXCR4 alone on target T lymphocytes was sufficient to diminish cells' susceptibility to X4 HIV-1 virions at the entry step. The downregulation of chemokine coreceptors is a conserved activity of Nef to modulate infected cells, an important functional consequence of which is an enhanced resistance to HIV superinfection.

scholarly journals HIV-1 Nef Antagonizes SERINC5 Restriction by Downregulation of SERINC5 via the Endosome/Lysosome System

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
Jing Shi ◽  
Ran Xiong ◽  
Tao Zhou ◽  
Peiyi Su ◽  
Xihe Zhang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Viral Pathogenesis ◽  
Living Cells ◽  
Restriction Factor ◽  
Accessory Protein ◽  
Viral Infectivity ◽  
Bafilomycin A1 ◽  
Mhc I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACTThe primate lentiviral accessory protein Nef downregulates CD4 and major histocompatibility complex class I (MHC-I) from the cell surface via independent endosomal trafficking pathways to promote viral pathogenesis. In addition, Nef antagonizes a novel restriction factor, SERINC5 (Ser5), to increase viral infectivity. To explore the molecular mechanism of Ser5 antagonism by Nef, we determined how Nef affects Ser5 expression and intracellular trafficking in comparison to CD4 and MHC-I. We confirm that Nef excludes Ser5 from human immunodeficiency virus type 1 (HIV-1) virions by downregulating its cell surface expression via similar functional motifs required for CD4 downregulation. We find that Nef decreases both Ser5 and CD4 expression at steady-state levels, which are rescued by NH4Cl or bafilomycin A1 treatment. Nef binding to Ser5 was detected in living cells using a bimolecular fluorescence complementation assay, where Nef membrane association is required for interaction. In addition, Nef triggers rapid Ser5 internalization via receptor-mediated endocytosis and relocalizes Ser5 to Rab5+early, Rab7+late, and Rab11+recycling endosomes. Manipulation of AP-2, Rab5, Rab7, and Rab11 expression levels affects the Nef-dependent Ser5 and CD4 downregulation. Moreover, although Nef does not promote Ser5 polyubiquitination, Ser5 downregulation relies on the ubiquitination pathway, and both K48- and K63-specific ubiquitin linkages are required for the downregulation. Finally, Nef promotes Ser5 colocalization with LAMP1, which is enhanced by bafilomycin A1 treatment, suggesting that Ser5 is targeted to lysosomes for destruction. We conclude that Nef uses a similar mechanism to downregulate Ser5 and CD4, which sorts Ser5 into a point-of-no-return degradative pathway to counteract its restriction.IMPORTANCEHuman immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) express an accessory protein called Nef to promote viral pathogenesis. Nef drives immune escapein vivothrough downregulation of CD4 and MHC-I from the host cell surface. Recently, Nef was reported to counteract a novel host restriction factor, Ser5, to increase viral infectivity. Nef downregulates cell surface Ser5, thus preventing its incorporation into virus particles, resulting in disruption of its antiviral activity. Here, we report mechanistic studies of Nef-mediated Ser5 downregulation in comparison to CD4 and MHC-I. We demonstrate that Nef binds directly to Ser5 in living cells and that Nef-Ser5 interaction requires Nef association with the plasma membrane. Subsequently, Nef internalizes Ser5 from the plasma membrane via receptor-mediated endocytosis, and targets ubiquitinated Ser5 to endosomes and lysosomes for destruction. Collectively, these results provide new insights into our ongoing understanding of the Nef-Ser5 arms race in HIV-1 infection.

HIV-1 Nef-GCC185 interaction regulates assembly of cellular protein complexes at TGN targeting MHC-I downregulation

Life Sciences ◽  
2019 ◽  
Vol 229 ◽  
pp. 13-20
Author(s):  
Sushila Kumari ◽  
Manjeet Kumar ◽  
Richa Verma ◽  
Jimut Kanti Ghosh ◽  
Raj Kamal Tripathi
Keyword(s):  
Protein Complexes ◽  
Cellular Protein ◽  
Mhc I ◽  
Hiv 1

scholarly journals Computational MHC-I epitope predictor identifies 95% of experimentally mapped HIV-1 clade A and D epitopes in a Ugandan cohort

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Daniel Lule Bugembe ◽  
Andrew Obuku Ekii ◽  
Nicaise Ndembi ◽  
Jennifer Serwanga ◽  
Pontiano Kaleebu ◽  
...  
Keyword(s):  
Mhc I ◽  
Hiv 1
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