AIDS pathogenesis: HIV envelope and its interaction with cell proteins

Habeshaw, J. A.; Dalgleish, Angus; Bountiff, Lynne; Newell, A.; Wilks, David; Walker, L. C.; Manca, Fabrizio

doi:10.1016/0167-5699(90)90162-3

Cited by 90 publications

(43 citation statements)

References 52 publications

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“…However, in our in vitro model, incubation of CD4 with anti-CD4 domain 1 antibodies up to 30 min did not reveal significant CD4 receptor endocytosis (data not shown). Other mechanisms, including dissociation of Lck from CD4 (42) and steric hindrance of CD4 participation during TCR-induced stimulation, have also been implicated (29,46,47,65). Epitope masking of CD4 molecules by gp120 or gp120-anti-gp120 complexes, thus blocking the interaction of CD4 with MHC in vivo, has also been alluded (2).…”

Section: Fig 4 Preengagement Of Cd4 Decreased Recruitment Of Lck Anmentioning

confidence: 99%

Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection

Nyakeriga

Fichtenbaum

Goebel

et al. 2009

J Virol

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Human immunodeficiency virus (HIV) infection is characterized by impaired cell-mediated immune responses, which are primarily manifested by a progressive decline in the number and function of CD4 ϩ T cells. Of note, the qualitative loss in the CD4 ϩ T-cell function begins well in advance of its quantitative decline during HIV infection (31, 59, 68), although there is a selective loss of memory/effector CD4 ϩ CCR5ϩ cells occurring early after HIV/simian immunodeficiency virus infection, particularly in the mucosal areas (reviewed in references 8, 52, and 55). This implies that the impairment in immune response could be due to mechanisms other than direct viral destruction. HIV-1 binds through its envelope glycoprotein, gp120, to the CD4 receptor molecule (13). The CD4 receptor plays a critical role during antigenic stimulation by major histocompatibility complex (MHC)-bearing cells. It is important in subsequent signal transduction through activation of the CD4-associated tyrosine kinase, p56Lck (Lck) (22), which in turn modulates T-cell differentiation as well as T-cell receptor (TCR)-induced signaling (67). This phenomenon could involve an up-or a downregulation of signaling effects depending on the timing of CD4 engagement relative to TCR-induced stimulation (26). Indeed, in vitro studies have demonstrated that CD4-induced stimulation, in the absence of or prior to TCR engagement, leads to apoptosis of the cell (1, 5) or inhibition of subsequent TCR-induced T-cell activation (6), which underscores the possible role of CD4 engagement in HIV pathogenesis.Lck is a member of the Src family of non-receptor tyrosine kinases expressed primarily in thymocytes and lymphocytes and predominantly in T cells. In MHC II-restricted T cells, approximately 75 to 95% of cellular Lck is found associated with the cytoplasmic portion of CD4, involving about 85 to 95% of CD4 molecules (7). Lck interacts specifically with CD4 molecule through a dicysteine motif which binds to a corresponding motif in the cytoplasmic domain of the CD4 molecule (62). TCR-induced signaling involves the activation of lck, which, in turn, phosphorylates the immuno-receptor tyrosine activation motifs (ITAMs) within the TCR complex, as well as the tyrosine kinase ZAP-70 that docks onto the phosphorylated ITAMs. In T lymphocytes, following stimulation, Lck redistributes into lipid rafts and accumulates at the stable region between T cells and antigen-presenting cells, the immunological synapse (IS) (20,43,60). Together with cytoskeletal reorganization (15,27,34,66), the membrane lipid raft domains are thought to orchestrate protein interactions in space and time by regulating raft coalescence and/or to control the recruitment of proteins to these domains. The temporal and

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Section: Fig 4 Preengagement Of Cd4 Decreased Recruitment Of Lck Anmentioning

confidence: 99%

Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection

Nyakeriga

Fichtenbaum

Goebel

et al. 2009

J Virol

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“…The virus grows exponentially and declines as a function of the immune reaction. The latter is supposedly due to specific antibodies and/or to cytotoxic T cells (3,21,23,24). For simplicity, we here assume that the immune reaction is proportional to the concentration of HIV-specific CD4+ helper T cells.…”

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confidence: 99%

Diversity and virulence thresholds in AIDS

Boer¹,

Boerlijst²

1996

Models for Infectious Human Diseases

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We propose a model for the interaction between human immunodeficiency virus and the immune system. Two differential equations describe the interactions between one strain of virus and one clone of T lymphocytes. We use the model to generalize earlier results pertaining to the AIDS diversity threshold [Nowak, M. A., Anderson, R. M., McLean The development of AIDS is associated with the selective depletion of the most crucial cell type of the immune system: the CD4+ helper T cell. The human immunodeficiency virus (HIV) infects helper T cells by binding the gpl20 virus envelope glycoprotein to CD4+ molecules (1). The selective infection and death of CD4+ T cells provides a simple explanation for the impairment of the immune system (2, 3). This explanation, however, is widely debated (4-7).One hallmark of HIV infection is the long and variable incubation period. Although the processes of infection and immune activation have a short time scale, a typical time scale for the incubation period is 10 years (8). Another hallmark of HIV is its enormous genetic diversity. The dominant surface antigen for the immune response is the V3 loop of gpl20 (9,10). This V3 loop is hypervariable: virus isolates from one infected individual have genetically different V3 loops (11, 12). Since HIV accumulates one point mutation per genome during an average replication cycle (12,13), the genetic variability will grow exponentially. However, antigenic variability is not unique to HIV: several pathogens possess antigenic variability which lets them "run ahead" of the immune response.A recent model (14-17) combines these two hallmarks of AIDS in that it attributes the long and variable incubation period to genetic variability. The authors of the model coinedThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. the term "diversity threshold" for the critical variability beyond which the immune system is no longer capable of controlling the virus. The diversity threshold emerges mathematically from their simple and quite reasonable model. The diversity threshold (14-17) is a generic property of a wide variety of models. (See refs. 17 and 18 for recent reviews of mathematical models for the various pathogenic effects of HIV.)The virus quasispecies (19) not only increases in diversity but also evolves physiologically different strains. Virus strains evolve different replication rates, cytotrophisms, and antigenicities (20)(21)(22). Here we develop a model that allows us to study the relation between the diversity of the virus quasispecies and the "virulence" of each virus strain. We derive a dimensionless virulence parameter and show that it is involved in well-known local and global bifurcations. Models of the Immune Response to HIVOur models describe the interactions between one strain of virus vj, where j is the strain number, and the clone(s) of CD4+ T cells tj that recognizes thi...

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“…This has been reported by several authors in different experimental systems [7][8][9][10][11][12][13][14][15] and recently reviewed by us [31]. Furthermore, "pretreatment of CD4+ antigen-specific T cells with soluble gpl20 enhances its inhibitory effect for antigendriven proliferation [32].…”

Section: Discusstonmentioning

confidence: 71%

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

Manca

Walker

Newell

et al. 1992

Clinical and Experimental Immunology

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SUMMARYHIV-1 envelope glycoprotein (gpl20), as a CD4-binding reactant, has been shown to inhibit in its native form human T cell responses to several antigens. Here we show that gp 120 in soluble form also inhibits activation ofa specific human T cell line that responds to gpl20-pulsed autologous antigenpresenting cells. In addition the inhibitory property of gpl20 for antigen-driven Tcell proliferation depends upon its ability to bind CD4 and is lost when CD4-binding capacity is abolished by denaturation, or blocked by complexing with soluble CD4 or with polyclonal antibodies. In contrast, antigenicity of denatured or complexed gpl 20 for specific human T cells is preserved. Similar effects are also observed with another CD4-binding reactant (i,e, anti-Leu 3a MoAb), which stimulates and/ or inhibits human T cells specific for mouse immunoglobulins depending on native or denatured conformation.Keywords gpl20 antigenicity T clones gpl20-CD4 complexes CD4 binding proteins tNTRODUCTtONThe antigen-specific response ofthe CD4+ T lymphocyte subset is MHC class II restricted [1], Interaction between CD4 and MHC Class II facilitates functional association between T lymphocytes and the antigen-presenting cells (APC) and enhances T cell receptor interaction with the presented peptide antigen [2,3], The envelope glycoprotein of HIV-1, gpl60, is composed of two moieties, gpl20 and gp41, one of which (gpl20) binds CD4 with high affinity [4], Interaction between gpl20 and CD4 accounts for the cellular tropism of the HIV-1 retrovirus [5,6], Antigen-specific activation ofT cells restricted to MHC class II can be prevented by the interaction of gpl20 with CD4, as well as by MoAb which block both MHC class II-CD4 association and gpl20-CD4 binding [7][8][9][10][11][12][13][14][15],The immunogenic properties of gpl20 have been demonstrated in both infected and uninfected individuals [16][17][18][19][20][21][22][23], Human T cell lines specific for gpl20 can also be generated in vitro from seronegative donors by pulsing irradiated autologous APC with gpl20, or exposing lymphocytes to low doses of soluble gpl20 [24][25][26], Since antigen processing by APC involves antigen fragmentation and loss of native conformation [27], it is likely that degradation of gpl20 results in loss of CD4-binding capacity and henceinhibitory activity of gpl 20 which is strictly dependent on native conformation. To test this hypotheCorrespondence: F, Manca MD, Department of Immunology, University of Genoa, San Martino Hospital, viale Benedetto XV, 10, 16132 Genoa, Italy, sis we compared the CD4-binding capacity of gpl20 with (i) inhibitory activity (i,e, capacity to interfere with antigen-driven T cell activation) and (ii) antigenicity (i,e, ability to stimulate gpl20-specific human T cell lines and clones).In a comparable system we also demonstrate that another CD4 binding reactant (the CD4-specific MoAb anti-Leu 3a) which inhibits antigen-specific T cell responses in native form, retains its antigenicity for human T cells specific for mouse immunoglobul...

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AIDS pathogenesis: HIV envelope and its interaction with cell proteins

Cited by 90 publications

References 52 publications

Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection

Engagement of the CD4 Receptor Affects the Redistribution of Lck to the Immunological Synapse in Primary T Cells: Implications for T-Cell Activation during Human Immunodeficiency Virus Type 1 Infection

Diversity and virulence thresholds in AIDS

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

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