Anthony S. Fauci, M.D.

Director, National Institute of Allergy and Infectious Diseases

Chief, Laboratory of Immunoregulation
Chief, Immunopathogenesis Section

Description of Research Program

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 the following: 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.

Major findings:

• 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.

Major findings:

• 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 Innate Immunity in the Pathogenesis of HIV Disease (Lead Investigators: Shyam Kottilil, M.D., Ph.D., and Domenico Mavilio, M.D.)
Natural killer (NK) cells are a critical component of host innate immune responses to a variety of viruses, fungi, parasites, bacteria, and certain tumors. The ability of NK cells to lyse targets does not depend on prior sensitization, and their activity is not MHC restricted. Upon activation, NK cells release cytokines and chemokines that induce inflammatory responses, modulate hematopoiesis, control monocyte and granulocyte cell growth and function, and influence the type of adaptive immune responses that follow. With regard to HIV infection, the non-specificity of NK-cell activity might be relevant to initiation of a degree of antiviral activity in the face of an evolving adaptive immune response and a high level of virus replication that negatively affects HIV-specific cellular and humoral immune responses. In earlier studies, we demonstrated that NK cells from HIV-infected individuals were able to secrete CC-chemokines and suppress HIV replication in vitro. The objective of this project is to further delineate the role of NK cells in the pathogenesis of HIV infection.

Major findings:

• HIV viremia is associated with modulation of the phenotype of NK cells and with NK-cell dysfunction.
• HIV viremia impairs the ability of NK cells to suppress endogenous HIV replication in CD4+ T cells.
• Exposure to HIV envelope impairs NK-cell function.
• Expansion of subset of NK cells with impaired function occurs in HIV viremic patients.
• NK cell markers were identified in monkeys.
• HIV viremia induces a broad array of gene expression in NK cells.
• HIV viremia disrupts dendritic cell-NK cell cross talk and contributes to impaired host immune response.
• An HIV receptor on NK cells was identified as the gut-homing alpha4 beta7 integrin.

Impact of the Immunoregulatory CD4+CD25+ T-Cell Subset on the Host Response to HIV Infection (Lead Investigator: Audrey Kinter)
Since its inception, the Immunopathogenesis Section has defined host factors involved in the pathogenesis of HIV disease, including the impact of the immune system on the propagation and/or control of virus replication. HIV infection is associated with chronic, aberrant immune activation that supports viral replication and contributes to the progressive immune dysfunction associated with HIV disease progression. Chronic immune activation, whether induced by persistent foreign antigens or loss of self-tolerance, activates and expands host-mediated immunosuppressive mechanisms that serve to prevent immune-mediated damage to the host. The principal objective of this study is to investigate the impact of these suppressive mechanisms, in particular CD25+ CD4+FoxP3+ regulatory T (Treg) cells and the negative regulatory surface molecule programmed death (PD)-1, on HIV disease immunopathogenesis. We have demonstrated that CD25+ Treg cells isolated from peripheral blood (PB) and lymphoid tissue (LT) HIV-positive subjects inhibit numerous HIV-specific CD4+ and CD8+ T cell immune responses in vitro, including the ability of CD8+ T cells to kill HIV-expressing cells. We have also demonstrated that engagement of the negative regulatory cell surface molecule PD-1 suppresses the expansion of functional HIV-specific T cells. In addition, the PD-1 ligands, PD-L1 and PD-L2, appear to exert differential effects on T-cell proliferation and survival. Finally, we demonstrated that IL-2, IL-7, IL-15, and IL-21, cytokines that play a critical role in normal T-cell expansion and survival, up-regulate the expression of PD-1 and its ligands on PB cells isolated from both HIV-infected and uninfected individuals. During periods of significant cytokine-driven T-cell expansion and activation, as can occur following depletion of T cells by a pathogen (such as HIV) or chemotherapy, elevated levels of PD-1 on T cells may inhibit immune responses to foreign or self antigens.

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.

Major findings:

• HIV envelope induces the phosphorylation of FAK and CCR5 on T cells.
• HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication.
• HIV envelope induces the expression of HIV from resting CD4+ T cells of HIV-infected patients in the absence of induction of markers of classical T-cell activation.
• HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.
• NK cells, armed and triggered by a recombinant immunoglobulin fusion protein, target lysis of HIV-infected cells.
• R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells.
• HIV envelope induces the activation and translocation of NFAT in resting primary lymphocytes.
• HIV-1 gp120 inhibits TLR9-mediated activation and IFN-alpha secretion in plasmacytoid dendritic cells.
• HIV-1 envelope binds to, and signals through alpha 4 beta 7 integrin, the gut mucosal homing receptor for peripheral T cells.

Development of Novel Strategies for Immune Reconstitution of HIV-1-Infected Individuals: Studies on IL-7 (Lead Investigator: Paolo Lusso, M.D., Ph.D.)
Interleukin-7 (IL-7) is a homeostatic cytokine that plays a key role in the regulation of the T-cell compartment of the immune system. Due to its ability to restore the T-lymphocyte pool under conditions of lymphopenia, IL-7 is currently under clinical investigation as a potential agent for the immune reconstitution of HIV-1-infected patients. We have investigated the effect of IL-7 on spontaneous apoptosis ex vivo in a cohort of HIV-1-infected subjects. We found that treatment with IL-7 resulted in a dramatic reduction in the levels of spontaneous apoptosis in both CD4+ and CD8+ T cells (naïve and memory) derived from HIV-1-infected subjects, with a significant inverse correlation between the magnitude of the effect and the patient CD4 counts. IL-7-mediated protection from apoptosis was temporally dissociated from cellular proliferation and was not associated with the induction of endogenous HIV-1 expression. Preliminary investigation of the mechanism(s) of anti-apoptotic effect of IL-7 demonstrated a dramatic increase in Bcl-2, associated with a decreased activation of both caspase-8 and caspase-9. In addition to these ex vivo studies, we have recently started an experimental trial to investigate the effects of IL-7 treatment in vivo in rhesus macaques during the acute and chronic phases of SIVmac251 infection. Preliminary results indicate that IL-7 treatment induced a significant increase in the absolute numbers of both CD4+ and CD8+ T cells in peripheral blood, with only a limited decrease during the phase of peak SIV replication. The anti-apoptotic activity that we documented for IL-7 provides an additional rationale for the use of this cytokine as an immunotherapeutic agent in the treatment of HIV-1 infection.

Major findings:

• Ex vivo treatment with IL-7 protects both CD4+ and CD8+ T cells derived from HIV-1-infected individuals from spontaneous apoptosis.
• The anti-apoptotic activity of IL-7 is not associated with cellular proliferation or induction of endogenous HIV-1 replication.
• Treatment of rhesus macaques with IL-7 in vivo maintains the number of circulating CD4+ T cells within the normal range throughout the acute phase of SIV infection.

Research Group Members

Bottom row (left to right): Susan Moir, Ph.D., Anthony S. Fauci, M.D., Claudia Cicala, Ph.D., Angela Malaspina, Ph.D. Top row: Tae-Wook Chun, Ph.D., Shyam Kottilil, M.D., Ph.D., James Arthos, Ph.D., Paolo Lusso, M.D., Ph.D., Audrey Kinter. Not pictured: Domenico Mavilio, M.D.

Selected Publications

(View list in PubMed.)

Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, Ward DJ, Kovacs JA, Mannon PC, Fauci AS. Persistence of HIV in Gut Associated Lymphoid Tissue Despite Antiviral Therapy. J Infec Dis. 2008;197:714-20.

Moir S, Malaspina A, Ho J, Wang W, Dipoto AC, O'Shea MA, Roby G, Mican JM, Kottilil S, Chun TW, Proschan MA, Fauci AS. Normalization of B Cell Counts and Subpopulations after Antiretroviral Therapy in Chronic HIV Disease. J Infect Dis. 2008 Feb 15;197(4):572-9

Kottilil S, Jackson JO, Reitano KN, O'Shea MA, Roby G, Lloyd M, Yang J, Hallahan CW, Rehm CA, Arthos J, Lempicki R, Fauci AS. Innate immunity in HIV infection: enhanced susceptibility to CD95-mediated natural killer cell death and turnover induced by HIV viremia. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):151-9.

Kinter AL, McNally J, Riggin L, Jackson, Roby G, Fauci AS. Suppression of HIV-Specific T Cell Activity by Lymph Node CD25+ Regulatory T Cells From HIV-infected Individuals. Proc Nat Acad Sci USA. 2007;104: 3390-5.

Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA, McLaughlin S, Pascuccio M, Gopaul R, McNally J, Cruz CC, Censoplano N, Chung E, Reitano KN, Kottilil S, Goode DJ, Fauci AS. HIV-1 envelope protein binds to and signals through integrin alpha(4)beta(7), the gut mucosal homing receptor for peripheral T cells. Nat Immunol. 2008 Feb 10.

Vassena L, Proschan M, Fauci AS, Lusso P. Interleukin-7 protects from spontaneous apoptosis both CD4+ and CD8+ T cells from HIV-1-infected individuals. Proc Nat Acad Sci USA. 2007;104:2355-60.

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