Proteomics analysis for the identification of biomarkers and potential therapeutic targets for HIV-1 control and HIV-related neurological dysfunction

Abstract

Combined antiretroviral therapy (cART) is the current treatment for people with HIV (PWH) that allows to turn this otherwise deadly disease into a chronic infection. Although these drugs maintain undetectable viral load and stop the progression of AIDS disease, access to cART is not ensured worldwide, requires life-long medication and can cause secondary effect associated with drug toxicity. Additionally, if the medication is stopped, a rapid viral rebound occurs due to the virus ability to establish a latent viral reservoir. One of the strategies to develop potential HIV-1 cure strategies, is to analyze a small subset of HIV-1 infected individuals that present the natural capacity to control the virus, known as elite controllers or long term non-progressors. Although some aspects such as neutralizing antibodies, NK cells and CD8 T-cell response or soluble factors differ between individuals that can control the infection versus those that cannot, the mechanisms associated with this natural control are not fully understood. In this thesis, we have used different proteomics approaches to identify plasma factors associated with HIV-1 control or non-control and to define biomarkers linked to neurological dysfunction in HIV-1 infection. In parallel, this proteomics analysis was applied to the BCN02 clinical trial, a “kick and kill” HIV-1 therapeutic strategy, to identify plasma factors that can predict viral rebound before initiating an antiretroviral treatment pause. In ChapterI, we identified different plasma factors associated with HIV-1 control in the absence of treatment compared to HIV-1 uninfected individuals. In brief, the plasma as well as cerebrospinal fluids were analyzed in individuals with different levels of control of HIV-1 infection and compared to HIV-1 uninfected individuals. Then, we selected those plasma markers that differed between individuals that control the virus and HIV-1 non-controllers. These markers were strongly associated with additional viral parameters and other well-known biomarker related to neuroinflammation. Interestingly, cART treatment restored the plasma levels of these proteins, suggesting that cART treatment may reduce HIV-related neurological dysfunction. ChapterII, we studied neuro-tailored plasma proteomes of PWH with different capabilities to control HIV-1 infection. Interestingly, a NAD (nicotinamide adenine dinucleotide)-dependent deacetylase, Sirtuin-2, was differentially detected and associated with viral control. Also, Sirtuin-2 was related to biomarkers described in other neurological diseases. The plasma levels of Sirtuin-2 were dependent on the time when cART was initiated and were associated with the involution of a specific brain region, in particular the orbitofrontal cortex. Moreover, in vitro targeting of SIRT2 reduced viral reactivation from latency and viral replication in peripheral blood cells and primary microglial cells. These results suggest that SIRT2 can serve as a biomarker of HIV-1 control and neurological dysfunction and could be a potential therapeutic target for a HIV-1 cure strategy. Chapter III, we analyzed the plasma proteome during the BCN02 clinical trial, which was based on a “kick and kill” HIV-1 cure strategy. Participants in the clinical trial were treated with romidepsin to reactivate HIV-1 in latently infected cells and vaccinated with HIVconsv vaccines to generate robust T-cell responses. Then, participants interrupted their cART treatment during a monitored antiretroviral pause (MAP) to evaluate the efficacy of this “kick and kill” strategy. In this context, we identified possible candidate plasma markers that predicted viral rebound during the monitored antiretroviral pause. This exploratory study revealed how this intervention modified the levels of plasma proteins, especially after romidepsin infusions. Moreover, proteomics analysis identified levels of the plasma CD33 protein to be associated with viral parameters, establishing it as a possible plasma biomarker indicative of monitored antiretroviral virus control, at least during short-term treatment interruption. Overall, proteomics allowed us to identify possible biomarkers that reflect pathogenic processes or responses to therapeutic interventions.

Date of Award	24 Apr 2023
Original language	English
Supervisor	Christian Brander Silva (Director) & Marta Ruiz Riol (Director)