HIV and the Gut: Novel Insights into HIV Pathogenesis, Clinical Implications and Therapeutic Approaches

Human immunodeficiency virus (HIV) infection results in substantial damage to the gastrointestinal tract (GIT), with disruption of the gut epithelial barrier function and impairment of the gut-associated lymphoid tissue (GALT), leading to alterations of gut microbiota and intestinal homeostasis. Accordingly, the translocation of microbial products from the lumen into systemic circulation contributes to chronic immune activation and HIV disease progression. Moreover, HIV-1 replication in the GIT causes severe CD4+ T-cell depletion with a rapid decline in Th17 cells and an increase in the ratio Tregs/Th17. The dysregulation of the Treg/Th17 balance is linked to the lack of repair of the tight junctions between enterocytes potentiating a vicious cycle that leads to microbial translocation and systemic inflammation. In people living with HIV (PLWH) this chronic inflammatory environment may cause fibrosis in GALT with CD4+ T-cell regenerative failure, less richness and variety of the gut microbiota and HIV disease progression, which is despite the available antiretroviral therapy (ART). Notably, Tregs, as well as CD4+ memory T cells, are important HIV reservoirs and the activation of intestinal T and dendritic cells may increase mucosal HIV-1 viral load, highlighting the importance of the gut compartment as a viral reservoir. Persistent chronic inflammation and immune activation in PLWH, related to the reduced gut microbiota diversity due to HIV-1 infection and ART, are the main drivers of opportunistic infections and comorbidities, such as cardiovascular and metabolic diseases, and neurocognitive disorders. Thereby, the abundance of potentially pathogenic bacteria in PLWH may alter the tryptophan metabolism, induce proinflammatory pathways mediated by lipopolysaccharide (LPS) synthesis, and oxidative stress, which are directly associated with injuries and altered functionality of several organs, such as liver, brain, adipose tissue, muscles and pancreas. The use of probiotics and prebiotics has been indicated to show promising outcomes in restoring gut microbiota alterations in PLWH, also improving innate and adaptive immunity.

Hence, the overall goal of this Research Topic is to broaden the knowledge of the interplay between HIV and gut, the host-microbiota interactions during HIV infection and the implications for disease progression and management, thereby providing new insights into the understanding of the immune pathogenesis of HIV infection. Also, a more in-depth evaluation of the metabolic changes and pathways as well as the role of age, gender, ethnicity and sexual behaviors warrants further investigation.

We welcome the submission of Original Research, Review, Mini-Review, Case report, and Perspective articles covering the following topics:

• Basic and novel concepts highlighting the role of microbiota species in the regulation of the immune status in the gastrointestinal tract of PLWH, the effects of HIV infection on microbiota composition, and the mechanisms driving microbiota-associated immune activation and inflammation.
• Understanding the contribution of the GALT, along with its abnormal architecture even while on effective ART, to the HIV latent reservoir and the relationship between HIV persistence and the gut microbiome.
• Evaluating the effects of different ART regimens on the microbiota and the GALT composition in PLWH, and the relationship with HIV reservoir dynamics.
• Basic and novel insights regarding the frequency, phenotype and functional status of CD4+ T-cell populations in the intestinal mucosa and their role in HIV persistence.
• Dissecting the mechanisms of intestinal mucosal dysfunction/microbial translocation and persistent immune activation related to the occurrence of comorbidities in PLWH.
• Defining new adjuvant treatments for PLWH, such as probiotics or postbiotics, to restore the GIT dysbiosis, facilitate HIV clearance and prevent and manage HIV-related comorbidities.
• Dissecting the effects of gender, age, and ethnicity in the interplay between gut microbiota and inflammation during HIV infection.