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Cytokine networks during HIV infection: Shifting the balance
Cytokine & Growth Factor Reviews 23 (2012) 139–141
Contents lists available at SciVerse ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Foreword
Cytokine networks during HIV infection: Shifting the balance
It has been almost 30 years since the discovery that HIV-1 causes Acquired Immunodeficiency Syndrome (AIDS) [1]. Since then, all levels of academic, government, and industrial research have directed an unparalleled effort toward understanding the molecular biology of the virus, the host immune responses to the virus, and the pathogenesis of disease. This accumulated knowledge has been harnessed to develop effective antiviral therapies that have changed the clinical landscape and management of the AIDS pandemic in developed countries. Despite ground-breaking discoveries that changed the lives of millions of people living with HIV/AIDS, ongoing research continues to unravel the intricate interrelationships between the HIV-1 and the host immune response, with the dual goal of eradicating residual virus in patients undergoing antiviral therapy and developing efficacious and protective vaccines that would stem the HIV/AIDS pandemic in the developing world. The invited reviews presented in this special edition of Cytokine and Growth Factor Reviews entitled ‘‘Cytokine networks regulating HIV infection: Shifting the balance’’ examine three major areas current in HIV/AIDS research: (1) the interplay between cytokines and HIV pathogenesis; (2) HIV latency and persistence, with discussion of novel strategies aimed at the eradication of HIV; and (3) development of HIV vaccines and immunotherapies. It is one of the rare occasions that such a topic has been addressed in this or other review formats. The hallmark of HIV infection is global activation of the immune response that begins early in infection, persists through the chronic stages of disease [2,3], and is even maintained in subjects receiving anti-retroviral therapy. This hyperactivation alters the local and systemic microenvironment and systematically perturbs T cell, B cell, and innate immunity. In fact, infection with HIV leads to gradual loss of CD4+ T cells (specifically in the functional memory T cell compartment) [4,5]. HIV infection also leads to dysfunction of T cells through the upregulation of receptors that negatively regulate T cell functions. For example, the increase in PD-1, LAG3, and CTLA-4 expression levels dampens CD8+ and CD4+ T cell proliferation and cytokine production [6–8]. HIV-associated immune activation also interferes with humoral defenses; most HIV-infected subjects fail to produce protective anti-HIV antibodies and have diminished responses to neo and recall non-HIV and HIV antigens and vaccines [9–11]. Innate immunity is also compromised during HIV infection; dendritic cells have reduced numbers and impaired function in HIV-infected individuals. Plasmacytoid dendritic cells have diminished capacity to produce IFN-a in vivo and in vitro in response to TLR triggering [12,13]. Understanding how changes in the cytokine, chemokine, and interferon networks impact HIV pathogenesis, latency, and persistence and vaccine design is essential for the development 1359-6101/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2012.05.012
of therapeutic vaccine and eradication strategies. These topics are the subject of the reviews of this issue of CGFR. 1. HIV latency and persistence Remoli and colleagues describe how modulation of transcription factor function can impact HIV gene expression and persistence. The authors describe the roles of NF-kB, IRFs, pTEFb, and other factors in the life cycle of HIV-1 and how these factors influence virus integration and/or re-activation. They suggest that therapeutic targeting of these factors may provide valuable tools to purge the viral reservoir. Evans et al. discuss how signaling through chemokine receptors alters T cell migration and influences the establishment of HIV latency. In particular, they focus on the chemokines CCL19 and CCL21 and their CCR7 receptors. Other chemokines such as CXCL9 and CXCL10 are also discussed in the context of HIV latency and reactivation. In addition, the authors also define strategies to interfere with chemokine–chemokine receptor interactions as a mechanistic strategy to modulate HIV viral latency. Vandergeeten and colleagues examine the role of cytokines in the reactivation and establishment of viral reservoir. They examine the impact of IL-7 and IL-15 on HIV infection in resting CD4+ T cells and how these cytokines impact the maintenance of latently infected CD4+ T cells during HAART. The authors further elaborate on how cytokines impact residual viral persistence and consequently viral eradication. 2. Immunotherapies and vaccines Pallinkkuth and colleagues describe the functional role of IL-21 production during HIV infection and provide new insights into the biology of IL-21 and its significance in enhancing T cell and B cell responses. The authors also discuss the potential therapeutic value of IL-21 and provide an update on numerous human clinical trials with IL-21. Reuter et al. discuss how differentiation programs of CD4 and CD8 T cell subsets are affected during HIV infection and propose that much could be learned about T cell immunity by studying successful and unsuccessful vaccine trials. This iterative approach to vaccine development would facilitate the design of novel interventions and vaccine strategies against HIV infection. Keating and colleagues summarize early and late events occurring in pathogenic and non-pathogenic HIV infection in humans and animal models and review recent literature on the production of cytokines from peripheral blood and tissues during HIV infection. In
140
Foreword / Cytokine & Growth Factor Reviews 23 (2012) 139–141
addition, they examine the relevance of these cytokines in the development of vaccines and immunotherapies, in the context of the most recent human trials involving IL-2, IFN-a, IL-7, and IL-15. Catalfamo and colleagues describe their studies on HIVassociated immune activation in HIV-infected subjects, with a focus on how the CD4 and CD8 T cell pools change during HIV infection. Catalfamo et al. define the role of cytokines and interferons in homeostatic proliferation of T cells in the context of altered HIV microenvironment and discuss the potential for vaccine studies using cytokines that control T cell homeostasis. 3. HIV pathogenesis Van Grevenynghe et al. examine the impact of cytokines, chemokines, and interferons on the regulatory transcription factor Foxo3a. The authors demonstrate that the microenvironment at sites of HIV infection alters the cytokine and interferon networks, leading to disruption of the balance of Foxo3a phosphorylation, which in turn favors Foxo3a translocation to the nucleus and transcriptional activation of pro-apoptotic genes. Interestingly, this regulatory circuit does not occur in HIV-infected subjects that naturally control the disease. Mir and Silvestri examine how cytokine and chemokine networks affect the capacity of monocytes, macrophages, and dendritic cells to contribute to immune activation, HIV dissemination, regulation of cell-specific restriction factors, and the establishment of viral reservoirs. The authors illustrate how HIV infection of these myeloid specific cell subsets alters the HIV microenvironment and promotes elevated production of inflammatory cytokines and interferons. Rancez and colleagues discuss how mucosal secretion of chemokines perturbs T cell trafficking during HIV infection. Rancez et al. examine tissue-specific chemokines and their role in the recruitment of immune cells and how this interplay perturbs the balance of cytokines and chemokines in the periphery and lymphatic tissues. Wang and Watts examine TNF and TNFR family members in regulating immune responses to HIV infection. The authors review the impact of these receptors on the ability to alter T cell and B cell
responses. These altered immune cell responses have major implications for vaccine development, as well as the establishment and maintenance of the latent HIV reservoir. In particular, this review focuses on the biology of CD40/CD40L interaction and the impact of TRAF1 in 4-1BB signaling. How these interactions regulate cytokine production and survival of immune cells is also discussed. Marsili et al. tackle the role of IFN signaling pathways and downstream transcription factors in regulating HIV replication and disease progression. The authors define how viral escape could occur through the binding of viral proteins—including Tat—to transcription factors such as the IRF family downstream of IFN signaling. The authors specifically review innate immune sensing of HIV and discuss the role of pattern recognition receptors (PRRs) in disease progression. Finally, the authors assess whether interferon response is beneficial or harmful during HIV infection. It should not escape the attention of readers of this Special Issue of CGFR that several invited authors—Chomont, Sekaly, Trautmann, the Guest Editor, Haddad, and the CGFR Editor, Hiscott—are located at the same institute. Indeed, it is our collective pleasure to introduce our new research home, the Vaccine & Gene Therapy Institute of Florida (VGTI Florida). VGTI Florida was founded in 2008 as part of a major economic initiative undertaken by the state of Florida to further develop the biomedical research industry in Florida by attracting top research institutes to the state. To date, Scripps Florida, Torrey Pines Institute for Molecular Studies, the Sanford-Burnham Research Institute, and Max Planck Florida, to name a few, have all established sister institutes in Florida as part of this initiative. VGTI Florida is a nonprofit research institute dedicated to the pursuit of translational research in the field of human immunology with a focus on infectious diseases, cancer immunotherapy, and chronic inflammatory disorders. Construction of the new 100,000sq.-ft. research institute located in Port St. Lucie, Florida, was completed in January 2012. The Institute currently houses a staff of nearly 90 individuals, utilizing state-of-the-art technologies and a systems biology approach to a comprehensive study of human immune function. As members of VGTI Florida, we are proud to introduce our new Institute and to present this integrated series of reviews on the subject of cytokine networks and HIV pathogenesis.
Foreword / Cytokine & Growth Factor Reviews 23 (2012) 139–141
References [1] Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868–71. [2] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine 2006;12:1365–71. [3] Douek D. HIV disease progression: immune activation, microbes, and a leaky gut. Topics in HIV Medicine 2007;15:114–7. [4] van Grevenynghe J, Halwani R, Chomont N, Ancuta P, Peretz Y, Tanel A, et al. Lymph node architecture collapse and consequent modulation of FOXO3a pathway on memory T- and B-cells during HIV infection. Seminars in Immunology 2008;20:196–203. [5] van Grevenynghe J, Procopio FA, He Z, Chomont N, Riou C, Zhang Y, et al. Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nature Medicine 2008;14:266–74. [6] Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006;443:350–4. [7] Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. Journal of Immunology 2009;182:5891–7. [8] Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Medicine 2006;12:1198–202. [9] Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O’Shea MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compart-
[10]
[11]
[12]
[13]
141
ment in HIV-infected viremic individuals. Journal of Experimental Medicine 2008;205:1797–805. Titanji K, De Milito A, Cagigi A, Thorstensson R, Grutzmeier S, Atlas A, et al. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood 2006;108:1580–7. van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, et al. Loss of memory B cells during chronic HIV infection is driven by Foxo3aand TRAIL-mediated apoptosis. Journal of Clinical Investigation 2011;121: 3877–88. Abb J, Kochen M, Deinhardt F. Interferon production in male homosexuals with the acquired immune deficiency syndrome (AIDS) or generalized lymphadenopathy. Infection 1984;12:240–2. Feldman S, Stein D, Amrute S, Denny T, Garcia Z, Kloser P, et al. Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors. Clinical Immunology 2001;101:201–10.
Elias K. Haddad* John Hiscott VGTI Florida, Port St. Lucie, Florida, USA *Corresponding author E-mail address: ehaddad@vgtifl.org (E.K. Haddad) Available online 4 July 2012
Contents lists available at SciVerse ScienceDirect
Cytokine & Growth Factor Reviews journal homepage: www.elsevier.com/locate/cytogfr
Foreword
Cytokine networks during HIV infection: Shifting the balance
It has been almost 30 years since the discovery that HIV-1 causes Acquired Immunodeficiency Syndrome (AIDS) [1]. Since then, all levels of academic, government, and industrial research have directed an unparalleled effort toward understanding the molecular biology of the virus, the host immune responses to the virus, and the pathogenesis of disease. This accumulated knowledge has been harnessed to develop effective antiviral therapies that have changed the clinical landscape and management of the AIDS pandemic in developed countries. Despite ground-breaking discoveries that changed the lives of millions of people living with HIV/AIDS, ongoing research continues to unravel the intricate interrelationships between the HIV-1 and the host immune response, with the dual goal of eradicating residual virus in patients undergoing antiviral therapy and developing efficacious and protective vaccines that would stem the HIV/AIDS pandemic in the developing world. The invited reviews presented in this special edition of Cytokine and Growth Factor Reviews entitled ‘‘Cytokine networks regulating HIV infection: Shifting the balance’’ examine three major areas current in HIV/AIDS research: (1) the interplay between cytokines and HIV pathogenesis; (2) HIV latency and persistence, with discussion of novel strategies aimed at the eradication of HIV; and (3) development of HIV vaccines and immunotherapies. It is one of the rare occasions that such a topic has been addressed in this or other review formats. The hallmark of HIV infection is global activation of the immune response that begins early in infection, persists through the chronic stages of disease [2,3], and is even maintained in subjects receiving anti-retroviral therapy. This hyperactivation alters the local and systemic microenvironment and systematically perturbs T cell, B cell, and innate immunity. In fact, infection with HIV leads to gradual loss of CD4+ T cells (specifically in the functional memory T cell compartment) [4,5]. HIV infection also leads to dysfunction of T cells through the upregulation of receptors that negatively regulate T cell functions. For example, the increase in PD-1, LAG3, and CTLA-4 expression levels dampens CD8+ and CD4+ T cell proliferation and cytokine production [6–8]. HIV-associated immune activation also interferes with humoral defenses; most HIV-infected subjects fail to produce protective anti-HIV antibodies and have diminished responses to neo and recall non-HIV and HIV antigens and vaccines [9–11]. Innate immunity is also compromised during HIV infection; dendritic cells have reduced numbers and impaired function in HIV-infected individuals. Plasmacytoid dendritic cells have diminished capacity to produce IFN-a in vivo and in vitro in response to TLR triggering [12,13]. Understanding how changes in the cytokine, chemokine, and interferon networks impact HIV pathogenesis, latency, and persistence and vaccine design is essential for the development 1359-6101/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cytogfr.2012.05.012
of therapeutic vaccine and eradication strategies. These topics are the subject of the reviews of this issue of CGFR. 1. HIV latency and persistence Remoli and colleagues describe how modulation of transcription factor function can impact HIV gene expression and persistence. The authors describe the roles of NF-kB, IRFs, pTEFb, and other factors in the life cycle of HIV-1 and how these factors influence virus integration and/or re-activation. They suggest that therapeutic targeting of these factors may provide valuable tools to purge the viral reservoir. Evans et al. discuss how signaling through chemokine receptors alters T cell migration and influences the establishment of HIV latency. In particular, they focus on the chemokines CCL19 and CCL21 and their CCR7 receptors. Other chemokines such as CXCL9 and CXCL10 are also discussed in the context of HIV latency and reactivation. In addition, the authors also define strategies to interfere with chemokine–chemokine receptor interactions as a mechanistic strategy to modulate HIV viral latency. Vandergeeten and colleagues examine the role of cytokines in the reactivation and establishment of viral reservoir. They examine the impact of IL-7 and IL-15 on HIV infection in resting CD4+ T cells and how these cytokines impact the maintenance of latently infected CD4+ T cells during HAART. The authors further elaborate on how cytokines impact residual viral persistence and consequently viral eradication. 2. Immunotherapies and vaccines Pallinkkuth and colleagues describe the functional role of IL-21 production during HIV infection and provide new insights into the biology of IL-21 and its significance in enhancing T cell and B cell responses. The authors also discuss the potential therapeutic value of IL-21 and provide an update on numerous human clinical trials with IL-21. Reuter et al. discuss how differentiation programs of CD4 and CD8 T cell subsets are affected during HIV infection and propose that much could be learned about T cell immunity by studying successful and unsuccessful vaccine trials. This iterative approach to vaccine development would facilitate the design of novel interventions and vaccine strategies against HIV infection. Keating and colleagues summarize early and late events occurring in pathogenic and non-pathogenic HIV infection in humans and animal models and review recent literature on the production of cytokines from peripheral blood and tissues during HIV infection. In
140
Foreword / Cytokine & Growth Factor Reviews 23 (2012) 139–141
addition, they examine the relevance of these cytokines in the development of vaccines and immunotherapies, in the context of the most recent human trials involving IL-2, IFN-a, IL-7, and IL-15. Catalfamo and colleagues describe their studies on HIVassociated immune activation in HIV-infected subjects, with a focus on how the CD4 and CD8 T cell pools change during HIV infection. Catalfamo et al. define the role of cytokines and interferons in homeostatic proliferation of T cells in the context of altered HIV microenvironment and discuss the potential for vaccine studies using cytokines that control T cell homeostasis. 3. HIV pathogenesis Van Grevenynghe et al. examine the impact of cytokines, chemokines, and interferons on the regulatory transcription factor Foxo3a. The authors demonstrate that the microenvironment at sites of HIV infection alters the cytokine and interferon networks, leading to disruption of the balance of Foxo3a phosphorylation, which in turn favors Foxo3a translocation to the nucleus and transcriptional activation of pro-apoptotic genes. Interestingly, this regulatory circuit does not occur in HIV-infected subjects that naturally control the disease. Mir and Silvestri examine how cytokine and chemokine networks affect the capacity of monocytes, macrophages, and dendritic cells to contribute to immune activation, HIV dissemination, regulation of cell-specific restriction factors, and the establishment of viral reservoirs. The authors illustrate how HIV infection of these myeloid specific cell subsets alters the HIV microenvironment and promotes elevated production of inflammatory cytokines and interferons. Rancez and colleagues discuss how mucosal secretion of chemokines perturbs T cell trafficking during HIV infection. Rancez et al. examine tissue-specific chemokines and their role in the recruitment of immune cells and how this interplay perturbs the balance of cytokines and chemokines in the periphery and lymphatic tissues. Wang and Watts examine TNF and TNFR family members in regulating immune responses to HIV infection. The authors review the impact of these receptors on the ability to alter T cell and B cell
responses. These altered immune cell responses have major implications for vaccine development, as well as the establishment and maintenance of the latent HIV reservoir. In particular, this review focuses on the biology of CD40/CD40L interaction and the impact of TRAF1 in 4-1BB signaling. How these interactions regulate cytokine production and survival of immune cells is also discussed. Marsili et al. tackle the role of IFN signaling pathways and downstream transcription factors in regulating HIV replication and disease progression. The authors define how viral escape could occur through the binding of viral proteins—including Tat—to transcription factors such as the IRF family downstream of IFN signaling. The authors specifically review innate immune sensing of HIV and discuss the role of pattern recognition receptors (PRRs) in disease progression. Finally, the authors assess whether interferon response is beneficial or harmful during HIV infection. It should not escape the attention of readers of this Special Issue of CGFR that several invited authors—Chomont, Sekaly, Trautmann, the Guest Editor, Haddad, and the CGFR Editor, Hiscott—are located at the same institute. Indeed, it is our collective pleasure to introduce our new research home, the Vaccine & Gene Therapy Institute of Florida (VGTI Florida). VGTI Florida was founded in 2008 as part of a major economic initiative undertaken by the state of Florida to further develop the biomedical research industry in Florida by attracting top research institutes to the state. To date, Scripps Florida, Torrey Pines Institute for Molecular Studies, the Sanford-Burnham Research Institute, and Max Planck Florida, to name a few, have all established sister institutes in Florida as part of this initiative. VGTI Florida is a nonprofit research institute dedicated to the pursuit of translational research in the field of human immunology with a focus on infectious diseases, cancer immunotherapy, and chronic inflammatory disorders. Construction of the new 100,000sq.-ft. research institute located in Port St. Lucie, Florida, was completed in January 2012. The Institute currently houses a staff of nearly 90 individuals, utilizing state-of-the-art technologies and a systems biology approach to a comprehensive study of human immune function. As members of VGTI Florida, we are proud to introduce our new Institute and to present this integrated series of reviews on the subject of cytokine networks and HIV pathogenesis.
Foreword / Cytokine & Growth Factor Reviews 23 (2012) 139–141
References [1] Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983;220:868–71. [2] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine 2006;12:1365–71. [3] Douek D. HIV disease progression: immune activation, microbes, and a leaky gut. Topics in HIV Medicine 2007;15:114–7. [4] van Grevenynghe J, Halwani R, Chomont N, Ancuta P, Peretz Y, Tanel A, et al. Lymph node architecture collapse and consequent modulation of FOXO3a pathway on memory T- and B-cells during HIV infection. Seminars in Immunology 2008;20:196–203. [5] van Grevenynghe J, Procopio FA, He Z, Chomont N, Riou C, Zhang Y, et al. Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nature Medicine 2008;14:266–74. [6] Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006;443:350–4. [7] Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. Journal of Immunology 2009;182:5891–7. [8] Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nature Medicine 2006;12:1198–202. [9] Moir S, Ho J, Malaspina A, Wang W, DiPoto AC, O’Shea MA, et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compart-
[10]
[11]
[12]
[13]
141
ment in HIV-infected viremic individuals. Journal of Experimental Medicine 2008;205:1797–805. Titanji K, De Milito A, Cagigi A, Thorstensson R, Grutzmeier S, Atlas A, et al. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood 2006;108:1580–7. van Grevenynghe J, Cubas RA, Noto A, DaFonseca S, He Z, Peretz Y, et al. Loss of memory B cells during chronic HIV infection is driven by Foxo3aand TRAIL-mediated apoptosis. Journal of Clinical Investigation 2011;121: 3877–88. Abb J, Kochen M, Deinhardt F. Interferon production in male homosexuals with the acquired immune deficiency syndrome (AIDS) or generalized lymphadenopathy. Infection 1984;12:240–2. Feldman S, Stein D, Amrute S, Denny T, Garcia Z, Kloser P, et al. Decreased interferon-alpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors. Clinical Immunology 2001;101:201–10.
Elias K. Haddad* John Hiscott VGTI Florida, Port St. Lucie, Florida, USA *Corresponding author E-mail address: ehaddad@vgtifl.org (E.K. Haddad) Available online 4 July 2012