Papel de las células plasmacitoides en el control del VHA1

Resumen

During the last five years I was focused on my PhD projects about HIV infection and innate immunity under the supervision of Dr Ezequiel Ruiz-Mateos and Dr Manuel Leal. My main research was focused on the role of plasmacytoid dendritic cells (pDCs) in the spontaneous control of HIV infection in ¿HIV elite Controllers¿ (EC). EC are a rare group of HIV-infected patients who are able to maintain undetectable viral loads during a long period of time in the absence of antiretroviral treatment (ART)[1]. Mechanisms responsible for this spontaneous control have been studied with the hope of developing a therapeutic vaccine against HIV. Preserved T cell functionality has been described for EC [2-4]; however, the innate immunity response needs to be characterized. The pDCs are innate immune cells that respond to viral infections, producing up to 1000-fold more alpha interferon (IFN-¿) than other cell types [5] through the stimulation of Toll-like receptor 7 (TLR-7) and TLR-9. The IFN-¿ produced by pDCs not only participates in the inhibition of viral replication but also has an adjuvant effect on different immune cells types[6-8], acting as a critical link between innate and adaptive immunity. The first aim of my thesis was to quantify pDCs levels and to analyze pDCs functionality in relation to the spontaneous control of HIV viremia observed for EC. When I joined the group, we first started characterizing our cohort of EC. We observed how the ability to control spontaneously HIV infection in EC is not infinite and that they eventually progress to AIDS [9]. Once the EC from our cohort were characterized, we started working on pDCs and began collaboration with Dr Jean-Phillipe Herbeuval (CNRS UMR 8147, Necker Hospital, Paris, France), who is an expert on pDCs, and Dr Olivier Lambotte (Bicêtre Hospital, Paris, France) who is an expert on HIV infection in EC. During my 9 months training at Dr Herbeuval¿s laboratory, we obtained very interesting discovery after learning several tools; and demonstrated for the first time the preserved frequency and functionality of pDCs in relation with the capacity to control HIV infection by EC when compared to other group of HIV infected individuals [10, 11]. Moreover, we showed a preserved capacity of pDCs from EC to suppress viral production in HIV-infected T cells and also showed the mechanisms by which pDCs induced this viral suppression. These findings highlight the important role of innate immunity in HIV immunopathogenesis and could have important immunotherapeutic applications. During my training, we also were wondering whether the EC are able to control other persistent infections as Hepatitis C virus (HCV), whose natural history is accelerated in HIV-co-infected patients. In this study [12], we interestingly found a lower HCV viral load in HIV controllers, alongside a different distribution of HCV genotypes in relation to the HIV/HCV co-infected comparison group. Thus, some of these subjects are able to control both infections, suggesting the possibility of shared control mechanisms. In this sense, as we previously observed a preserved capacity of pDCs from EC to suppress HIV replication: we wondered whether pDCs are also implicated in the control of both infections HCV/HIV. For this purpose, I participated tightly with my mentor Dr Ruiz-Mateos in the development of this project and the design of the experiments. In parallel, analyzing shared control mechanisms of HIV and HCV infections, we were also interested in a single nucleotide polymorphism (SNP) rs12979860, near the IL28B gene, which codes for interferon ¿3 (IFN-¿3) and has been associated with the spontaneous clearance of HCV [13] and with sustained virological response (SVR) after HCV-specific treatment [14]. Although it is still unknown how this SNP affects the antiviral activity of IFN-¿, several studies have demonstrated the antiviral activity of IFN-¿ against different viruses, including HIV [15]. However, no association was found between these protective alleles and spontaneous HIV control in African American individuals [16, 17]. We wondered whether this IL28B SNP would be overrepresented in white HIV controllers, thus our aim was to analyze the association of the IL28B SNP with the spontaneous control of HIV infection. Our study demonstrates that the IL28B-CC genotype is independently associated with spontaneous HIV control in white individuals [18]. Our finding adds to the suggestion of common shared mechanisms involved in the control of persistent infections, such as HIV and HCV infection. We are now focusing our efforts to explain these results. As the pDCs also produce IFN-¿3 [19] and we already showed the preserved functionality of pDCs in EC, it is unknown whether this SNP alter IFN-¿3 production by pDCs. Recently, a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ¿G), which is in high linkage disequilibrium with IL28B rs12979860, has been discovered [20]. ss469415590 [¿G] is a frameshift variant between IFNL2 and IFNL3 that creates a novel gene, designated IFNL4, encoding the IFN-¿4, which is moderately similar to IFN-¿3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians [20]. We were interested in analyzing whether ss469415590 SNP is associated with the main parameters associated with HIV progression, i. e. HIV viral load and CD4+ T-cells, which have not been studied in HIV-infected patients. For this aim, we included 389 HIV-infected subjects, in chronic phase of HIV infection and ART-naïve. Briefly, we observed a higher prevalence of presenting AIDS-defining illness in subjects¿ carriers of ss469415590 ¿G variant. We showed that ss469415590 TT variant is independently associated with a lower proportion of CDC events. I REFERENCES 1. Deeks, S.G. and B.D. Walker, Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity, 2007. 27(3): p. 406-16. 2. 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