Presence of HIV-1 Gag-Specific IFN-γ+IL-2+ and CD28+IL-2+ CD4 T Cell Responses Is Associated with Nonprogression in HIV-1 Infection1

HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/μl. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-γ and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2+IFN-γ−) or IFN-γ alone (IFN-γ+IL-2−) did not differ between LTNPs and SPs. The decrease in p24-specific CD28+IL-2+ cells with a concomitant increase of p24-specific CD28−IL-2+ cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28−IL-2+ cells were evident in LTNPs and SPs, whereas the CMV-specific CD28−IL-2+ response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-γ+IL-2+ response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-γ+IL-2+ but not of IFN-γ+IL-2− CD4s correlated inversely with virus load. The Gag-specific IFN-γ+IL-2+ CD4 response also correlated positively with the percentage of Gag-specific IFN-γ+ CD8 T cells in these subjects. Accumulation of specific CD28−IL-2+ helpers and loss of IFN-γ+IL-2+ CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.

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

[2]  B. Palmer,et al.  Discordance between Frequency of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Producing CD4+ T Cells and HIV-1-Specific Lymphoproliferation in HIV-1-Infected Subjects with Active Viral Replication , 2002, Journal of Virology.

[3]  M. Altfeld,et al.  The role of CD4(+) T helper cells in the cytotoxic T lymphocyte response to HIV-1. , 2000, Current opinion in immunology.

[4]  P. Rabinovitch,et al.  CD28 ligation in T-cell activation: evidence for two signal transduction pathways. , 1990, Blood.

[5]  M. Mulligan,et al.  A Significant Number of Human Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes Detected by Tetramer Binding Do Not Produce Gamma Interferon , 2000, Journal of Virology.

[6]  D. Davies,et al.  CD7 expression distinguishes subsets of CD4+ T cells with distinct functional properties and ability to support replication of HIV‐1 , 2000, European journal of immunology.

[7]  B. Gazzard,et al.  Chemokine receptor polymorphisms and human immunodeficiency virus disease progression. , 1999, The Journal of infectious diseases.

[8]  A. Fauci,et al.  Host factors in the pathogenesis of HIV disease , 1997, Immunological reviews.

[9]  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.

[10]  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.

[11]  C. Pitcher,et al.  Use of overlapping peptide mixtures as antigens for cytokine flow cytometry. , 2001, Journal of immunological methods.

[12]  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.

[13]  T. Kepler,et al.  Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors. , 1999, AIDS research and human retroviruses.

[14]  P. Frei,et al.  Expansion of T cells negative for CD28 expression in hiv infection. Relation to activation markers and cell adhesion molecules, and correlation with prognostic markers , 1996, Medical Microbiology and Immunology.

[15]  S. Hammer,et al.  Host Determinants in HIV Infection and Disease: Part 1: Cellular and Humoral Immune Responses* , 2001, Annals of Internal Medicine.

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

[17]  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.

[18]  Douglas D. Richman,et al.  HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function , 2000, The Journal of experimental medicine.

[19]  Spyros A. Kalams,et al.  The Critical Need for CD4 Help in Maintaining Effective Cytotoxic T Lymphocyte Responses , 1998, The Journal of experimental medicine.

[20]  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.

[21]  B. Walker,et al.  Lack of Viral Escape and Defective In Vivo Activation of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes in Rapidly Progressive Infection , 1999, Journal of Virology.

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

[23]  V. Maino,et al.  Enhancement of HIV type 1 antigen-specific CD4+ T cell memory in subjects with chronic HIV type 1 infection receiving an HIV type 1 immunogen. , 2000, AIDS research and human retroviruses.

[24]  H. Thomas,et al.  Evolution of Epitope-Specific Memory CD4+ T Cells After Clearance of Hepatitis C Virus , 2002, The Journal of Immunology.

[25]  S. Riddell,et al.  Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. , 1995, The New England journal of medicine.

[26]  P. Linsley,et al.  CD28 engagement by B7/BB-1 induces transient down-regulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling. , 1993, Journal of immunology.

[27]  Sousa,et al.  Single‐cell analysis of lymphokine imbalance in asymptomatic HIV‐1 infection: evidence for a major alteration within the CD8+ T cell subset , 1998, Clinical and experimental immunology.

[28]  Z. Grossman,et al.  HIV preferentially infects HIV-specific CD4+ T cells , 2002, Nature.

[29]  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.

[30]  S. Rowland-Jones,et al.  Skewed maturation of memory HIV-specific CD8 T lymphocytes , 2001, Nature.

[31]  M. Mulligan,et al.  Magnitude of Functional CD8+ T-Cell Responses to the Gag Protein of Human Immunodeficiency Virus Type 1 Correlates Inversely with Viral Load in Plasma , 2002, Journal of Virology.

[32]  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.

[33]  L. Weinberger,et al.  Dramatic Rise in Plasma Viremia after CD8+ T Cell Depletion in Simian Immunodeficiency Virus–infected Macaques , 1999, The Journal of experimental medicine.

[34]  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.

[35]  P. Easterbrook,et al.  Long-term nonprogression in HIV infection: methodological issues and scientific priorities. Report of an international European community-National Institutes of Health Workshop, The Royal Society, London, England, November 27-29, 1995. Scientific Coordinating Committee. , 1998, AIDS Research and Human Retroviruses.

[36]  M. McElrath,et al.  Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. , 1997, The New England journal of medicine.

[37]  A. Rao,et al.  T cell differentiation: a mechanistic view. , 2000, Current opinion in immunology.

[38]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[39]  P. Easterbrook,et al.  Workshop Summary: Long-Term Nonprogression in HIV Infection: Methodological Issues and Scientific Priorities Report of an International European Community–National Institutes of Health Workshop, The Royal Society, London, England, November 27–29, 1995 , 1998 .

[40]  B. Walker,et al.  Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection. , 1996, AIDS research and human retroviruses.

[41]  R. Koup,et al.  Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production. , 2001, Immunology letters.

[42]  T. Ottenhoff,et al.  T90/44 (9.3 antigen). A cell surface molecule with a function in human T cell activation , 1986, European journal of immunology.

[43]  G. Trinchieri,et al.  Association between HIV‐specific T helper responses and CTL activities in pediatric AIDS , 2000, European journal of immunology.

[44]  A. E. Sousa,et al.  Comparison of the frequency of interleukin (IL)-2-, interferon-gamma-, and IL-4-producing T cells in 2 diseases, human immunodeficiency virus types 1 and 2, with distinct clinical outcomes. , 2001, The Journal of infectious diseases.

[45]  H. Ostrer,et al.  Shortened telomeres in clonally expanded CD28-CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. , 1996, Journal of immunology.

[46]  S. Swain,et al.  CD4+ T cell effectors can become memory cells with high efficiency and without further division , 2001, Nature Immunology.

[47]  D. Ho,et al.  Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. , 1995, The New England journal of medicine.

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

[49]  M. Jenkins,et al.  CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. , 1991, Journal of immunology.

[50]  D. Birx,et al.  Comprehensive Screening for Human Immunodeficiency Virus Type 1 Subtype-Specific CD8 Cytotoxic T Lymphocytes and Definition of Degenerate Epitopes Restricted by HLA-A0207 and -CW0304 Alleles , 2002, Journal of Virology.

[51]  B. Walker,et al.  The Role of CD4+ T Cell Help and CD40 Ligand in the In Vitro Expansion of HIV-1-Specific Memory Cytotoxic CD8+ T Cell Responses , 2000, The Journal of Immunology.

[52]  M. Lederman,et al.  Differential Expression of Interleukin-2 and Gamma Interferon in Human Immunodeficiency Virus Disease , 2001, Journal of Virology.