HIV Cure
L10 and its role on HIV reservoir maintenance
ART has reduced HIV-related morbidities and mortality for the majority of infected individuals, however a therapeutic regimen able to eradicate or functionally cure HIV infection does not currently exist. Thus, lifelong administration of ART is necessary, placing an inordinate burden on individuals and public health systems. Furthermore, while the benefits of ART are unquestionable, long-term treated HIV-infected subjects continue to have significantly shorter life spans. For these reasons, eradicating or at least functionally curing HIV infection would have an extraordinary impact on global health. Major obstacles to cure HIV infection include low levels of continuous viral replication, particularly in tissues, the presence of a small pool of long-lived latently infected CD4 T cells including the recently identified Tfh reservoir in B cell sanctuaries and Tregs, and functional exhaustion of antiviral T cells due in part to Tregs, which are unable to clear the virus.
The cAMP pathway and not Interferons regulate the IgG response to ALVAC.
Studies focused on prime-boost vaccines believed to be crucial in creating both humoral and cellular immunity. Prime-boost vaccines consist of prime vaccine (canary pox recombinant vaccine) to activate cytotoxic lymphocytes (CTL), followed by rgp120 vaccine to boost humoral immunity. VPC 1521: The prime vaccine used was VPC 1521, cultivated from canary pox virus, which included a particular gene isolated from Thailand. B/E gp120: The boost vaccine was developed from viruses extracted from patients and laboratory- cultured sub-types E and B.
PD1 and LAG3 drive HIV persistence by regulation of T-cell homeostasis through distinct mechanisms
Significance: Although modern antiretroviral drugs are able to suppress nearly all HIV replication, the virus persists indefinitely as stably integrated genomes within long-lived memory CD4+ T-cells. Understanding how memory cells are generated and identifying biomarkers of latently infected cells and the mechanisms that drive the establishment and persistence of HIV is of high importance to specifically target and eliminate the persistent reservoir.
Identification of NLRX1, a molecular target that can shut the door to HIV-1 and help make better vaccines and therapies.
Utilizing non-human primates (NHPs) to model HIV infection in humans has been well established and provides the opportunity to derive mechanistic insight in a controlled yet physiologically relevant system. We have been able to demonstrate that a dys-regulated inflammatory response leads to viral dissemination as early as day 1 of infection. We performed serial necropsies at Timepoints (0-Naiive) and (days 1, 3, 7 and 10 post SIV infection) and collected several tissues from over 40 monkeys that participated in this study. Using an unbiased systems biology approach, we were able to observe:
Impact of anti-inflammatory molecule Statin (Atorvastatin) treatment of the graft in the context of mobilized stem cell transplantation
Statins are mostly known for inhibiting mevalonate and cholesterol biosynthesis, however a new biological function in hampering immune response against autoantigens and alloantigens has been identified. Statins drive Th2 polarization, enrich the Tregs subset and limits lymphocyte trafficking to sites of inflammation, suggesting its role in promoting an overall anti-inflammatory environment. Parallelly Mielcarek’s group showed that donor statin usage was associated with protection against severe acute graft-versus-host disease (GVHD) after hematopoietic cell transplant (HCT) from HLA-identical related donors.
Using LARA model and OMICS sequencing to identify the role of cytokines in HIV integration and chromatin remolding during latency
The generation of a small pool of latently infected cells harboring replication competent HIV occurs very early after HIV infection. The precise mechanisms responsible for the establishment of this small pool of latently infected CD4+ T cells are not fully elucidated. Cytokines may contribute to this phenomenon, as the steep rise in the HIV viral load coincides with a large burst of inflammatory cytokines during acute HIV infection. IFN-α and IL-15 are the first cytokines elevated within 5 days after detection of viremia, followed by TNF-α, CXCL10, and IFN-γ, and then by IL-12. Following this initial burst of proinflammatory cytokines, an anti-inflammatory response is observed with a delayed peak of IL-10 production, along with the upregulation of the TGF-β，IL-1 receptor antagonist (IL-1RA). The development of this anti-inflammatory response, which characterizes the transition from the acute to the chronic phase of the infection, contribute to the generation of a reservoir of long lived latently infected cells.
An unbiased OMICs approach to identify mechanisms of Cocaine regulation of the HIV reservoir
Survival rates of HIV+ substance users are significantly lower compared to non-users, even in settings in which ART is generally available. Among substance-abuse, chronic cocaine use is associated with high incidence of HIV infection.
We apply an unbiased systems biology approach, which combined with the highly characterized subject cohort, identify the pathways triggered by chronic use of cocaine in cART treated HIV infected subjects which lead to HIV persistence and failure to reconstitute the immune system.
Baseline Predictors Bioinformatics Analysis of the Human Immune Response to Yellow Fever YF-17D Vaccine
The factors influencing variations in the human immune response to vaccines and infection diseases are still not well understood. Pre-vaccination environmental factors such as demographics, physiological and nutritional factors could play an important role in this regard. To address the influence of the baseline parameters on vaccine response, we performed a computational systems biology analysis that uses and combines gene expression, cell subset frequency and cytokines measurements to predict vaccine response in two different cohorts, from Africa (Entebbe) and Europe (Lausanne), vaccinated with the YF-17D vaccine. The project provides an important resource for studying human immune response to vaccination and infectious diseases.
V43DNA
Qualitative differences in the innate and adaptive responses elicited by different human immunodeficiency virus (HIV) vaccine candidates has not been thoroughly investigated. We tested the ability of Aventis Pasteur’s canarypox vector (ALVAC)–simian immunodeficiency virus (SIV), DNA–SIV and Ad26–SIV vaccine prime modalities together with two ALVAC–SIV + gp120 protein boosts to reduce the risk of SIVmac251 acquisition in rhesus macaques in the V43DNA study (Nature Med., 2018). We found that the DNA and ALVAC prime (RV144-like, Nature Med., 2016) regimens were effective, but the Ad26 prime was not. Several datasets have been generated that quantify several parameters of immune mechanisms associated with the vaccine response (protection from infection after vaccination).
Influenza
Influenza is a major cause of morbidity and mortality worldwide. Seasonal vaccination represents the best protection against influenza infection. However, Influenza vaccine effectiveness varies among the overall population and it is known to depend on age and immune competence. By using a systems biology approach, which gives a general picture of the immune system role in vaccination rather than focusing on single molecules, we have identified (pre)vaccination parameters that could explain lack of responsiveness. We have found a general state of inflammation as well as a metabolic gene expression signatures as predictors of poor response to vaccination. Moreover, the analysis of proteomic and metabolomics data suggests a role of cholesterol metabolism in impairing response to influenza vaccination. These signatures are independent of age, gender and (pre)vaccination antibody status. Importantly, the integration of data from different OMICs identifies a network of inflammation components and cholesterol metabolites that affect response to influenza vaccination, suggesting possible mechanism of intervention.
Dengue Virus
Dengue virus (DENV) is a mosquito-borne viral infection, which has reached epidemic proportions in several countries in South America and Southeast Asia. A safe and efficacious vaccine can stop the dissemination of this infection. A vaccine manufactured by Sanofi has yielded only partial protection against the disease caused by the four DENV serotypes.
In collaboration with other research groups, we are studying a novel DENV vaccine manufactured and tested in Brazil (TV003) that has been shown to yield high protection to the four DENV serotypes in Phase I trials. Our objective is to identify and validate assays, which can predict the immunogenicity and efficacy of the TV003. The results obtained in this study will contribute to decision-making concerning not only vaccination for DENV infection on a nation-wide scope but may be used as a milestone for other vaccine studies.
So far, the innate and adaptive immune responses have been tested at baseline and at different time points until 6 months following vaccination in 40 individuals with different levels of activation (Low Responders and High Responders). Preliminary results show that the vaccine has similar effects in both groups, irrespective of their levels of activation. Furthermore, the frequencies of immune populations change after vaccination indicating the effect of the vaccine-induced response. We have successfully developed multivariate models for prediction of vaccine outcome using flow cytometry data at baseline, which will be improved following our integration of the transcriptomic and cytokine signatures. Our data will be put together with work from our collaborators to identify predictors and correlates of immunogenicity to dengue vaccination.