NATURAL AUTOANTIBODIES TARGETING CHEMOKINES IN HIV-1 INFECTION AND PATHOGENESIS

Untreated HIV-1 infection results in a gradual deterioration of the immune system, eventually leading to acquired immunodeficiency syndrome (AIDS). This progression typically involves high viral loads, decline in circulating and mucosal CD4+ T-cells and the emergence of dysfunctional B cells, culminating in AIDS. Antiretroviral therapy (ART) is the primary therapeutic option for HIV-1, and it is now understood that early initiation of ART reduces the risk of severe illness and death. However, despite its effectiveness, ART cannot completely eradicate the virus that establishes reservoirs in various tissues, including the central nervous system and gut-associated lymphoid tissue (GALT).

Chemokines play a vital role in guiding immune cells to sites of inflammation and infection but can also contribute to the seeding of viral reservoirs. In people living with HIV (PLWH) effectively treated with ART, viral reactivation and incomplete restoration of CD4+ T-cells in the GALT lead to persistent immune dysregulation and chronic inflammation. This not only results in immune aging but also affects the host's responses to other pathogens and vaccines. Our research revealed that chronic immune activation is associated with alterations in T-cell trafficking, due to impaired responses to chemotactic signals, which may contribute to the incomplete restoration of GALT even in effectively ART-treated individuals. Additionally, we more recently uncovered the emergence of autoantibodies targeting specific chemokines in PLWH.

Similar to what we observed in COVID-19 (Nature Immunology, 2023), we hypothesize that specific patterns of autoantibodies targeting chemokines (and their receptors) develop in PLWH experiencing diverse disease trajectories (e.g. Elite Controllers vs. Rapid Progressors; development of vs. protection from neurological disorders; co-infection vs. single-infection). These autoantibodies may contribute to disease manifestation by either beneficially dampening inflammation or, conversely, by impairing immune responses and thus facilitating disease progression.

Therefore, resting on preliminary data obtained with small cohorts of PLWH and macaques infected with SIV, this proposal aims at gaining novel insights into the formation, evolution and biological significance of natural autoantibodies targeting the chemokine system during HIV-1 infection.

This will be achieved by investigating the anti-chemokine antibodies over time in PLWH with different disease courses and treatments, which will be possible thanks to access to samples from highly curated patient cohorts (from Switzerland and United States). The findings will be extended and validated by looking at existing samples from pathogenic and non-pathogenic SIV-infection of non-human primates (NHP), thanks to established collaborations with prominent scientists in the field (United States and France). Correlation with clinical data will enable the identification of patterns of autoantibodies specifically associated with the divergent disease trajectories. To determine whether autoantibodies targeting the chemokine system are biologically active, we will discover and characterize, biochemically and functionally, anti-chemokine monoclonal antibodies derived from PLWH. Finally, we will use murine models of HIV-1 infection to evaluate their potential relevance in vivo.

Overall, the study will examine, for the first time, autoantibodies to the chemokine system in PLWH, their association with specific disease courses and possible biological contribution, either beneficial or detrimental, to HIV-1 pathogenesis. Our research will potentially pave the way to further preclinical studies aimed at assessing the efficacy of anti-chemokine (receptor) treatment to prevent/reduce HIV-associated neurological disorders, to diminish mucosal reservoir and to implement gut barrier function by targeting cell trafficking.