Laboratory of Molecular Immunology of Infection and Inflammation, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille cedex, France
Keywords: immunotherapy, murabutide, HIV-1
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The need for immunotherapy in the management of HIV disease |
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The impact of HIV-1 infection on elements of innate immunity is as dramatic as the one observed on the adaptive immune system. This is exemplified by the capacity of the virus to infect, persist and induce functional defects in natural killer (NK) cells, monocytes/macrophages and dendritic cells.68 Moreover, these cells, which mediate innate immunity, are believed to act as HAART-resistant virus reservoirs, to contribute heavily towards virus dissemination, to act as a source of virus in patients on HAART and to be at the origin of defective HIV-specific CD4 and CD8 lymphocyte responses in infected subjects.69 Although successful HAART has been reported to increase the number and improve limited functions of certain subpopulations of NK cells and antigen-presenting cells (APCs), profound impairment in the number and function of other subpopulations was found to persist, despite long-term control of viral replication.2,4,6,10,11 Thus, it is apparent that successful immunotherapy in HIV disease would need to address, as a priority, the sustained defects in innate immunity in order to achieve a global restoration of immune responses, including those that are HIV specific.
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Experimental evidence supporting the use of murabutide for the immunotherapy of HIV-1 infection |
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The encouraging results on HIV suppression by murabutide in APCs led to the investigation of the effects of this immunomodulator on viral replication in endogenously infected lymphocytes obtained from HIV-1 patients. These studies have also demonstrated the highly potent capacity of murabutide to suppress viral replication in activated lymphocytes, maintained in culture in the presence of IL-2; the effect was equally evident on cells harbouring macrophage-tropic, dual-tropic or T-tropic virus strains.16 In addition, the immunomodulator presented a similar capacity to inhibit HIV replication in lymphocytes originating from asymptomatics, symptomatics and AIDS patients. The virus-suppressive activity of murabutide was shown to target HIV transcription, and to correlate with a regulated expression of different cellular factors in endogenously infected lymphocytes. Based on these results, the ability of murabutide to control viral replication was then examined in severe, combined immunodeficient mice, repopulated with human peripheral blood mononuclear cells and infected with HIV-1. In infected mice receiving murabutide immunotherapy for 2 weeks, a highly significant drop in plasma viral loads (pVLs) was noted, as compared with the levels detected in untreated mice, and no associated toxicity could be observed in human cells.16 More importantly, when immunotherapy was stopped, viral rebound was minimal or even absent. This suggested that, unlike HIV-1 control by antiretrovirals, the ability to maintain virus suppression through immunomodulation of host cell activity could generate a long lasting effect on viral replication. In addition, immune control of the virus would not provoke the emergence of drug-resistant strains. Taken together, these studies provided evidence that activation of HIV-infected APCs and lymphocytes with murabutide could lead to the secretion of HIV-suppressive chemokines, and to the regulation of multiple cellular factors that render infected cells non-permissive for HIV replication. Furthermore, the strategy of targeting host cells to block viral replication could represent a very attractive and complementary approach to HAART, and may lead to a more efficacious long-term control of the virus.
In an effort to understand the mechanism of action of murabutide at the molecular level, analysis of the profile of regulated gene expression in macrophages and lymphocytes was addressed using, respectively, microarrays and differential display RTPCR. Murabutide-stimulated macrophages were found to upregulate the expression of three cellular factors with known activity in inhibiting HIV-1 replication, and to downregulate the expression of two others that have been implicated in facilitating virus entry or replication.17 On the other hand, differential display analysis of murabutide-treated lymphocytes from HIV-1-infected subjects led to the identification of a novel DExH RNA helicase, named RH116, which was inhibited by the immunomodulator. RH116 was then identified as a key cofactor driving viral replication at the transcriptional level.18 These studies provided a molecular basis for the HIV-suppressive activity of murabutide, and linked the concept of immunomodulation with the strategy of attacking the virus through host cell regulation.
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Clinical development of murabutide in HIV-1 disease |
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Today, immunotherapy of HIV-1 infection seems to be of utmost necessity, to improve on the achievements made following the introduction of HAART in the management of infected subjects. The questions being debated concern the nature, target and timing of immunotherapy. Ultimately, one would like to see the immunotherapy of choice resulting in normalization of innate immune functions, recovery of sizeable and functional adaptive immunity, restoration of cytokine homeostasis and long-term control or eradication of the virus. This would be too ambitious to expect from a single immunotherapeutic regimen, and therefore we should aim to develop multiple immunotherapeutics, which we propose to call CICVI (combined immunotherapy of chronic viral infections). CICVI may be customized to treat HIV, or other chronic viral infections such as hepatitis C, and should contain virus-specific and non-specific components. In the case of HIV-1 infection, the virus-specific component could be one or more of the currently tested therapeutic vaccines, and the non-specific component could be murabutide, either alone or in association with IL-2 or IFN-. Moreover, the timing of the administration of CICVI components would have to be chosen, depending on the stage of infection (acute or chronic), the duration of, and the response to, HAART, and the eventual practice of STI. It is of interest to note that under the setting of STI, non-specific immunotherapy with murabutide could significantly contribute to the immune control of HIV-1, thereby allowing for extended duration of drug holidays. This would also be particularly relevant under conditions where the use of STI alone had not resulted in improved clinical parameters.5 Furthermore, this approach may be among the fastest to demonstrate the clinical benefit of non-specific immunotherapy, as judged by effects on pVL levels, in addition to improved parameters of global immune restoration.
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Footnotes |
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References |
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2
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20 . De La Tribonniere, X., Yazdanpanah, Y., Mouton, Y. & Bahr, G. M. (2002). Non-specific immunotherapy with murabutide significantly improves responses to recall and to HIV-1 antigens, in patients naive to antiretroviral therapy. In Program and Abstracts of the Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2002. Abstract 522, p. 247. Foundation for Retrovirology and Human Health, Alexandria, VA, USA.