Opportunistic infections and CD4 lymphocytopenia with interferon treatment in HIV-1 infected patients

Pesce, A.; Rosenthal, Eric S.; Vinti, H.; Taillan, B.; Garnier, G.; Dujardin, P; Cassuto, Jill‐Patrice

doi:10.1016/0140-6736(93)90736-z

Cited by 54 publications

(26 citation statements)

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“…Taken together, an opposite role for type I and type II IFN might be a generalized finding in human infections with intracellular pathogens. Likewise, increased susceptibility to opportunistic infections has been occasionally described (41,42) as an undesirable side effect during treatment of viral infections or cancer with type I IFN, without further evidence of the molecular and cellular mechanism(s) involved.…”

Section: Discussionmentioning

confidence: 99%

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

Khouri¹,

Báfica

Silva³

et al. 2009

The Journal of Immunology

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Type I IFNs (IFN-α/β) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-β has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-β dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-β significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-β-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-β inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-β/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well as L. braziliensis infection, major human pathogens.

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Section: Discussionmentioning

confidence: 99%

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

Khouri¹,

Báfica

Silva³

et al. 2009

The Journal of Immunology

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“…33,[35][36][37][38] To determine the effects of IFN-I signaling augmentation as induced by rmIFN␣2 on CD4 ϩ T-cell homeostasis in chronically SIV-infected SMs, PBMCs and mononuclear cells derived from LNs and RBs were analyzed by multiparametric flow cytometry. This analysis revealed that rmIFN␣2 did not induce any significant change in the absolute number or percentage of CD4 ϩ T cells in any of the examined anatomic compartments ( Figure 3A-D), aside from an isolated finding of lower CD4 ϩ T-cell percentage and count at day 84 in peripheral blood and RBs (Friedman test with Dunn multiple comparisons, P Ͻ .05), which returned to baseline levels by the last time point during treatment.…”

Section: Administration Of Rmifn␣2 To Chronically Siv-infected Sms Domentioning

confidence: 99%

Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation

Vanderford

Slichter

Rogers

et al. 2012

Blood

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IntroductionIn stark contrast to HIV infection in humans and experimental SIV infection of macaques, both of which lead to AIDS, SIV infection of natural host sooty mangabeys (SMs) is typically nonprogressive despite similarly high levels of virus replication. 1,2 The reasons that SIV-infected SMs are resistant to AIDS remain incompletely understood, and it is hoped that their elucidation will help to define the mechanisms responsible for the development of AIDS in HIV-infected humans. 3 Several studies have shown that 2 consistent features of naturally SIV-infected SMs are the absence of generalized immune activation during the chronic phase of the infection and a pattern of in vivo-infected cells that results in a preferential preservation of central memory CD4 ϩ T cells from SIV infection. 4,5 The low immune activation observed in chronically SIVinfected SMs represents a key phenotypic difference from pathogenic HIV/SIV infection of humans and macaques, in which chronic immune activation is a major marker and predictor of disease progression, both in the natural history and in the setting of antiretroviral treatment. [6][7][8][9][10][11] In SIV-infected SMs, the low immune activation that is observed during the chronic phase of infection is established as the result of the relatively rapid resolution of a strong innate and adaptive immune response to the virus that occurs during the acute phase of infection and lasts approximately 4-6 weeks after the initial inoculation. 4,12 Similar kinetics of the immune responses to SIV have been reported in another natural host, the African green monkey. 13,14 The mechanisms by which SIV-infected SMs are able to tune down their immune activation remain unclear, but may involve specific virus properties, better ability to activate immune regulatory pathways, decreased sensing of viral antigens, preservation of mucosal immunity with consequent absence of microbial translocation, and differences in the pattern and anatomic location of infected cells. 3 Regardless of the mechanisms involved, the low immune activation observed during the chronic phase of SIV infection in SMs is associated with the absence of up-regulation of type I IFN (IFN-I)-stimulated genes (ISGs), which is a consistent feature of the transcriptional profile of pathogenic HIV/SIV infections. 4,13 At this time, however, it remains unknown whether and to what extent this lack of an IFN-I gene-expression signature in chronically SIV-infected natural hosts represents a cause or a consequence of the low immune activation. To address this issue, in the present study, we treated 8 naturally SIV-infected SMs for 16 weeks with a recombinant IFN-I agonist (a recombinant rhesus macaque [RM] IFNa2-Ig fusion protein, rmIFN␣2) that induces a strong ISG up-regulation both in vitro and in vivo, thus demonstrating that SMs are not intrinsically resistant to IFN-I signaling. The main result of this treatment was a significant, approximately 1-log decline in viral load that persisted for approximately 6 weeks, coincident wi...

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Section: Introductionmentioning

confidence: 99%

“…In addition, IFN-␣ treatment causes a leukopenia, including a decrease of lymphocyte numbers and thus of CD4 count, often leading to premature treatment interruption. [8][9][10][11][12] Therefore, to enhance the efficiency of anti-HVC therapy in coinfected patients, it is critically important to develop an alternative treatment that limits the lymphopenic effect of IFN-␣ therapy.Interleukin 7 (IL-7), a cytokine that promotes precursor B-and T-cell maturation [13][14][15] and supports peripheral T-cell homeostasis, [16][17][18] is currently in phase I/II trials in patients with persistent lymphopenia. This therapy has demonstrated its efficacy in restoring circulating CD4 ϩ T-cell counts in HAART-treated HIV-infected patients 19,20 as well as in increasing T-cell diversity in patients under chemotherapy for cancer.…”

mentioning

confidence: 99%

Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

Parker

Dutrieux

Beq

et al. 2010

Blood

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Interferon-␣ (IFN-␣)-based therapy ispresently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-␣-induced lymphopenia. We showed that low-dose IFN-␣ treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-␣ treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-␣. Indeed, the association of both cytokines resulted in increased circulating T-cell IntroductionCoinfection with HIV and hepatitis C virus (HCV) has become an increasingly common occurrence, with an estimated 25% to 30% of HIV ϩ patients also being HCV ϩ . 1 As a consequence, since the appearance of highly active antiretroviral therapy (HAART), chronic liver disease has become one of the most common causes of morbidity and mortality in HIV patients. 2,3 Although the effectiveness of standard HCV treatment, based on interferon-␣ (IFN-␣) injections, is known to decrease the longer a patient has been infected with the virus, HCV patients are not systematically put under treatment. Rather, initiation of treatment depends on the state of the patient's liver (fibrosis markers, serum aminotransferases, HCV RNA, hepatitis B virus status) and other parameters, which in turn are used to determine whether the potential benefits of therapy outweigh the risks of treatment-related toxicity. 4 For HIV-HCV-coinfected patients, some of these parameters are: the assessment of HIV disease status, such as current and past opportunistic infections, HIV-associated malignancies, CD4 count, HIV viral load, and details of HAART therapy, with CD4 count being one of the main criteria. Unfortunately, coinfected patients are poor responders to standard treatment as a sustained viral response occurs in only 27% to 40% of these patients, approximately half the rate seen in HCV-monoinfected patients. [5][6][7] The main reason for this difference can be attributed to exhaustion of the immune system. In addition, IFN-␣ treatment causes a leukopenia, including a decrease of lymphocyte numbers and thus of CD4 count, often leading to premature treatment interruption. [8][9][10][11][12] Therefore, to enhance the efficiency of anti-HVC therapy in coinfected patients, it is critically important to develop an alternative treatment that limits the lymphopenic effect of IFN-␣ therapy.Interleukin 7 (IL-7), a cytokine that promotes precursor B-and T-cell maturation [13][14][15] and supports peripheral T-cell homeostasis, [16][17][18...

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Opportunistic infections and CD4 lymphocytopenia with interferon treatment in HIV-1 infected patients

Cited by 54 publications

References 2 publications

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation

Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

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