PROJECT SUMMARY The pathology of disease caused by HIV infection is complex and multifaceted. HIV infection results in a vicious cycle of mucosal damage, chronic inflammation and overall immunological dysfunction, which are closely associated with disease, and are not ameliorated with antiretroviral therapy (ART). This chronic inflammation is strongly associated with gastrointestinal (GI) mucosal barrier damage and microbial translocation, which also do not resolve completely with ART and is associated with morbidities an mortality. Thus, it is imperative that novel therapeutic strategies aimed at enhancing mucosal function are developed. However, it is still unclear what pathways lead to damage to the GI tract during HIV infection, and thus a substantial hurdle for the development of targeted therapies. Our recent studies of mucosal surfaces show that an altered proteome consisting of elevated neutrophil proteases is associated with damage to the mucosal barrier. However the proteomic mechanisms underlying mucosal damage in the context of HIV pathogenesis have not been elucidated. Dysbiosis of the microbiome occurs in HIV infected individuals, which is characterized by increased adherent and inflammatory bacteria, which are more likely to be translocated. Neutrophil levels in mucosal tissue are also increased, and are hyperactive as well as dysfunctional, and these cells can release a multitude of highly inflammatory mediators and oxidative-proteolytic pathways to drive immune responses, which can paradoxically cause tissue damage, particularly to the mucosal epithelium. Our preliminary data supports microbial dysbiosis and the accumulation of dysfunctional neutrophils in the gut mucosa of HIV-infected individuals, the hyperactivity of neutrophil secretions, and that neutrophil proteases are linked to mucosal barrier disruption. Here, our global hypothesis is that an inflammatory proteome comprised of neutrophil secretions in the GI tract is driven by microbiome dysbiosis, and is the mechanism underlying tight epithelial barrier disruption and mucosal dysfunction. We will test these hypotheses in HIV-infected individuals with high versus low disease pathogenesis profiles (measured by CD4/CD8 ratio), as well as in uninfected individuals, in the following aims: (I) We will assess whether an altered GI proteome underlies mucosal dysfunction in HIV infection; (II) We will determine if neutrophil accumulation and dysfunction in the GI tract results in this inflammatory GI proteome; (III) We will assess whether the mechanism underlying neutrophil dysfunction and accumulation is HIV-associated microbiome dysbiosis. Our ultimate goal is to define mechanisms and novel targets for therapeutic interventions by identifying pathways associated with mucosal inflammation and epithelial damage in HIV-infected individuals.
|Effective start/end date||2/1/17 → 1/31/22|
- National Institutes of Health: $160,120.00
- National Institutes of Health: $331,573.00
- National Institutes of Health: $379,401.00
- National Institutes of Health: $216,744.00