Cód. SSPA: IBiS-A-15
In our laboratory we intend to tackle what we consider to be the two main challenges in HIV infection, such as: i) reducing inflammation and thus the prevalence of comorbidities in people living with HIV and ii) curing this infection.
Within our research lines, we have determined immunovirological factors that allowed us to characterise two different phenotypes of elite controllers: persistent and transient. Persistent controllers are characterised by a low viral evolution, preserved metabolomic profile and immune system, with high polyfunctionality, low levels of proinflammatory cytokines and low immune activation compared to the transient controller phenotype. All these features, together with the host genetic factors, have helped us to define the persistent controller as the best model for a functional cure for HIV. (Figure courtesy of Laura Tarancón Díez).
Priority research lines of the group
- Mechanisms involved in the spontaneous control of HIV.
In this line, immunogenetic, clinical/epidemiological factors are addressed, as well as virological mechanisms, and the innate and adaptive immune response, related to the spontaneous control of HIV. Knowledge of these mechanisms will allow us to design immunotherapies that achieve spontaneous control of the virus without the need for antiretroviral treatment.
Currently our group is the coordinator of the RIS Controllers Study Group, which has managed to implement a database of 800 HIV controllers nationwide (ECRIS Base), this group has been a fundamental part for articulating the work package of "HIV control mechanisms" within the Immunopathogenesis Program of the AIDS Research Network (RIS). It is in this scenario where we initially observed that HIV-controllers had a heterogeneous progression phenotype (León et al. AIDS. 2016), this was corroborated in the COHERE cohort at the European level (Chereau et al. PLoS One. 2017). After identifying immunological factors, such as thymic function (Yang et al. AIDS. 2012, Ferrando-Martinez et al. Clin Infect Dis. 2017) and immunogenetic markers (Machmach et al. J Inf Dis. 2013, Dominguez- Molina et al. Clin Infect Dis. 2016) associated with HIV spontaneous control, we performed a multifactorial analysis of parameters (virological, immunological, genetic and -omic) associated with the loss of virological and immunological control in elite controllers (Pernas et al J Virol 2018, Tarancon-Diez et al EBiomedicine 2019, Rodriguez-Gallego et al. J Infect Dis 2019, Masip et al. Clin Trasnl Med 2021). This has allowed us to identify and characterize the best controller model that most closely resembles a "functional cure" or "persistent remission" of the disease (Persistent Controller vs. Transient Controller) (Tarancon-Diez et al. EBiomedicine 2018, Casado C et al. Sci Reports 2020, Dominguez-Molina et al. J Int AIDS Soc 2020). In this model we are analyzing how immune pressure impacts in the quantity and quality of the viral reservoir in elite controllers (Lian X et al. Sci Transl Med 2021).
We also analyze innate immunity factors involved in the controller phenomenon. We have discovered how plasmacytoid dendritic cells (pDCs) are involved in the spontaneous control of viremia. We have observed how elite controllers have preserved levels and antiviral function of pDC in peripheral blood (Machmach et al. J Virol. 2012; Barblu et al. J Inf Dis. 2012) and we are analyzing the role of this cell type in tissue. Currently, we are working on the hypothesis of common mechanisms involved in the universal control of chronic viral infections (Dominguez-Molina et al. J Virol 2018; Dominguez-Molina et al. Front Immunol 2018).
- Immunosenescence and mechanisms involved in the appearance of non-AIDS events
After the introduction of highly effective antiretroviral therapy (HAART), the morbidity and mortality associated with AIDS decreased dramatically. However, today despite the fact that current antiretroviral treatments (cART) succeed in suppressing the viral load in the vast majority of people living with HIV, they present a chronic state of activation of the immune system and persistent low-grade inflammation that is related to the development of non-AIDS events (NADEs), such as cardiovascular events and neurocognitive disorders and cancer, among others, pathologies that are also prevalent in the aging population not infected by HIV. We analyze factors associated with the type of antiretroviral treatment and immunological and –omic factors in order to identify therapeutic targets reducing inflammation and thus the prevalence of NADEs in people living with HIV.
We have identified the monocyte as one of the main sources of inflammation in people with cART. We have analyzed the role of this cell type in the immunopathogenesis of HIV infection and its differences with chronological aging (De Pablo-Bernal et al J Gerontol A Biol Sci Med Sci. 2016, De Pablo-Bernal et al J Infect Dis. 2016, De Pablo-Bernal et al. Antimicrob Agents Chemother 2020) and we have verified how monocytes are associated with the appearance of cardiovascular events in patients under suppressive cART (Tarancón-Diez et al. Thromb Haemost. 2017, Tarancón-Diez et al. AIDS 2018). In addition, we have analyzed the prevalence and factors associated with NADEs in HIV controllers (Dominguez-Molina et al. Clin Infect Dis. 2016).
- Design of strategic clinical trials based on immunotherapies in order to achieve persistent virological remission in HIV-infected patients
Currently there is no cure for HIV infection, except anecdotal cases of patients who have undergone bone marrow transplantation after hematological cancer, so that cART is necessary for life. In this research line, we intend to carry out studies and clinical trials with immunomodulatory molecules. Based on the elite controller model, we are identifying factors of innate and adaptive immunity associated with viral control. We will analyze interventions with immunological check points blockers, Toll-like receptor agonists and other immunomodulatory therapies in order to achieve a reduction in the HIV reservoir and persistent virological remission in the absence of cART.
- Mechanisms of innate and adaptive immunity in SARS-CoV-2 infection and therapeutic options for COVID-19
Related issues between the interaction of SARS-CoV-2 infection with the host's immune system are largely unknown. This knowledge is essential for the development of better vaccines, to interpret the pathogenesis of the disease, to calibrate measures to control the pandemic, and to avoid long-term side effects. In this sense, it is essential to know prognostic biomarkers of COVID-19, of the vaccine response and which parameters remain altered after infection. Currently, we analyze aspects related to the innate immune (type I interferon response mediated by plasmacytoid dendritic cells (pDC)) and adaptive response (specific SARS-CoV-2 T response) in order to stratify different degrees of progression and complications of the disease, differentiating between patients who will have mild or moderate symptoms from those who will progress to severe respiratory failure and analyze the immunological sequelae at the medium/long term. Based on these results, existing therapies could be applied more effectively, as well as implementing alternative therapies against the disease, as well as obtaining knowledge for the design and improvement of a more effective and complete vaccine, as well as developing immunomodulatory therapies that improve the immune sequelae present after this infection.
