Natural type 1 interferon producing cells in HIV infection

Natural Type 1 Interferon Producing Cells in HIV Infection Vassili Soumelis, Iain Scott, Yong-Jun Liu, and Jay Levy ABSTRACT: Natural type 1 interferon producing cells (IPCs) are in the first line of defense against infectious pathogens. Besides the known properties of type 1 interferons in inhibiting human immunodeficiency virus (HIV) replication, the recent characterization of human IPCs and the possibility to purify them for in vitro studies has greatly accelerated the study of their role in HIV infection. The blood IPC numbers and function are decreased in HIV primary infection and in advanced stages of HIV infection. Loss of circulating IPCs correlates with a high HIV viral load and the occurrence of opportunistic ABBREVIATIONS AIDS Acquired immune deficiency syndrome

INTRODUCTION Despite major progress in the understanding of the physiopathology of human immunodeficiency virus (HIV) and in anti-retroviral therapy, HIV infection remains a challenge both for researchers and clinicians. The early identification of CD4⫹ T lymphocytes as one of the main targets of HIV [1] has led to the extensive study of the adaptive T-cell immune responses during the course of HIV infection [2]. The reduction in circulating CD4⫹ T cells remains the main feature of HIV infection and the CD4⫹ T cell count together with the HIV viral load define the clinical stages of HIV infection and the risk of developing life-threatening opportunistic infections [3]. However, many questions cannot be answered solely on the basis of CD4 T-cell immunity [2, 4]: Some patients, called long-term survivors with normal CD4⫹ T-cell numbers, are infected with HIV, but remain asymptomFrom the Department of Hematology, Hopital Necker, Paris, France (V.S.); Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California (I.S., J.L.); Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California (Y.-J.L.) Address reprint requests to: Dr. Vassili Soumelis, Hopital Necker, Department of Hematology, 156 Rue de Vaugirand, Paris, Cedex 15 75730, France; E-Mail: [email protected]. Received July 22, 2002; accepted September 27, 2002. Human Immunology 63, 1206 –1212 (2002) © American Society for Histocompatibility and Immunogenetics, 2002 Published by Elsevier Science Inc.

infections. Moreover, HIV can directly infect IPCs in vitro, providing a potential explanation for their in vivo depletion. Thus, the balance between IPCs and HIV replication might be critical in determining the control or progression of HIV infection. Human Immunology 63, 1206 –1212 (2002). © American Society for Histocompatibility and Immunogenetics, 2002. Published by Elsevier Science Inc. KEYWORDS: Innate immunity; interferon-alpha; HIV; opportunistic infection; AIDS

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atic for more than 10 years without any antiretroviral therapy [5, 6]; Some AIDS patients have extremely low CD4⫹ T-cell counts, but do well and do not develop opportunistic infections [2]; Others have normal CD4⫹ T-cell counts, but develop HIV-related complications such as Kaposi’s sarcoma [2]. Finally, our knowledge of the interactions between HIV, CD4⫹ T cells, and B cells has not yet led to the development of an effective HIV vaccine or major approaches to immunotherapy [2]. For all these reasons, the innate immune system has progressively become an important focus in HIV research [7–9]. Its place in the first line of defense against invading pathogens and its role in shaping the subsequent adaptive immune response suggests that it might shed new light on some of the diagnostic and therapeutic challenges of HIV infection. As a key cell-type in innate antiviral immunity, natural type 1 interferon producing cells (IPCs) [10, 11], also known as plasmacytoid dendritic cell precursors (PDC), are being studied in more detail in the setting of HIV infection. The recent characterization of the precise nature of human IPC [12, 13] and the possibility to purify them from human blood and secondary lymphoid organs has hastened research in the field. In this review, 0198-8859/02/$–see front matter PII S0198-8859(02)00760-7

Natural Type 1 IPCs in HIV

we will analyze recent developments in information on IPCs in HIV infection. For clarity, we will discuss separately the role of IPCs in anti-HIV immunity and the protection against opportunistic pathogens, the role of antiretroviral therapy in IPC restoration, the infection of IPCs by HIV in vitro and in vivo, and, finally, the potential diagnostic and therapeutic implications of IPC research. The Role of IPCs in Anti-HIV Immunity An important role of IPCs in anti-HIV immunity was first suggested by the antiretroviral effects of type 1 interferons (type 1 IFN), which directly inhibit HIV replication in vitro [10, 14 –16] and in vivo [17]. IFN-␣/␤ also have strong adjuvant effects on a variety of immune cell types, such as monocytes [18], natural killer (NK) cells [19], and T cells [20–22], which can act at different levels in antiviral immunity. With the discovery of IPCs [12, 13], the potential role of type 1 interferons in HIV infection, previously emphasized [23, 24], could be more directly evaluated. The inhibitory effect of IPCs and IPC-derived type 1 IFNs on HIV replication in vivo is suggested by several recent studies. The number of circulating IPCs was characterized to be negatively correlated with HIV viral loads [25, 26]. High IPC numbers were associated with undetectable or low HIV ribonucleic acid (RNA) levels in the blood, whereas decreased IPC numbers were associated with high HIV loads, as assessed by plasma HIV RNA levels [25] (Fig 1). In addition, Pacanowski et al. [27] found that this negative correlation is also observed after HIV primary infection, where a transient decrease in IPC counts is associated with viral replication. Likewise, a similar relationship has been observed between the capacity of peripheral blood mononuclear cells (PBMC) to produce IFN-␣/␤ and HIV viral loads [25] (Fig 1). More indirect evidence that IPCs might play a role in the control of HIV replication comes from the study of long-term survivors (or long-term nonprogressors), a particular subset of patients defined by at least 10 years of HIV infection with no sign of disease and no need for antiretroviral therapy [5, 6]. In a study including 24 long-term survivors, we found that the blood IPC number and function were increased in this population as compared with other HIV-infected subjects with either progressive disease or AIDS and even uninfected subjects [25]. To firmly establish that IPCs can exert direct antiretroviral effects, a key question is the ability of HIV to induce type 1 IFN production by IPCs in vitro and in vivo. Ferbas et al. [28] illustrated that HIV induced IFN-␣ production by cluster designation CD4⫹HLADR⫹Lin (cluster desgnation [CD]; human leukocyte antigen [HLA]; lineage [Lin]) cells in amounts comparable to those induced by herpes simplex virus (HSV).

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However, our studies, using highly purified IPCs, have suggested that HIV does not induce high levels of IFN (Scott I, Levy, JA: unpublished observations). Further evaluation of this observation is needed. IPCs and the Protection Against Opportunistic Pathogens Besides inhibiting HIV replication, IPCs might play a role in preventing opportunistic pathogens, thus potentially protecting against life-threatening complications, which continue to compromise the prognosis of HIV infection. Early work by Siegal and associates illustrated that the capacity of PBMC to produce type 1 IFN was impaired during the course of HIV infection and this impairment was associated with the occurrence of opportunistic infections [23, 24]. We recently confirmed these findings and further demonstrated that the capacity of peripheral blood mononuclear cells (PBMC) to produce type 1 IFN correlated with the number of circulating IPCs [25]. Using a slightly different approach, Feldman et al. illustrated that the IFN-␣ producing capacity of IPCs was reduced at the single cell level in infected people with disease [29]. This finding indicated a qualitative dysfunction of IPCs. In these studies, patients developing opportunistic infections experienced an impairment of both adaptive and innate immunity, as assessed by CD4⫹ T cell counts and IPC numbers and function. The results suggested that these two types of immunity are both important against opportunistic pathogens. Supporting this view, we observed that some rare HIV-infected healthy subjects with low CD4⫹ Tcell counts (⬍100/mm3), but conserved IPCs (⬎2/mm3) do not develop opportunistic infections or cancer [25]. To help establish causality between the loss of IPCs and the occurrence of opportunistic infections, large prospective studies are now needed with a thorough IPC monitoring to enable (i) the precise description of the kinetics of IPC loss compared with the occurrence of HIV-related complications and (ii) a detailed multivariate statistical analysis including all major confounding factors such as corticosteroid therapy and myelosuppressive or antiretroviral therapies, which can influence immune reconstitution independently of HIV replication. The fact that IPC loss is associated with the occurrence of various types of opportunistic infections, such as cytomegalovirus (CMV) infection, progressive multifocal leukoencephalopathy or Pneumocystis carinii infection, suggests that the function of IPC is not restricted to antiviral immunity [24, 25]. These clinical observations fit with recent results [30] and (Kadowaki N: unpublished data) illustrate that nonviral stimuli, such as gram-positive bacteria and mycobacteria, can strongly induce IPC to produce IFN-␣ in vitro. IPC response to pathogens was recently revealed to be mediated in part

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by the expression of a restricted profile of toll-like receptors (TLRs), mostly TLR-7 and TLR-9 [30 –33]. Although no study has yet focused on the TLRs mediating responses to opportunistic pathogens, this receptor family might be widely involved and merits further study. Important progress might also come from animal models of infection. Mouse IPC were recently identified and share many characteristics with human IPCs, including the plasmacytoid morphology and the high and rapid production of type 1 interferons in response to virus [34 –37]. Dalod et al. have demonstrated that IPCs are needed for the control of mouse CMV infection [38]. Although translation to the human clinical disease must be cautious, this finding suggests a role for IPCs in the protection against CMV infection. Antiretroviral Therapy and IPC Restoration In past years, a dramatic decrease in the rate of opportunistic infections and acquired immune deficiency syndrome (AIDS)-related mortality has occurred. This result reflects the introduction of highly active antiretroviral therapy (HAART) and its positive effect on immune restoration [39, 40]. However, the magnitude of the immune restoration after HAART, as assessed by CD4⫹ T-cell counts, is variable and often incomplete [39]. Given their potential role against opportunistic pathogens, IPCs might participate in the positive effects induced by HAART. In a study of HIV primary infection, blood IPC numbers were found to be restored after an early initiation of HAART [27]. The capacity of PBMC to produce IFN-␣ also increased after HAART in a large prospective follow-up trial [8, 41]. However, IPC number and function remained decreased after HAART in another study [42], further highlighting the variability of the immune reconstitution after antiretroviral therapy. Infection of IPCs by HIV CD4⫹ T-helper lymphocytes are the major cells, which can be directly infected by HIV [2]. However, HIV can also infect other immune cell types, such as macrophages [2, 43] and dendritic cells [44 – 46]. Whether IPCs are potential targets for HIV was considered because of three important characteristics, which IPCs share with CD4⫹ T cells: (i) they express high levels of surface CD4 [47, 48], (ii) they constitutively express the chemokine receptors CCR5 and CXCR4 [45, 49], which are the major coreceptors for HIV infection of a cell [50], and (iii) they can be present in blood, thymus, and secondary lymphoid organs [47, 48, 51, 52], where HIV is able to replicate actively [53]. Recently, Patterson et al. illustrated that IPCs could be productively infected in vitro with both T-cell-tropic (T-tropic) and macrophagetropic (M-tropic) HIV strains [54, 55]. However, the IPCs were not highly purified in these studies and recent

FIGURE 1 Blood interferon producing cells (IPC) numbers, cluster designation (CD)4⫹ T-cell numbers and human immunodeficiency virus (HIV) ribonucleic acid (RNA) levels by clinical subgroup of HIV-infected subjects [25]. Each open circle represents a value for a different study subject. Horizontal bars indicate the median. The p values are based on the comparison of the group means. (A) The number of blood IPC is increased in leukotrienes (LTS) (p ⬍ 0.05 for all group comparisons vs LTS) and decreased in acquired immune deficiency syndrome (AIDS) patients (p ⬍ 0.01, for all group comparisons vs AIDS). Progressors and healthy donors have comparable IPC numbers (p ⬎ 0.05). (B) CD4⫹ T-cell numbers are comparable in healthy donors and LTS (p ⬎ 0.05) and follow a stage-specific decrease from LTS to progressors and AIDS (p ⬍0.05 for the comparison of LTS vs progressors and LTS vs AIDS). (C) HIV viral load is comparable in LTS and progressors (p ⬎ 0.05) and increased in AIDS subjects as compared with the two other groups (p ⬍ 0.05 for each of these comparisons).

Natural Type 1 IPCs in HIV

investigations suggest very pure populations of IPC (⬎99%) after HIV inoculation produce only extremely low levels of virus (Scott I, Levy JA: unpublished observations). Important questions remain regarding the fate of HIV-infected IPCs: Do they survive? Do they differentiate into mature DC, as they do after HSV stimulation [30]? Can they present HIV-specific antigens to T cells or directly transmit HIV to T cells? The answer to these questions might change the physiopathologic significance of IPC infection by HIV. If HIV induces type I IFN production, IPC survival and differentiation into a potent antigen-presenting cell (APC), it would have a beneficial effect by stimulating anti-HIV immunity. If, on the contrary, HIV induces death of IPCs, this would have a deleterious effect and could explain the in vivo depletion of circulating IPCs and the subsequent predisposition of the host to opportunistic infections. In recent studies, HIV has not been present to kill IPC nor induce their maturation (Scott I, Levy JA: unpublished observations), but these observations require further evaluation. Concerning the capture and transmission of HIV to T cells, DCs were revealed to efficiently transmit HIV to T cells via DC-SIGN, a novel C-type lectin [56 –58]. However, DC-SIGN expression by DC subsets is heterogeneous. Soilleux et al. illustrated that cells with a phenotype of IPCs (blood dendritic cell antigens [BDCA]2⫹CD123⫹) expressed surface DC-SIGN in the blood, but also in the nasal mucosa [59]. Patterson et al. could not detect DC-SIGN expression by blood IPCs at the RNA level [55]. Moreover, in a study of plasmacytoid DCs in the Peyer patch, DC-SIGN expression was not detected [60] and we have not detected DC-SIGN nor DC-SIGN-R on highly purified human IPC (Scott I, Levy JA: unpublished observations). Finally, in a functional study of the binding of HIV gp120 protein to blood CD11c⫹ DCs and IPCs, Turville et al. illustrated that both cell types only bound gp120 via CD4 [61]. The in vivo significance of these findings is still to be determined. Diagnostic and Therapeutic Implications The immune monitoring of HIV-infected subjects is currently based on CD4⫹ T-cell counts [2]. Measuring the IPC number, as a reflection of the innate immunity, together with the CD4⫹ T-cell count, should provide an improved method for evaluating immune function and for predicting the occurrence of HIV-related complications. With patients manifesting reductions in both CD4⫹ T cells and IPCs, preventive anti-infectious strategies or a change in antiretroviral therapy would be recommended to favor immune restoration. An important question is the ability of IFN-␣ therapy

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to replace the function of missing or defective IPCs. Clinical trials of IFN-␣ in advanced-stage HIV-infected patients [62] have exhibited no benefit for IFN-␣ therapy. One explanation could be that IPCs have the potential to migrate to the site of viral replication, instead of circulating in the blood like the cytokine alone does. Moreover, IPCs produce all type I IFNs (Kanzler H: unpublished data), including IFN-␤ and ␻, and perhaps other unidentified antiviral substances. However, IFN-␣ could also have been used too late in these trials. Data from the study of long-term survivors suggests that IPCs and IFN-␣ production might be important for the early control of HIV replication to prevent progression of the disease [25]. Studies of IFN-␣ as an early treatment in asymptomatic HIV-infected subjects have been reported [63] and other trials are in progress. Preliminary results indicate that control of viral replication was equivalent between IFN-␣ and antiretroviral therapy [63]. The availability of the pegylated form of IFN-␣, which is easier to use and better tolerated, will certainly facilitate evaluation of such long-term therapeutic trials. Drugs increasing the number and/or function of IPC could become an option in the future to both control HIV replication and HIV-related clinical conditions. FMS-like tyrosine kinase 3 (FLT3) ligand, which is a key factor for the generation of IPCs both in vitro [64, 65] and in vivo [66, 67] could be used or granulocyte colony stimulating factor (G-CSF), which can mobilize IPCs from bone marrow to peripheral blood in vivo [68]. Questions similar to those for the use of IFN-␣ apply to these strategies, especially when to administer them in the course of the disease. Finally, IPC-based cell therapy could also be envisioned in the setting of HIV infection. The elucidation of the differentiation pathways from hematopoietic stem cells will be key to generate large numbers of IPCs in a therapeutic perspective. CONCLUSION The interactions between IPCs and HIV are at the interface of two exciting and evolving fields. Our basic understanding of the biology of IPCs in terms of differentiation and migration pathways, surface receptors, and secreted molecules might have direct implications on our understanding and management of HIV infection. Progress in the HIV field will guide research and give new directions for IPC biologists. The recent findings that IPC number and function are affected in HIV infection, and that HIV can directly infect IPCs, has opened up many questions, which need to be addressed promptly: What is the role of IPCs in HIV primary infection? Can their level in blood reflect prognosis of the infection? What is the function of IPCs after infection with HIV in vitro or in vivo? What is the mechanism of

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IPC depletion in vivo? Is there causality between the loss of IPCs and the occurrence of opportunistic infections? The potential implications for the management of HIV infection are major motivations to pursue the study and characterization of IPCs. We hope that this new knowledge will prove complimentary to progress in other areas for developing efficient therapeutic strategies.

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15. ACKNOWLEDGMENTS

The authors thank Dr. Melissa Pope and Natalia Telesho for critical review of the manuscript.

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