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HIT HIDDEN HIV Sintesi della relazione

Project ID: 305762
Finanziato nell'ambito di: FP7-HEALTH
Paese: France

Periodic Report Summary 2 - HIT HIDDEN HIV (Paving the way towards HIV eradication/control)

Project Context and Objectives:
Major advances in HIV/AIDS treatment regimens have fundamentally altered the natural history of the disease and sharply reduced HIV-related morbidity and mortality in countries where such treatments are accessible. The most notable advance is the use of combination antiretroviral therapy or ART. However, ART is unable to achieve virus eradication or “sterilizing cure”. Indeed, in most cases viral rebound is observed after ART interruption. Thus, life-long treatment is currently needed to control HIV. Drug resistance, cumulative side-effects and high cost, represent major drawbacks of such treatments. The persistence of HIV in treated patients results from the establishment of a viral reservoir insensitive to ART and poorly visible to the immune system. Thus, understanding HIV persistence and developing drugs able to flush out HIV, in order to achieve viral eradication or “sterilizing cure” remain outstanding challenges.
Two main lines of research are being proposed. The first starts from the recent discovery by partners of this consortium of the immune-modulator Samhd1 as the cellular factor restricting HIV-1 infection in myeloid cells. The partners explore a role for Samhd1 in immune activation and inflammation, and its impact on the balance between viral replication and persistence. To understand further HIV persistence, the partners study the molecular mechanisms underlying post-integrative latency. The second aims at identifying and optimizing novel naturally occurring inducers of HIV reactivation. Additionally, a novel non-human primate model is developed, allowing the study of viral persistence in vivo by tracking latently-infected cells.
The project aims at: (i) increasing knowledge on the contribution of immune activation and inflammation to HIV persistence (ii) deciphering the cellular and molecular mechanisms of viral persistence (iii) translating this basic knowledge into novel targets to achieve a cure for HIV/AIDS.

Project Results:
Major progress has been made towards the achievement of our objectives.

1) We engineered lentiviral reporter constructs with constitutive expression of GFP and Cre recombinase-dependent expression of the RFP. These allow to start establishing the NHP animal model dedicated track and localize latently-infected cells in vivo. Importantly, when tested in single animal, SIV carrying the Cre recombinase as nef-IRES-Cre, shows a stable expression of the Cre up to 5 weeks post inoculation. Transduction efficiency of cord blood CD34 cells and its impact phenotypical reconstitution of immune cells was assessed in immune-compromised mice. Using this model we could observe the expression of the RFP reporter only in infected CD4 T cells. Presently, experiments in Non-Human primates is ongoing.

2) We were able to purify and identify NELF and its associated nuclear partners. We uncovered the mechanism by which NELF represses HIV-1 transcription (Stadelmayer et al. Nature comm. 2014. Nov 20; 5:5531) and identified integrator complex and its catalytic subunit as a regulator of NELF-mediated RNAPII pausing at the viral promoter. Knockdown of Integrator subunits result in reactivation of transcriptionally silent HIV. In addition, partner 4 was able to provide the community with a bioinformatics tools to assess for cellular genes regulated by HIV. GuavaH is a compendium of host genomic data in HIV biology and disease (Bartha, et al. 2014). The dynamic of HIV latency and reactivation in primary T cells model was also explored. We could demonstrate the importance of posttranscriptional regulation of viral mRNA in HIV latency (Mohammadi et al. 2014). More recently, effort towards the reactivation of HIV and the targeting of latently infected cells results in the identification of a modified form of the viral Tat protein as potent inducer and killer of persistent cells. Additionally, and as part of WP3, partner 5 has identified a natural peptide able to reactivate latent virus using J-Lat model of latency. We were able to purify the peptide and uncover its amino-acid sequence. In vitro synthesized peptide show a similar reactivation capacity. Partner 2 determined the contribution of ADCC in bNAbs-mediated neutralization of HIV. They optimized a strategy aiming at combining HIV reactivating agent and bNAbs to eliminate HIV persistent cells using PBMCs isolated from cART treated HIV infected patients.

3) We were able to demonstrate that SAMHD1 is the HIV-1 restriction factor operating in resting CD4 T cells (Descours et al 2013). We uncovered the mode of regulation of SAMHD1 by showing that its restriction activity is regulated by phosphorylation (Cribier et al. 2013). Finally, we reported evidence that the presence of SAMHD1 in myeloid cells allows HIV-1 to escape from innate immune sensing (Puigdomenech et al. 2013). SAMHD 1 cellular function was also uncovered. Indeed, we demonstrated that SAMHD1 is key regulator of cell response to DNA damage (Clifford R, Louis, T et al. 2014). More recently, we uncovered a function of SAMHD1 in the establishement of HIV reservoir. Indeed, we found that IL7 induces SAMHD1 phosphorylation and inactivation allowing HIV to complete its replication cycle up to integration (Coiras et al. Cell report 2015. In press). Importantly, we were able to demonstrate the efficiency of broadly neutralizing antibodies to prevent cell-to-cell transmission of HIV, which is known to mediate residual viral replication in patient under suppressive ART (Malbec et al, 2013; Horwitz et al. 2013) other cellular factors which may play role in viral induced inflammation were identified. Those include, the SLX4 resolvase complex targeted by the viral accessory protein Vpr (Laguette et al. 2014), IFI16 (manuscript submitted) and others (Malbec et al. 2013; Sauter et al. 2013). Partner 2 has also identified Sun2 as an inhibitor of HIV replication (Donahue et al. submitted). However, the mechanism of action is still to be uncovered.

Potential Impact:
HIT HIDDEN HIV addresses a gap and provides a highly innovative strategy in the study of the HIV virus. HAART is able to control the infection but remains unable to permanently eradicate HIV or to achieve a functional cure in infected people leaving a huge reservoir of virus within the population. The project faces this issue and tends to diminish its effects while translating basic knowledge generated by the partners into novel therapies for HIV/AIDS. It bases on the successful investigations led by the partners: (i) basic mechanisms of HIV post integrative latency and transcriptional reactivation leading to the identification of novel potential antiviral targets; (ii) a specific class of antiviral chemicals that showed a good therapeutic index towards HIV and (iii) a novel primate animal model that perfectly mimics HIV infection and antiretroviral treatment. Hence, the network aims at harmonizing these interconnected lines of research to ultimately obtain a novel strategy for anti-HIV treatment.
The expected scientific impact of HIT HIDDEN HIV is the creation of an European research environment where highly innovative ideas are turned into new approaches to treatment of HIV/AIDS. To this end, expertise from different discipline, including biochemistry, molecular biology, cell biology, molecular virology and medicinal chemistry, and exploitation of highly innovative techniques to describe the intimate virus-host interactions that occur during viral persistence and reactivation, are included in the project. The network actively promotes the translation of novel findings into products of broad anti-HIV spectrum that are affordable and easy to administer to target populations in low-income countries.
As mentioned above, HAART shall under no circumstances be considered as an effective therapy to permanently eradicate HIV from infected people although it is able to control the infection. Such a deficiency implies two main impacts on the European countries and population: (i) a major impact on public health, because of the persistence of latent HIV reservoirs which results in the likely emergence of resistant viruses, that may subsequently spread uncontrolled in the population; (i) a financial impact because HAART is a life-long treatment involving a heavy burden on public health care. The problem is even more pronounced in developing countries where HAART is not financially and logistically sustainable. In fact, HAART conducted without a strict control on compliance may results in the emergence of resistant viruses thus rendering the whole approach useless. Women in these countries are particularly confronted to this issue, as regards their central role in family’s health care but also and mainly because they are the first victims of HIV new infections. Thus, there is a clear need to find either a prophylactic vaccine or a mean to confront the infection with a short-term and possibly definitive antiviral regimen. Both issues are highly challenging and need an investment in research to approach the problems from a different perspective with respect to what has been thought up to now. Taken together, these considerations highlight that the HIT HIDDEN HIV consortium meets both the needs of EU citizens and of Europe’s agenda for life sciences, which are based on the needs of its citizens. Furthermore, the consortium has a strong international connotation, particularly towards developing countries that are those where HIV/AIDS is prevalent and a major health and social problem.

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