Hendrik Streeck
Massachusetts General Hospital
Project start date: 2011-02-10
Project end date: 2016-01-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Hendrik Streeck
MODULATION OF HIV-SPECIFIC CD8+ T AND B CELL FUNCTION BY CD4+ T HELPER RESPONSES
Hendrik Streeck, Instructor
Massachusetts General Hospital, Partners Research Management, Boston, Ma 02199
Grant 1R01AI091450-01 from National Institute Of Allergy And Infectious Diseases
Abstract: An estimate 6,800 new HIV-1 infections daily dramatically underscores the desperate need for the development of an HIV-1 vaccine. Despite significant advances in our understanding of both the humoral and cellular immune response in HIV-1 infection, the correlates of protection have still not been defined. The recent failure of the Merck vaccine trial and the unexpected modest success of the RV144 HIV vaccine trial using ALVAC-HIV (vCP1521) in a prime boost combination with AIDSVAX B/E, have challenged our notion of what constitutes a protective vaccine. Strikingly, the vaccine induced not only strong antibody responses, but also a robust HIV-1-specific CD4+ T cell response. Approaches to induce HIV-1-specific CD4+ T cell responses have been met with skepticism thus far as these attempts may expand the pool of HIV-1 specific CD4+ T cells targets. However, compelling studies in the lymphochoriomeningitis virus (LCMV) mouse model suggest that virus-specific Interleukin-21 (IL21) secreting CD4+ T cell responses are a critical key factor to establish effective and long-lived virus-specific immunity. Mice lacking IL21 or IL21 receptor (IL21R) were more susceptible to chronic LCMV infection. IL21+CD4+ T cell responses have been shown to enhance cytotoxicity of virus-specific CD8+ T cells and direct antibody class switching and activation of B cells. Thus, IL21+CD4+ T cell responses play a central role in the coordination of virus-specific immunity. Surprisingly little is known about the role of IL21+ CD4+ T cells in human viral infections. Our preliminary data suggest that robust HIV-1- specific IL21+CD4+ T cell responses exist in HIV-1 elite controllers with a preferential targeting of epitopes within the Gag protein. In contrast, in subjects with chronic-progressive HIV-1 infection virtually no IL21+CD4+ T cell responses are detectable. Moreover, we have evidence that IL21 signals can transform non-controlling CD8+ T cell responses into CD8+ T cell responses with strong inhibitory activity. Thus, our preliminary data suggest that IL21+CD4+ T cell responses might be a critical factor for the generation of an effective CD8+ T cell or B cell based vaccine. Specifically we propose to 1) Determine the presence and specificity of HIV-1-specific IL21+CD4+ T cells as well as their role in the control of viral replication. 2) Determine whether early antiretroviral treatment in primary HIV-1 infection preserves these particular responses. 3.) Assess how HIV-1-specific IL21+CD4+ T responses modulate HIV-1-specific CD8+ T cells and enhance their capacity to inhibit viral replication. 4.) Investigate whether therapeutic CD4-targeted vaccination can induce such responses and finally 5.) assess how IL21+CD4+ T cells modulate HIV-1-specific B cell functions. The underlying hypotheses of this proposal are that HIV-1-specific IL21+ CD4+ T cells have a key function in the control of viral replication by modulating HIV-1-specific B cell function and increasing the inhibitory activity of HIV-1-specific CD8+ T cells. The induction and propagation of these responses in a prophylactic or therapeutic vaccine will be essential for long-lived effective virus-specific immunity. With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX; "Thai trial") drastically demonstrate our poor understanding how to develop an effective vaccine. Strikingly, the used vaccine not only induced antibodies, but also a robust HIV-1-specific CD4+ T cell response. Recent data from the mouse model suggest that virus-specific Interleukin-21 (IL21)-secreting CD4+ T cell responses are critical to support virus-specific CD8+ T cell and B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific IL21+CD4+ T cell responses in the control of HIV-1 infection to determine whether the induction of these responses should be a key component of a prophylactic and therapeutic vaccine
Keywords: AIDS; AIDS Virus; ATGN; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Antigenic Determinants; Antigens; Antiretroviral Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Antiviral Drugs; Antivirals; Autoimmune Diseases; B blood cells; B-Cell Activation; B-Cells; B-Lymphocytes; Binding Determinants; Biological Preservation; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cell Communication and Signaling; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Cessation of life; Chronic; Class Switching; Combined Vaccines; Communicable Diseases; Data; Death; Development; Epitopes; Exclusion; FLR; Failure (biologic function); Gene Products, gag; Generations; HAART; HIV; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; HIV-I; HIV/AIDS Vaccines; HIV1; HIV1 vaccine; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Helper Cells; Helper T-Cells; Helper-Inducer T-Lymphocyte; Highly Active Antiretroviral Therapy; History; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; IL-21; IL-21 receptor; IL21; IL21R; Immune; Immune response; Immune system; Immunity; Immunodeficiency Virus Type 1, Human; Immunoglobulin Class Switching; Immunologic Deficiency Syndrome, Acquired; Individual; Inducer Cells; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Intracellular Communication and Signaling; Isotype Switching; LAV-HTLV-III; LYT3; Life; Lymphadenopathy-Associated Virus; Lytotoxicity; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediator; Mediator of Activation; Mediator of activation protein; Mice; Murine; Mus; Play; Predisposition; Preservation, Biologic; Preservation, Biological; Production; Receptor Protein; Recording of previous events; Reporting; Retroviral Antigen gag Protein; Role; Signal Transduction; Signal Transduction Systems; Signaling; Specificity; Subcellular Process; Susceptibility; Switchings, Class; Switchings, Immunoglobulin Class; Switchings, Isotype; T cell response; T-Cells; T-Cells, Helper-Inducer; T-Lymphocyte; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T-Lymphotropic Virus Type III Infections, Human; T4 Cells; T4 Lymphocytes; Therapeutic; Thymus-Dependent Lymphocytes; Vaccination; Vaccine Design; Vaccine Research; Vaccines; Vaccines, Combination; Vaccines, Combined; Viral; Viral Burden; Viral Diseases; Viral Load; Viral Load result; Viral gag Proteins; Virus; Virus Diseases; Virus-HIV; Viruses, General; anti-retroviral; anti-retroviral therapy, highly active; antibody biosynthesis; antiretroviral; autoimmune disorder; base; biological signal transduction; body system, allergic/immunologic; cost; cytotoxicity; failure; gag Antigens; gag Gene Products; gag Polyproteins; gag Protein; group specific antigen; helper T cell; host response; human T cell leukemia virus III; human T lymphotropic virus III; human immunodeficiency virus vaccine; immunogen; immunoglobulin biosynthesis; immunoresponse; interleukin-21; interleukin-21 receptor; meetings; memory CD4 T cell; memory CD4 T lymphocyte; mouse model; organ system, allergic/immunologic; pandemic; pandemic disease; pathogen; preservation; prophylactic; public health relevance; receptor; response; social role; success; theories; therapeutic vaccine; thymus derived lymphocyte; vaccine candidate; viral infection; virus infection
Relevance: narrative project With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX; "Thai trial") drastically demonstrate our poor understanding how to develop an effective vaccine. Strikingly, the used vaccine not only induced antibodies, but also a robust HIV-1-specific CD4+ T cell response. Recent data from the mouse model suggest that virus-specific Interleukin-21 (IL21)-secreting CD4+ T cell responses are critical to support virus-specific CD8+ T cell and B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific IL21+CD4+ T cell responses in the control of HIV-1 infection to determine whether the induction of these responses should be a key component of a prophylactic and therapeutic vaccine
Project start date: 2010-08-18
Project end date: 2014-07-31
Budget start date: 18-AUG-2010
Budget end date: 31-JUL-2011
PFA/PA: RFA-AI-09-024
1R01AI091450-01 (2010): $549055