Anthony S. Fauci, M.D.
Building 31, Room 7A03
31 Center Drive
Bethesda, MD 20892
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.)
We and others previously demonstrated that the latent viral reservoir in the resting CD4+ T-cell compartment persists in virtually all infected individuals receiving effective antiretroviral therapy (ART). As a result of our work, this viral reservoir has been considered to be a major impediment to the eradication of HIV in vivo. In recent years, our studies have demonstrated that HIV continually replicates at low levels in chronically infected individuals who have been consistently aviremic for prolonged periods of time as a result of effective ART. Based on this observation, the Immunopathogenesis Section has focused its research on 1) dynamics of persistent viral reservoirs in infected individuals who initiated ART during the acute phase of HIV infection, 2) delineation of the mechanism by which HIV persists in infected individuals receiving effective ART for extended periods of time, and 3) role of gut-associated lymphoid tissues (GALT) in the persistence of viral reservoirs in infected individuals receiving effective ART for extended periods of time.
- The latent HIV reservoir in resting CD4+ T cells decays in patients receiving ART for extended periods of time; this decay is most pronounced in patients who initiated ART in the early phase of infection.
- Elimination of a detectable viral reservoir in peripheral blood mononuclear cells may be achievable in selected patients who initiate therapy early and suppress HIV replication for several years.
- HIV-infected individuals who initiate ART during the chronic phase of infection continually replenish their viral reservoirs via cross-infection between resting and activated CD4+ T-cell compartments. This replenishment occurs despite extended periods of effective therapy.
- HIV persists in GALT in infected individuals receiving effective ART for extended periods of time.
Role of B cells in the pathogenesis of HIV disease (Lead Investigator: Susan Moir, Ph.D.)
Twenty years ago, LIR demonstrated that B cells of HIV-infected individuals manifested numerous signs of aberrant hyperactivity and dysfunction. Over the past several years, we have directed our efforts to delineating the mechanisms of B-cell dysfunction associated with ongoing HIV replication and disease progression. This has been made possible by the ability to study HIV-infected patients during the viremic and aviremic states, the latter induced by effective ART. Insight into B-cell dysfunction in HIV disease has been achieved using both basic science and clinical approaches. We have determined that ongoing HIV replication and CD4+ T-cell lymphopenia contribute to the expansion of aberrant B-cell subpopulations that, in turn, are unable to mount an effective antibody response against HIV and common immunogens.
- HIV viremia leads to the up-regulation of numerous genes in B cells, including interferon-induced genes and genes associated with terminal differentiation. Both pathways are associated with increased B-cell turnover, activation, and death by extrinsic apoptosis.
- 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.
- The HIV-specific B cells that arise following HIV infection are concentrated in a subpopulation of B cells that show signs of HIV-induced exhaustion. This exhaustion is characterized by a high expression of inhibitory receptors, leading to poor proliferation and a reduced capacity to undergo affinity maturation. These properties may help explain the inefficiency of the antibody response against HIV in infected individuals.
Role of HIV gp120 signal transduction in viral replication and immune dysfunction (Lead Investigators: James Arthos, Ph.D., and Claudia Cicala, Ph.D.)
The goal of this project is to characterize the interaction between the HIV envelope and its cellular receptors. This characterization will provide information fundamental to the basic pathogenic mechanisms that underlie HIV disease. The HIV envelope is remarkable in its ability to interact with at least three different cell surface receptors, and it is this unique property that has led us to undertake this project. Our approach involves combining biochemical characterization of envelope proteins with the responses of cells involved in immune responses to envelope treatment. We have recently developed a recombinant envelope expression system to produce and evaluate over a dozen different recombinant envelopes. These recombinants will be used to fully characterize the effects of HIV envelope proteins on the functionality of CD4+ T cells, CD8+ T cells, NK cells, dendritic cells, and B cells. HIV-1 gp120 transduces near-simultaneous signals through CD4 and a chemokine receptor (CCR5 and/or CXCR4). Recent findings involve HIV-1 envelope protein gp120 binding to an activated form of α4β7 on CD4+ T cells, NK cells, and CD8+ T cells. 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.
- HIV-1 envelope binds to, and signals through alpha 4 beta 7 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 gut associated lymphoid tissue, where HIV replicates at high levels, especially in acute-early infection, the specific affinity observed suggests that envelope-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.
Therapeutic strategies for management of hepatitis C/HIV co-infection (Lead Investigator: Shyam Kottilil, M.D., Ph.D.)
Co-infection with hepatitis C virus (HCV) is seen in 15 to 30 percent of all HIV-infected individuals in the United States. With the marked reduction in AIDS-associated opportunistic infections due to the judicious use of antiretroviral therapy (ART), liver disease is becoming a leading cause of death in this group. Co-infection with HCV and HIV results in increased morbidity and mortality, rapid progression of liver fibrosis to cirrhosis, and poor cure rates for HCV. The pathophysiologic mechanisms that lead to poor outcomes in HIV/HCV co-infected individuals are currently unknown. We have focused on developing a translational research program to study HIV/HCV co-infection with an emphasis on innate immune responses and development of therapeutic approaches that maximize the cure rates of HCV infection and avoid serious adverse events among HIV/HCV co-infected individuals.
- HIV-induced immune activation, defective innate immunity, and altered immune regulatory pathways all contribute significantly to accelerated liver disease in HIV/HCV co-infected subjects. Furthermore, acquisition of HIV infection results in IL-15-mediated activation of hepatic stellate cells, accelerating liver fibrosis in HIV/HCV co-infected subjects.
- Several biomarker-based prediction algorithms have been developed and validated to not only provide a molecular basis for therapeutic response but also accurately predict stage of liver disease and emergence of adverse events to anti-HCV therapy
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._
Glimcher LH, Lindvall O, Aguirre V, Topalian SL, Musunuru K, Fauci AS. Translating research into therapies. Cell. 2012;148(6):1077-8.
Blazkova J, Murray D, Justement JS, Funk EK, Nelson AK, Moir S, Chun TW, Fauci AS. Paucity of HIV DNA methylation in latently infected, resting CD4+ T cells from infected individuals receiving antiretroviral therapy. J Virol. 2012;86(9):5390-2.
Moir S, Malaspina A, Fauci AS. Prospects for an HIV vaccine: leading B cells down the right path. Nat Struct Mol Biol. 2011;18(12):1317-21.
Johnston MI, Fauci AS. HIV vaccine development--improving on natural immunity. N Engl J Med. 2011;365(10):873-5.
Kardava L, Moir S, Wang W, Ho J, Buckner CM, Posada JG, O'Shea MA, Roby G, Chen J, Sohn HW, Chun TW, Pierce SK, Fauci AS. Attenuation of HIV-associated human B cell exhaustion by siRNA downregulation of inhibitory receptors. J Clin Invest. 2011;121(7):2614-24.