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Chapter 11 : T-Lymphocyte Immune Responses in HIV Infection
Author:
Jay A. Levy1
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Affiliations:
1: Department of Medicine, Laboratory for Tumor and AIDS Virus Research and Cancer Research Institute University of California, School of Medicine San Francisco, California
Content Type: Monograph
Publication Year:
2007
Category: Viruses and Viral Pathogenesis
Book DOI:
10.1128/9781555815653
Chapter DOI:
10.1128/9781555815653.ch11
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Abstract:
In most viral infections, the cell-mediated immune response plays a vital role in arresting or eliminating the infectious agent. For HIV, this antiviral activity involves both the innate and adaptive immune systems. This chapter provides a review of the adaptive T-cell immune responses that appear to be directed against HIV through recognition of viral proteins associated with HIV or virus-infected cells. Since HIV infection disturbs the immune system, some of the findings also have direct relevance to this discussion. In addition, the noncytotoxic anti-HIV activity of CD8+ cells that appears to be an innate immune activity is reviewed. The chapter concludes with a discussion of T regulatory cells.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
Figures
T-Lymphocyte Immune Responses in HIV Infection
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig01
Figure 11.1
Differentiation of CD4+ lymphocytes. This overall development of various T-cell subsets is mirrored as well in the formation of CD8+ T-cell subsets. Naïve cells after exposure to antigen develop into effector cells, which in terms of CD4+ cells are of the TH1 or TH2 type (
Table 11.2
). Effector cells can revert to effector/memory cells or resting (central) memory cells in the presence of low antigen. With reexposure to antigens, the T effector memory cells quickly respond and evolve into terminal effector cells. These cells are shortlived with high antigen specificity and, particularly in the case of CD8+ cells, show cytotoxic activity. Figure from reference 1340.
10.1128/9781555815653/f0260-01_thmb.gif
10.1128/9781555815653/f0260-01.gif
Figure 11.1
Differentiation of CD4+ lymphocytes. This overall development of various T-cell subsets is mirrored as well in the formation of CD8+ T-cell subsets. Naïve cells after exposure to antigen develop into effector cells, which in terms of CD4+ cells are of the TH1 or TH2 type ( Table 11.2 ). Effector cells can revert to effector/memory cells or resting (central) memory cells in the presence of low antigen. With reexposure to antigens, the T effector memory cells quickly respond and evolve into terminal effector cells. These cells are shortlived with high antigen specificity and, particularly in the case of CD8+ cells, show cytotoxic activity. Figure from reference 1340.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig02
Figure 11.2
Generation of the T-cell repertoire. (a) Undifferentiated lymphoid stem cells (prothymocytes), as they pass through the thymus, express CD4 and CD8 molecules. Their T-cell receptor (TCR) genes are rearranged and expressed, and the resulting thymocytes undergo negative and positive selection. T-cell clones released into circulation have a diverse TCR pattern, indicating their potential for polyclonal responses. (b) With destruction of T cells by HIV, a limited T-cell repertoire may exist which, when allowed to regenerate through a variety of therapeutic interventions, may not recover the entire repertoire initially present in the host. (c) The end-stage T-cell repertoire may be limited so that it cannot react quickly to a particular antigen. In a sense, as shown here, the T-cell repertoire could not respond in a way that would require the spelling of ZEBRA. Nevertheless, by other processes, it might be able to respond (although more slowly) by recognizing the antigen as “a horse with white and black stripes.” Ideas derived from figures and discussions provided by H. Cliff Lane.
10.1128/9781555815653/f0262-01_thmb.gif
10.1128/9781555815653/f0262-01.gif
Figure 11.2
Generation of the T-cell repertoire. (a) Undifferentiated lymphoid stem cells (prothymocytes), as they pass through the thymus, express CD4 and CD8 molecules. Their T-cell receptor (TCR) genes are rearranged and expressed, and the resulting thymocytes undergo negative and positive selection. T-cell clones released into circulation have a diverse TCR pattern, indicating their potential for polyclonal responses. (b) With destruction of T cells by HIV, a limited T-cell repertoire may exist which, when allowed to regenerate through a variety of therapeutic interventions, may not recover the entire repertoire initially present in the host. (c) The end-stage T-cell repertoire may be limited so that it cannot react quickly to a particular antigen. In a sense, as shown here, the T-cell repertoire could not respond in a way that would require the spelling of ZEBRA. Nevertheless, by other processes, it might be able to respond (although more slowly) by recognizing the antigen as “a horse with white and black stripes.” Ideas derived from figures and discussions provided by H. Cliff Lane.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig03
Figure 11.3
Cytokine-driven type 1 cell differentiation. Bacteria, protozoa, probably viruses, and helminths can induce the production of IL-12 by macrophages or other cells. IL-12 then induces differentiation of naïve or TH0 cells into a TH1 subset, which encourages cell-mediated immunity. Other pathogens, particularly helminths, stimulate IL-4 production by cells not yet defined. IL-4 induces TH0 cells toward TH2 cell differentiation. The TH2 cells mediate help for antibody production. What determines the predominant TH1 (type 1) or TH2 (type 2) response in the host is not known. Modified from reference 4023 with permission. Copyright 1993 AAAS.
10.1128/9781555815653/f0266-01_thmb.gif
10.1128/9781555815653/f0266-01.gif
Figure 11.3
Cytokine-driven type 1 cell differentiation. Bacteria, protozoa, probably viruses, and helminths can induce the production of IL-12 by macrophages or other cells. IL-12 then induces differentiation of naïve or TH0 cells into a TH1 subset, which encourages cell-mediated immunity. Other pathogens, particularly helminths, stimulate IL-4 production by cells not yet defined. IL-4 induces TH0 cells toward TH2 cell differentiation. The TH2 cells mediate help for antibody production. What determines the predominant TH1 (type 1) or TH2 (type 2) response in the host is not known. Modified from reference 4023 with permission. Copyright 1993 AAAS.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig04
Figure 11.4
Cross-regulation of the TH1 and TH2 subsets of CD4+ cells. The production of certain cytokines by TH1 and TH2 cells can suppress production of cytokines by the corresponding cell subset (3786). From reference 2520 with permission.
10.1128/9781555815653/f0267-01_thmb.gif
10.1128/9781555815653/f0267-01.gif
Figure 11.4
Cross-regulation of the TH1 and TH2 subsets of CD4+ cells. The production of certain cytokines by TH1 and TH2 cells can suppress production of cytokines by the corresponding cell subset (3786). From reference 2520 with permission.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig05
Figure 11.5
Effect of CD8+ cells and CD8+ cell antiviral factor (CAF) on parameters of HIV replication. The CD8+ cell noncytotoxic antiviral response blocks viral replication, as indicated by decreased reverse transcriptase (RT) activity, viral protein expression measured by immunofluorescent antibody (IFA) techniques, and in situ RNA production. This activity has no effect on the number of infected cells in the culture. The antiviral effect is observed as well in a reduction in unspliced (us), single-spliced (ss), and double-spliced (ds) HIV RNA levels compared to a normal expression of β-actin RNA. Finally, the suppressing effect of CD8+ cells or CAF does not affect the basal-level expression of HIV LTR-driven transcription but blocks induction of this transcription by HIV, simian virus 40 tat expression, or phorbol myristate acetate (PMA) using cells in which the HIV LTR has been linked to a reporter gene (2738).
10.1128/9781555815653/f0280-01_thmb.gif
10.1128/9781555815653/f0280-01.gif
Figure 11.5
Effect of CD8+ cells and CD8+ cell antiviral factor (CAF) on parameters of HIV replication. The CD8+ cell noncytotoxic antiviral response blocks viral replication, as indicated by decreased reverse transcriptase (RT) activity, viral protein expression measured by immunofluorescent antibody (IFA) techniques, and in situ RNA production. This activity has no effect on the number of infected cells in the culture. The antiviral effect is observed as well in a reduction in unspliced (us), single-spliced (ss), and double-spliced (ds) HIV RNA levels compared to a normal expression of β-actin RNA. Finally, the suppressing effect of CD8+ cells or CAF does not affect the basal-level expression of HIV LTR-driven transcription but blocks induction of this transcription by HIV, simian virus 40 tat expression, or phorbol myristate acetate (PMA) using cells in which the HIV LTR has been linked to a reporter gene (2738).
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig06
Figure 11.6
Effect of cytokines on the CD8+ cell noncytotoxic anti-HIV response. CD8+ cells were stimulated in the presence of type 1 or type 2 cytokines for 3 days. After being washed, they were tested for their ability to suppress HIV replication in acutely infected CD4+ lymphocytes. From reference 258 with permission.
10.1128/9781555815653/f0282-01_thmb.gif
10.1128/9781555815653/f0282-01.gif
Figure 11.6
Effect of cytokines on the CD8+ cell noncytotoxic anti-HIV response. CD8+ cells were stimulated in the presence of type 1 or type 2 cytokines for 3 days. After being washed, they were tested for their ability to suppress HIV replication in acutely infected CD4+ lymphocytes. From reference 258 with permission.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig07
Figure 11.7
Costimulation of CD8+ T cells. The lymphocyte response is optimal following the interaction of the T-cell receptor (TCR) with an MHC class I molecule associated with antigen, together with the interaction of the CD28 molecules on the T cells with the B7 molecules on antigen-presenting cells [APC]) (e.g., macrophages and dendritic cells). The response appears to be mediated by increased IL-2 production and expression of the IL-2 receptor (IL-2R) (663, 3282). A role of IL-15 produced by the APC has also been noted (635).
10.1128/9781555815653/f0283-01_thmb.gif
10.1128/9781555815653/f0283-01.gif
Figure 11.7
Costimulation of CD8+ T cells. The lymphocyte response is optimal following the interaction of the T-cell receptor (TCR) with an MHC class I molecule associated with antigen, together with the interaction of the CD28 molecules on the T cells with the B7 molecules on antigen-presenting cells [APC]) (e.g., macrophages and dendritic cells). The response appears to be mediated by increased IL-2 production and expression of the IL-2 receptor (IL-2R) (663, 3282). A role of IL-15 produced by the APC has also been noted (635).
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig08
Figure 11.8
When CD8+ cells are stimulated in the presence of antibodies to the T-cell receptor (TCR) complex (anti-CD3 antibody) together with antibodies to the costimulatory molecule CD28, their ability to suppress HIV replication in infected CD4+ cells is increased both in asymptomatic individuals and particularly in AIDS patients (progressors). From reference 255 with permission. © 1997 The American Association of Immunologists, Inc.
10.1128/9781555815653/f0284-01_thmb.gif
10.1128/9781555815653/f0284-01.gif
Figure 11.8
When CD8+ cells are stimulated in the presence of antibodies to the T-cell receptor (TCR) complex (anti-CD3 antibody) together with antibodies to the costimulatory molecule CD28, their ability to suppress HIV replication in infected CD4+ cells is increased both in asymptomatic individuals and particularly in AIDS patients (progressors). From reference 255 with permission. © 1997 The American Association of Immunologists, Inc.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11fig09
Figure 11.9
Quantity of CD8+ cell antiviral factor (CAF) produced by CD8+ cells. Dilutions of CAF-containing fluid from cultured CD8+ cells from an asymptomatic individual indicate that a 1:4 dilution will still show a 50% reduction in HIV replication as measured by virus reverse transcriptase (RT) activity in the culture fluid. Fluids from CD8+ cells of healthy uninfected individuals or those with AIDS do not show evidence of CAF production.
10.1128/9781555815653/f0284-02_thmb.gif
10.1128/9781555815653/f0284-02.gif
Figure 11.9
Quantity of CD8+ cell antiviral factor (CAF) produced by CD8+ cells. Dilutions of CAF-containing fluid from cultured CD8+ cells from an asymptomatic individual indicate that a 1:4 dilution will still show a 50% reduction in HIV replication as measured by virus reverse transcriptase (RT) activity in the culture fluid. Fluids from CD8+ cells of healthy uninfected individuals or those with AIDS do not show evidence of CAF production.
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
References
/content/book/10.1128/9781555815653.ch11
Tables
T-Lymphocyte Immune Responses in HIV Infection
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab01
Table 11.1
Comparisons of assays for T-cell responses
a
Table 11.1
Comparisons of assays for T-cell responses a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab02
Table 11.2
Characterization of CD4+ T helper cell subsets
Table 11.2
Characterization of CD4+ T helper cell subsets
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab03
Table 11.3
Human CD4+ T-cell subset heterogeneity
a
Table 11.3
Human CD4+ T-cell subset heterogeneity a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab04
Table 11.4
Human CD8 T-cell subset heterogeneity
Table 11.4
Human CD8 T-cell subset heterogeneity
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab05
Table 11.5
Anti-HIV responses by CD8+ T cells
Table 11.5
Anti-HIV responses by CD8+ T cells
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab06
Table 11.6
Possible mechanisms of virus resistance to anti-HIV CTL activity
a
Table 11.6
Possible mechanisms of virus resistance to anti-HIV CTL activity a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab07
Table 11.7
Possible evidence for detrimental effects of CD8+ CTL activity in HIV infection
a
Table 11.7
Possible evidence for detrimental effects of CD8+ CTL activity in HIV infection a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab08
Table 11.8
Characteristics of the CD8+ cell noncytotoxic anti-HIV response (CNAR)
Table 11.8
Characteristics of the CD8+ cell noncytotoxic anti-HIV response (CNAR)
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab09
Table 11.9
CD8+ cell noncytotoxic antiviral response is part of the innate immune system
Table 11.9
CD8+ cell noncytotoxic antiviral response is part of the innate immune system
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab10
Table 11.10
Potential clinical value of CD8+ cell noncytotoxic antiviral activity in HIV infection
Table 11.10
Potential clinical value of CD8+ cell noncytotoxic antiviral activity in HIV infection
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab11
Table 11.11
Characteristics of the CD8+ cell anti-HIV factor
a
Table 11.11
Characteristics of the CD8+ cell anti-HIV factor a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab12
Table 11.12
Proteins lacking identity to the CD8+ cell antiviral factor (CAF)
Table 11.12
Proteins lacking identity to the CD8+ cell antiviral factor (CAF)
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab13
Table 11.13
Natural human factors with anti-HIV activity
Table 11.13
Natural human factors with anti-HIV activity
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11
/content/10.1128/9781555815653.ch11.ch11tab14
Table 11.14
Characteristics of human CD4+ T regulatory cells
a
Table 11.14
Characteristics of human CD4+ T regulatory cells a
Citation:
Levy J.
2007.
T-Lymphocyte Immune Responses in HIV Infection,
p 259-292.
In
HIV and the Pathogenesis of AIDS, Third Edition.
ASM Press, Washington, DC.
doi: 10.1128/9781555815653.ch11