The PTAP Sequence within the p6 Domain of Human Immunodeficiency Virus Type 1 Gag Regulates Its Ubiquitination and MHC Class I Antigen Presentation

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) early gene product Nef is a multifunctional protein that alters numerous pathways of T-cell function, including endocytosis, signal transduction, vesicular trafficking, and immune modulation, and is a major determinant of pathogenesis. Individual Nef functions include PAK-2 activation, CD4 downregulation, major histocompatibility complex (MHC) class I downregulation, and enhancement of viral particle infectivity. How Nef accomplishes its multiple tasks presents a difficult problem of mechanistic analysis because of the complications associated with multiple, overlapping functional domains in the context of significant sequence variability. To address these issues we determined the conservation of each Nef residue based on 1,643 subtype B Nef sequences. Mutational analysis based on conservative substitutions and Nef sequence data allowed us to search for amino acids on the surface of Nef that are specifically required for PAK-2 activation. We found residues 85, 89, and 191 to be highly significant determinants for Nef's PAK-2 activation function but functionally unlinked to CD4 and MHC class I downregulation or enhancement of infectivity. These residues are not conserved across HIV-1 subtypes but are confined to separate sets of surface elements within a subtype. Thus, L85/H89/F191 and F85/F89/R191 are dominant in subtype B and subtype E or C, respectively. Our results provide support for developing subtype-specific interventions in HIV-1 disease.

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Differential Effects of Primary Human Immunodeficiency Virus Type 1 nef Sequences on Downregulation of CD4 and MHC Class I

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.5026 ◽

2001 ◽

Vol 284 (3) ◽

pp. 638-642 ◽

Cited By ~ 4

Author(s):

Keejung Yoon ◽

Jae Gyun Jeong ◽

Hayan Yoon ◽

Joo-Shil Lee ◽

Sunyoung Kim

Keyword(s):

Human Immunodeficiency Virus ◽

Mhc Class I ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Class I ◽

Differential Effects ◽

Immunodeficiency Virus

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Autoreactive cytotoxic T lymphocytes in human immunodeficiency virus type 1-infected subjects.

Journal of Experimental Medicine ◽

10.1084/jem.183.6.2509 ◽

1996 ◽

Vol 183 (6) ◽

pp. 2509-2516 ◽

Cited By ~ 39

Author(s):

F di Marzo Veronese ◽

D Arnott ◽

V Barnaba ◽

D J Loftus ◽

K Sakaguchi ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Lymphocytes ◽

Mhc Class I ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Class I ◽

Immunodeficiency Virus ◽

Hla A2.1 ◽

Hiv 1

A subtractive analysis of peptides eluted from major histocompatibility complex (MHC) class I human histocompatibility leukocyte antigen (HLA)-A2.1 molecules purified from either human immunodeficiency virus type-1 (HIV-1)-infected or uninfected cells was performed using micro high-performance liquid chromatography and mass spectrometry. Three peptides unique to infected cells were identified and found to derive from a single protein, human vinculin, a structural protein not known to be involved in viral pathogenesis. Molecular and cytofluorometric analyses revealed vinculin mRNA and vinculin protein overexpression in B and T lymphocytes from HIV-1-infected individuals. Vinculin peptide-specific CTL activity was readily elicited from peripheral blood lymphocytes of the majority of HLA-A2.1+, HIV+ patients tested. Our observations suggest that atypical vinculin expression and MHC class I-mediated presentation of vinculin-derived peptides accompany HIV infection of lymphoid cells in vivo, with a resultant induction of antivinculin CTL in a significant portion of HIV+ (HLA-A2.1+) individuals.

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Mutation of a Conserved Residue (D123) Required for Oligomerization of Human Immunodeficiency Virus Type 1 Nef Protein Abolishes Interaction with Human Thioesterase and Results in Impairment of Nef Biological Functions

Journal of Virology ◽

10.1128/jvi.74.11.5310-5319.2000 ◽

2000 ◽

Vol 74 (11) ◽

pp. 5310-5319 ◽

Cited By ~ 72

Author(s):

Lang Xia Liu ◽

Nikolaus Heveker ◽

Oliver T. Fackler ◽

Stefan Arold ◽

Sylvie Le Gall ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Mhc Class I ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

T Cell Activation ◽

Class I ◽

Viral Infectivity ◽

Immunodeficiency Virus ◽

Conserved Residue

ABSTRACT Nef is a myristoylated protein of 27 to 35 kDa that is conserved in primate lentiviruses. In vivo, Nef is required for high viral load and full pathological effects. In vitro, Nef has at least four activities: induction of CD4 and major histocompatibility complex (MHC) class I downregulation, enhancement of viral infectivity, and alteration of T-cell activation pathways. We previously reported that the Nef protein from human immunodeficiency virus type 1 interacts with a novel human thioesterase (hTE). In the present study, by mutational analysis, we identified a region of the Nef core, extending from the residues D108 to W124, that is involved both in Nef-hTE interaction and in Nef-induced CD4 downregulation. This region of Nef is located on the oligomer interface and is in close proximity to the putative CD4 binding site. One of the mutants carrying a mutation in this region, targeted to the conserved residue D123, was also found to be defective in two other functions of Nef, MHC class I downmodulation and enhancement of viral infectivity. Furthermore, mutation of this residue affected the ability of Nef to form dimers, suggesting that the oligomerization of Nef may be critical for its multiple functions.

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

Journal of Virology ◽

10.1128/jvi.77.3.2124-2133.2003 ◽

2003 ◽

Vol 77 (3) ◽

pp. 2124-2133 ◽

Cited By ~ 67

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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Faculty Opinions recommendation of A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718386627.793495240 ◽

2014 ◽

Author(s):

Angus Dalgleish

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Histone Deacetylases ◽

Class I ◽

Immunodeficiency Virus

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Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes

Journal of Virology ◽

10.1128/jvi.01580-06 ◽

2006 ◽

Vol 81 (4) ◽

pp. 1619-1631 ◽

Cited By ~ 64

Author(s):

Xu G. Yu ◽

Mathias Lichterfeld ◽

Senica Chetty ◽

Katie L. Williams ◽

Stanley K. Mui ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Viral Escape ◽

Class I ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703+ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

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HLA Class I Alleles Associated with Susceptibility or Resistance to Human Immunodeficiency Virus Type 1 Infection among a Population in Chaco Province, Argentina

The Journal of Infectious Diseases ◽

10.1086/315854 ◽

2000 ◽

Vol 182 (5) ◽

pp. 1523-1526 ◽

Cited By ~ 21

Author(s):

Alicia Habegger de Sorrentino ◽

Karina Marinic ◽

Patricia Motta ◽

Adrián Sorrentino ◽

Roxana López ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Class I ◽

Immunodeficiency Virus ◽

Chaco Province

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Favorable and Unfavorable HLA Class I Alleles and Haplotypes in Zambians Predominantly Infected with Clade C Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.76.16.8276-8284.2002 ◽

2002 ◽

Vol 76 (16) ◽

pp. 8276-8284 ◽

Cited By ~ 106

Author(s):

Jianming Tang ◽

Shenghui Tang ◽

Elena Lobashevsky ◽

Angela D. Myracle ◽

Ulgen Fideli ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Class I ◽

Hla Class I Molecules ◽

Immunodeficiency Virus ◽

Clade C ◽

Hiv 1

ABSTRACT The setpoint of viral RNA concentration (viral load [VL]) during chronic human immunodeficiency virus type 1 (HIV-1) infection reflects a virus-host equilibration closely related to CD8+ cytotoxic T-lymphocyte (CTL) responses, which rely heavily on antigen presentation by the human major histocompatibility complex (MHC) (i.e., HLA) class I molecules. Differences in HIV-1 VL among 259 mostly clade C virus-infected individuals (137 females and 122 males) in the Zambia-UAB HIV Research Project (ZUHRP) were associated with several HLA class I alleles and haplotypes. In particular, general linear model analyses revealed lower log10 VL among those with HLA allele B*57 (P = 0.002 [without correction]) previously implicated in favorable response and in those with HLA B*39 and A*30-Cw*03 (P = 0.002 to 0.016); the same analyses also demonstrated higher log10 VL among individuals with A*02-Cw*16, A*23-B*14, and A*23-Cw*07 (P = 0.010 to 0.033). These HLA effects remained strong (P = 0.0002 to 0.075) after adjustment for age, gender, and duration of infection and persisted across three orders of VL categories (P = 0.001 to 0.084). In contrast, neither B*35 (n = 15) nor B*53 (n = 53) showed a clear disadvantage such as that reported elsewhere for these closely related alleles. Other HLA associations with unusually high (A*68, B*41, B*45, and Cw*16) or low (B*13, Cw*12, and Cw*18) VL were either unstable or reflected their tight linkage respecting disequilibria with other class I variants. The three consistently favorable HLA class I variants retained in multivariable models and in alternative analyses were present in 30.9% of subjects with the lowest (<10,000 copies per ml) and 3.1% of those with the highest (>100,000) VL. Clear differential distribution of HLA profiles according to level of viremia suggests important host genetic contribution to the pattern of immune control and escape during HIV-1 infection.

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