CD4+ T helper cells and the role they play in viral control

The natural history of untreated HIV-1 infection is characterized by progressive erosion of the immune system with eventual loss of viral control. T helper cell responses to HIV-1 are typically weak or absent in chronically HIV-1 infected individuals. CD4+ T helper cell responses have been shown to be important in a number of experimental viral infection systems, and here we explore the ways in which T helper cells might aid in the control of viruses in general and HIV-1 in particular. We first review the relationship between T helper cells and other arms of the immune system. We then focus on the role T helper cells play in viral control in murine and nonhuman primate models, and finally review what is known of CD4+ T helper cell function in HIV-1 infection.

[1]  K. Mozdzanowska,et al.  CD4+ T cells are ineffective in clearing a pulmonary infection with influenza type A virus in the absence of B cells. , 1997, Virology.

[2]  K. Cease,et al.  Antigenic peptides recognized by T lymphocytes from AIDS viral envelope-immune humans , 1988, Nature.

[3]  B. Moss,et al.  Reduction of Simian-Human Immunodeficiency Virus 89.6P Viremia in Rhesus Monkeys by Recombinant Modified Vaccinia Virus Ankara Vaccination , 2001, Journal of Virology.

[4]  C. Leclerc,et al.  In vivo induction of cytotoxic T cell response by a free synthetic peptide requires CD4+ T cell help. , 1991, Journal of immunology.

[5]  D. Watkins,et al.  Viremia control following antiretroviral treatment and therapeutic immunization during primary SIV251 infection of macaques , 2000, Nature Medicine.

[6]  G. Kelsoe,et al.  Alternative pathways for the selection of antigen-specific peripheral T cells , 1996, Nature.

[7]  D. Brooks,et al.  Critical Role for CD4+ T Cells in Controlling Retrovirus Replication and Spread in Persistently Infected Mice , 1998, Journal of Virology.

[8]  B. Chesebro,et al.  Requirement for CD4+ T Cells in the Friend Murine Retrovirus Neutralizing Antibody Response: Evidence for Functional T Cells in Genetic Low-Recovery Mice , 1998, Journal of Virology.

[9]  R. Zinkernagel,et al.  Cd4+ T Cell Subsets during Virus Infection , 2000, The Journal of experimental medicine.

[10]  C. Hallahan,et al.  High-level HIV-1 viremia suppresses viral antigen-specific CD4+ T cell proliferation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  E. Daar,et al.  Antibody from Patients with Acute Human Immunodeficiency Virus (HIV) Infection Inhibits Primary Strains of HIV Type 1 in the Presence of Natural-Killer Effector Cells , 2001, Journal of Virology.

[12]  M. Ostrowski,et al.  Quantitative and qualitative assessment of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cell immunity to gag in HIV-1-infected individuals with differential disease progression: reciprocal interferon-gamma and interleukin-10 responses. , 2001, The Journal of infectious diseases.

[13]  R. Paredes,et al.  HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection , 2001, AIDS.

[14]  E. Rosenberg,et al.  Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. , 1997, Science.

[15]  R. Kurth,et al.  Characteristics of the specific cell-mediated immune response in human immunodeficiency virus infection , 1987, Journal of virology.

[16]  Jeffrey A. Ledbetter,et al.  How B and T cells talk to each other , 1994, Nature.

[17]  J. Lieberman,et al.  Absence of recoverable infectious virus and unique immune responses in an asymptomatic HIV+ long-term survivor. , 1994, AIDS research and human retroviruses.

[18]  H. McFarland,et al.  Measles virus-specific T4+ human cytotoxic T cell clones are restricted by class II HLA antigens. , 1984, Journal of immunology.

[19]  E. Rosenberg,et al.  Immune control of HIV-1 after early treatment of acute infection , 2000, Nature.

[20]  R M Zinkernagel,et al.  Natural antibodies and complement link innate and acquired immunity. , 2000, Immunology today.

[21]  J. Forman,et al.  Helper activity is required for the in vivo generation of cytotoxic T lymphocytes , 1982, The Journal of experimental medicine.

[22]  I. Stroehmann,et al.  Phenotypic heterogeneity of cerebrospinal fluid-derived HIV-specific and HLA-restricted cytotoxic T-cell clones , 1988, Nature.

[23]  A. Simon,et al.  Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. , 2000, Science.

[24]  K. Überla,et al.  Suppression of Acute Viremia by Short-Term Postexposure Prophylaxis of Simian/Human Immunodeficiency Virus SHIV-RT-Infected Monkeys with a Novel Reverse Transcriptase Inhibitor (GW420867) Allows for Development of Potent Antiviral Immune Responses Resulting in Efficient Containment of Infection , 2000, Journal of Virology.

[25]  E. Ingulli,et al.  Visualization of specific B and T lymphocyte interactions in the lymph node. , 1998, Science.

[26]  S. Rowland-Jones,et al.  Cellular immune responses to HIV , 2001, Nature.

[27]  B. Walker,et al.  Acute human immunodeficiency virus type 1 infection. , 1998, The New England journal of medicine.

[28]  R. Koup,et al.  Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection , 2001, Journal of Virology.

[29]  C. Pitcher,et al.  HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression , 1999, Nature Medicine.

[30]  Control of a Mucosal Challenge and Prevention of AIDS by a Multiprotein DNA/MVA Vaccine , 2001, Science.

[31]  F. Ennis,et al.  A CD4+ cytotoxic T-lymphocyte clone to a conserved epitope on human immunodeficiency virus type 1 p24: cytotoxic activity and secretion of interleukin-2 and interleukin-6 , 1992, Journal of virology.

[32]  R. Ahmed,et al.  T4+ T helper cell function in vivo: differential requirement for induction of antiviral cytotoxic T-cell and antibody responses , 1988, Journal of virology.

[33]  P. Klenerman,et al.  The influence of antigenic variation on cytotoxic T lymphocyte responses in HIV-1 infection , 1998, Journal of Molecular Medicine.

[34]  R. Ahmed,et al.  CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection , 1994, Journal of virology.

[35]  H. Pircher,et al.  Qualitative and quantitative requirements for CD4+ T cell-mediated antiviral protection. , 1999, Journal of immunology.

[36]  S. Kent,et al.  Lymphoproliferative immune function in the Sydney Blood Bank Cohort, infected with natural nef/long terminal repeat mutants, and in other long‐term survivors of transfusion‐acquired HIV‐1 infection , 1997, AIDS.

[37]  P. Lane,et al.  Co-stimulation and selection for T-cell help for germinal centres: the role of CD28 and OX40. , 2000, Immunology today.

[38]  J. Altman,et al.  Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function , 1998, The Journal of experimental medicine.

[39]  D. Baarle,et al.  Dysfunctional Epstein-Barr virus (EBV)-specific CD8(+) T lymphocytes and increased EBV load in HIV-1 infected individuals progressing to AIDS-related non-Hodgkin lymphoma. , 2001, Blood.

[40]  A. Townsend,et al.  Antigen recognition by class I-restricted T lymphocytes. , 1989, Annual review of immunology.

[41]  A. Rothman,et al.  Bystander Target Cell Lysis and Cytokine Production by Dengue Virus-Specific Human CD4+ Cytotoxic T-Lymphocyte Clones , 1999, Journal of Virology.

[42]  P. Morrissey,et al.  Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[43]  P. Cresswell,et al.  Class I processing-defective Burkitt's lymphoma cells are recognized efficiently by CD4+ EBV-specific CTLs. , 1997, Journal of immunology.

[44]  H. Schuitemaker,et al.  Kinetics of Gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics , 1995, The Journal of experimental medicine.

[45]  P. Doherty,et al.  Clearance of an Influenza A Virus by CD4+ T Cells Is Inefficient in the Absence of B Cells , 1998, Journal of Virology.

[46]  S. Varga,et al.  Stability of virus-specific CD4+ T cell frequencies from acute infection into long term memory. , 1998, Journal of immunology.

[47]  B. Rouse,et al.  Genetic immunization against herpes simplex virus. Protection is mediated by CD4+ T lymphocytes. , 1995, Journal of immunology.

[48]  J. Lifson,et al.  Development of virus-specific immune responses in SHIV(KU)-infected macaques treated with PMPA. , 2001, Virology.

[49]  A. Perelson,et al.  HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time , 1996, Science.

[50]  K. Steimer,et al.  Lymphocyte proliferative responses to human immunodeficiency virus antigens in vitro. , 1989, The Journal of clinical investigation.

[51]  M A Nowak,et al.  Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. , 1998, Science.

[52]  D. Montefiori,et al.  Polyvalent Envelope Glycoprotein Vaccine Elicits a Broader Neutralizing Antibody Response but Is Unable To Provide Sterilizing Protection against Heterologous Simian/Human Immunodeficiency Virus Infection in Pigtailed Macaques , 2001, Journal of Virology.

[53]  I. Keet,et al.  Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. , 1999, AIDS research and human retroviruses.

[54]  W. Heath,et al.  Induction of a CD8+ Cytotoxic T Lymphocyte Response by Cross-priming Requires Cognate CD4+ T Cell Help , 1997, The Journal of experimental medicine.

[55]  E. Rosenberg,et al.  Multiple Effector Functions Mediated by Human Immunodeficiency Virus-Specific CD4+ T-Cell Clones , 2001, Journal of Virology.

[56]  Stephen P. Schoenberger,et al.  T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions , 1998, Nature.

[57]  Kevin A. Robertson,et al.  Regression of a Murine Gammaherpesvirus 68-Positive B-Cell Lymphoma Mediated by CD4 T Lymphocytes , 2001, Journal of Virology.

[58]  D. Montefiori,et al.  Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. , 1999, Science.

[59]  M. Yasukawa,et al.  Human cytotoxic T cell clones directed against herpes simplex virus-infected cells. I. Lysis restricted by HLA class II MB and DR antigens. , 1984, Journal of immunology.

[60]  D. Burton,et al.  Role of Antibodies in Controlling Viral Disease: Lessons from Experiments of Nature and Gene Knockouts , 2000, Journal of Virology.

[61]  B. Fleischer Acquisition of specific cytotoxic activity by human T4+ T lymphocytes in culture , 1984, Nature.

[62]  P. Kinchington,et al.  Equivalent recognition of a varicella-zoster virus immediate early protein (IE62) and glycoprotein I by cytotoxic T lymphocytes of either CD4+ or CD8+ phenotype. , 1991, Journal of immunology.

[63]  G. M. Ortiz,et al.  The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection , 2001, AIDS.

[64]  D. Richman,et al.  T cell recognition of HIV synthetic peptides in a natural infection. , 1989, Journal of immunology.

[65]  X. Jin,et al.  Quantitative analysis of the human immunodeficiency virus type 1 (HIV- 1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein- Barr virus in late disease , 1993, The Journal of experimental medicine.

[66]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[67]  M. Graham,et al.  Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection , 1994, The Journal of experimental medicine.

[68]  P. Rácz,et al.  Enhanced cellular immune response and reduced CD8(+) lymphocyte apoptosis in acutely SIV-infected Rhesus macaques after short-term antiretroviral treatment. , 2001, Virology.

[69]  R. Zinkernagel,et al.  Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice , 1994, Journal of virology.

[70]  Stephen P. Schoenberger,et al.  Naïve CTLs require a single brief period of antigenic stimulation for clonal expansion and differentiation , 2001, Nature Immunology.

[71]  D. Nixon,et al.  Strong human immunodeficiency virus (HIV)-specific CD4+ T cell responses in a cohort of chronically infected patients are associated with interruptions in anti-HIV chemotherapy. , 2000, The Journal of infectious diseases.

[72]  T. Braciale,et al.  Differences in antigen presentation to MHC class I-and class II- restricted influenza virus-specific cytolytic T lymphocyte clones , 1986, The Journal of experimental medicine.

[73]  E. Reinherz,et al.  Separation of functional subsets of human T cells by a monoclonal antibody. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[74]  H. Katinger,et al.  Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. , 1999, Immunity.

[75]  P. Doherty,et al.  Progressive Loss of Cd8 + T Cell-mediated Control of a ~/-herpesvirus in the Absence of Cd4 + T Cells , 1996 .

[76]  P. Doherty,et al.  Immune CD4+ T cells promote the clearance of influenza virus from major histocompatibility complex class II -/- respiratory epithelium , 1996, Journal of virology.

[77]  R. Rott,et al.  Recognition of viral antigens by human influenza A virus-specific T lymphocyte clones. , 1985, Journal of immunology.

[78]  P. Klenerman,et al.  Impairment of Cd4+ T Cell Responses during Chronic Virus Infection Prevents Neutralizing Antibody Responses against Virus Escape Mutants , 2001, The Journal of experimental medicine.

[79]  M. V. von Herrath,et al.  CD4-deficient mice have reduced levels of memory cytotoxic T lymphocytes after immunization and show diminished resistance to subsequent virus challenge , 1996, Journal of virology.

[80]  Tahir A. Rizvi,et al.  Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian–human immunodeficiency virus infection , 2000, Nature Medicine.

[81]  R. Jaenisch,et al.  Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells , 1991, The Journal of experimental medicine.

[82]  D. Brooks,et al.  Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection , 1999, Nature Medicine.

[83]  Richard A. Flavell,et al.  Help for cytotoxic-T-cell responses is mediated by CD40 signalling , 1998, Nature.

[84]  Polly Matzinger,et al.  A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell , 1998, Nature.

[85]  Susan M. Kaech,et al.  Memory CD8+ T cell differentiation: initial antigen encounter triggers a developmental program in naïve cells , 2001, Nature Immunology.

[86]  B. M. Flynn,et al.  Containment of Simian Immunodeficiency Virus Infection: Cellular Immune Responses and Protection from Rechallenge following Transient Postinoculation Antiretroviral Treatment , 2000, Journal of Virology.

[87]  S. Nikiforow,et al.  CD4+ T-Cell Effectors Inhibit Epstein-Barr Virus-Induced B-Cell Proliferation , 2001, Journal of Virology.

[88]  C. Biron,et al.  NK cells and NKT cells in innate defense against viral infections. , 2001, Current opinion in immunology.

[89]  E. Reinherz,et al.  Human cytotoxic T cell clones directed at autologous virus-transformed targets: further evidence for linkage of genetic restriction to T4 and T8 surface glycoproteins. , 1983, Journal of immunology.

[90]  E. Rosenberg,et al.  Association between Virus-Specific Cytotoxic T-Lymphocyte and Helper Responses in Human Immunodeficiency Virus Type 1 Infection , 1999, Journal of Virology.

[91]  J. Wilson,et al.  Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease. , 2000, The Journal of infectious diseases.

[92]  J. Mascola,et al.  Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies , 2000, Nature Medicine.

[93]  P. Scherle,et al.  Functional analysis of influenza-specific helper T cell clones in vivo. T cells specific for internal viral proteins provide cognate help for B cell responses to hemagglutinin , 1986, The Journal of experimental medicine.

[94]  K. Peterson,et al.  CD4+ T Cells and Gamma Interferon in the Long-Term Control of Persistent Friend Retrovirus Infection , 2001, Journal of Virology.