Major Areas of Research
- Roles of latently infected, resting CD4+ T cells, B cells, and innate immunity in the pathogenesis and treatment of HIV disease
- Role of HIV envelope signaling in viral replication and immune dysfunction
- Therapeutic strategies for management of hepatitis C/HIV co-infection
- Novel approaches to the inhibition of HIV binding and entry into CD4+ T cells
- Novel approaches to the treatment of recently acquired and chronic HIV infection
The Immunopathogenesis Section investigates the cellular and molecular mechanisms underlying the immune dysfunction caused by HIV infection. Several major projects ongoing in the section are described below.
Role of persistent viral reservoirs in the pathogenesis and treatment of HIV disease (Lead Investigator: Tae-Wook Chun, Ph.D.)
Over the past two decades, advances in the treatment of HIV infection have led to dramatic improvements in health outcomes of infected individuals receiving antiretroviral therapy (ART). However, despite sustained suppression of HIV replication by ART, the persistence of reservoirs carrying replication-competent HIV is thought to be a major reason for the inability of ART to eradicate the virus in infected individuals. Consequently, a major current thrust of HIV therapeutic research is the development of strategies aimed to “cure” HIV infection, defined as the indefinite remission of HIV infection in the absence of ART. The pursuit of a “cure” has been a long-term goal for investigators in the Immunopathogenesis Section of LIR. Our approach over the past several years has been to delineate the role of persistent viral reservoirs in the pathogenesis of HIV infection and to explore and develop novel therapeutic strategies aimed at achieving sustained virologic remission in infected individuals in the absence of ART.
- HIV continually replicates in elite controllers in the absence of detectable plasma viremia, as evidenced by short-term administration of ART that dramatically decreases the size of the pool of persistently infected CD4+ T cells.
- Highly potent and broadly neutralizing HIV-specific antibodies (bNAbs) can effectively block HIV present in the persistent viral reservoir of infected individuals receiving ART for prolonged periods of time.
- Multiple infusions of a bNAb VRC01 are safe and well tolerated in HIV-infected individuals. However, given recent findings that VRC01 monotherapy failed to prevent and/or suppress plasma viremia following discontinuation of ART, future therapeutic strategies involving passive transfer of bNAbs will require a combination of antibodies and/or resistance prescreening.
- An ongoing randomized therapeutic vaccine trial in HIV-infected individuals is designed to address whether harnessing the host immunity against the virus could result in sustained virologic remission in the absence of antiretroviral drugs in a cohort of patients who initiated ART during the acute/early phase of infection.
Role of B cells in the pathogenesis of HIV disease (Lead Investigator: Susan Moir, Ph.D.)
In 1983, LIR made the first observation that B cells of HIV-infected individuals manifested numerous signs of aberrant hyperactivity and dysfunction. More recently, LIR has pursued the investigation of B-cell dysfunction in the setting of HIV disease by evaluating various facets of B cells isolated from HIV-infected individuals. We have used various genotypic, phenotypic, and functional assays to identify several subpopulations of B cells in the peripheral blood of HIV-viremic individuals. Certain B-cell subpopulations are associated with early HIV infection, while others are more associated with chronic HIV viremia and disease progression. Most recently, we have developed the ability to directly interrogate antigen specificities of B cells and demonstrate deficiencies in HIV-specific B-cell responses. The inadequacy of the HIV-specific humoral immune response to HIV infection and its role in the inability of the immune response to control the progression of HIV infection, as well as its impact on our ability to develop an effective HIV vaccine, are critical issues in the field of HIV research.
- Chronic HIV viremia leads to HIV-associated B-cell exhaustion that is partly mediated by the over-expression of inhibitory receptors.
- HIV-specific B cells arise early after infection but are non-neutralizing and become concentrated within abnormal B-cell subpopulations that are deficient in providing long-lasting effective immunity.
- HIV-induced CD4+ T-cell lymphopenia is associated with the expansion of immature/transitional B cells that respond poorly to B-cell stimuli and rapidly undergo intrinsic apoptosis due to insufficient expression of survival proteins.
- HIV disease is associated with an inability of B cells to mount an effective response against immunogens such as the influenza vaccine. The most defective component is the influenza-specific memory B-cell response, which correlates with a loss of memory B cells in chronic HIV infection.
Role of HIV envelope-target cell interactions in the pathogenesis of HIV infection (Lead Investigators: James Arthos, Ph.D., and Claudia Cicala, Ph.D.)
The primary aim of this project is to better understand the role of the HIV envelope protein in HIV pathogenesis. To that end, we have focused on the complex interplay between the viral envelope and several of the known cell surface receptors to which it binds (CD4, CCR5, CXCR4, integrin α4β7). Understanding the complexities and significance of the signaling processes that gp120 mediates will enhance our understanding of HIV-1 pathogenesis and may facilitate the discovery of new strategies for the treatment and prevention of HIV-1 disease. The finding that gp120 engages integrin α4β7, the gut-homing receptor, opens up many new and potentially important questions. Because α4β7 mediates leukocyte homing to gut-associated lymphoid tissue (GALT), which is a principal site of HIV replication during the acute phase of infection, we explored the role of α4β7-expressing CD4+ T cells in HIV transmission. We previously determined that human α4β7high CD4+ T cells are highly susceptible in vitro to productive infection by HIV, in part because α4β7high CD4+ T cells are enriched with metabolically active cells. We then tested this hypothesis in a non-human primate in vivo model of HIV/SIV infection and determined that an antibody specific for α4β7 prevented transmission in a rhesus macaque model of mucosal transmission. In addition, we have investigated the interaction between HIV and α4β7 on primary B cells. We have learned that some of the defects associated with HIV disease result from direct interactions between gp120 and receptors on B cells. These findings have relevance to our understanding of early HIV transmission and viral dissemination, particularly in GALT, providing new avenues of investigation regarding the potential role of α4β7+ as a therapeutic target against HIV infection.
- HIV-1 envelope binds to, and signals through α4β7 integrin, the gut mucosal homing receptor for peripheral T cells.
- The HIV envelope protein gp120 binds to a conformationally active form of α4β7 on CD4+ T cells. This binding is independent of the binding of envelope to the CD4 molecule. Because the function of α4β7 is intimately linked to GALT, where HIV replicates at high levels especially in acute/early infection, the specific affinity observed suggests that envelope-α α4β7 interactions play an important role in HIV pathogenesis.
- α4β7high CD4+ T cells are more susceptible to productive infection by HIV than are α4β7low/neg CD4+ T cells, in part because this cellular subset is enriched with metabolically active cells.
- Removal of N-linked glycosylation sites in HIV envelopes results in large increases in the specific affinity of gp120 for α4β7. Several envelopes derived from viruses isolated shortly after transmission react with α4β7 to a substantially higher level than do the great majority of envelopes derived from viruses isolated in the chronic phase of infection. These results suggest that mucosal transmission may frequently involve a relative requirement for the productive infection of α4β7+ CD4+ T cells.
- Targeting α4β7 significantly reduces intravaginal mucosal transmission and subsequent tissue dissemination of SIV in a non-human primate model of HIV/AIDS. This supports our hypothesis that α4β7+/CD4+ T cells can play an important role in mucosal transmission of HIV.
Dr. Fauci received his A.B. from the College of the Holy Cross and his M.D. from Cornell University Medical College. He then completed an internship and residency at The New York Hospital-Cornell Medical Center. In 1968, Dr. Fauci came to NIH as a clinical associate in the NIAID Laboratory of Clinical Investigation. In 1980, he was appointed chief of the Laboratory of Immunoregulation, a position he still holds. Dr. Fauci became director of NIAID in 1984. He serves as one of the key advisors to the White House and U.S. Department of Health and Human Services on global AIDS issues and on initiatives to bolster medical and public health preparedness against emerging infectious disease threats such as pandemic influenza.
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Chun TW, Moir S, Fauci AS. HIV reservoirs as obstacles and opportunities for an HIV cure. Nat Immunol. 2015 Jun;16(6):584-9.
Kardava L, Moir S, Shah N, Wang W, Ho J, Wilson R, Buckner CM, Santich BH, Kim LJY, Spurlin EE, Nelson AK, Wheatley AK, Harvey CJ, McDermott AB, Wucherpfennig KW, Chun TW, Tsang JS, Li Y, Fauci AS. Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals. J Clin Invest. 2014 Aug;124(8):3352-63.
Byrareddy SN, Kallam B, Arthos J, Cicala C, Nawaz F, Hiatt J, Kersh EN, McNicholl JM, Hanson D, Reimann KA, Brameier M, Walter L, Rogers K, Mayne AE, Dunbar P, Villinger T, Little D, Parslow TG, Santangelo PJ, Villinger F, Fauci AS, Ansari AA.Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med. 2014 Dec;20(12):1397-400.
Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, Lempicki RA, Pascuccio M, Van Ryk D, Schwing C, Hiatt J, Okwara N, Wei D, Roby G, David A, Hwang IY, Kehrl JH, Arthos J, Cicala C, Fauci AS. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat Immunol. 2013 Dec;14(12):1256-65.
- Arthos J, Good D, Cicala C, Fauci AS, inventors; The United States of America, as represented by the Secretary, Department of Health and Human Services, assignee. Use of antagonists of the interaction between HIV GP120 and A4B7 integrin. United States patent US 9,193,790. 2015 Nov 24.
- Arthos J, Cicala C, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Fusion protein including of CD4. United States patent US 7,368,114. 2008 May 6.
- Scala G, Chen X, Cohen OJ, Fauci AS, inventors; The United States of America as represented by the Secretary of the Department of Health and Human Services, assignee. HIV related peptides. United States patent US 6,911,527. 2005 Jun 28.
- Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,548,055. 2003 Apr 15.
- Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 6,190,656. 2001 Feb 20.
- Lane HC, Kovacs JA, Fauci AS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Immunologic enhancement with intermittent interleukin-2 therapy. United States patent US 5,696,079. 1997 Dec 9.