Figure 1.

Mechanisms potentially influencing HAND manifestation. In the HIV negative context, immune cells produce cytokines and influence the functioning of the brain (negatively or positively depending on the presence of inflammation or not, respectively) (Haroon et al., 2014, 2016; Haroon and Miller, 2017). They reach the brain through the systemic circulation. Gut microbiota, particularly SCFA-producing microbiota, induce the production of neurotransmitters (serotonin) and metabolites (acetate, butyrate, and SCFAs). Consequently, the vagus nerve is stimulated by these molecules and transmits signals to the brain (Needham et al., 2020). Neurotransmitters and metabolites are able to cross the blood–brain barrier (via the systemic circulation) to subsequently directly affect brain health. Conversely, in the context of HIV infection, the gut epithelial/endothelial barrier and the blood brain barrier are disrupted and consequently are unable to selectively filter elements, which originate in the gut and consequently enter the brain. The production of different dysfunctional elements are also promoted. SCFA-producing microbiota are depleted and replaced by LPS/endotoxin-producing microbiota. The latter are potentially pathogenic microbes, which produce endotoxins. The reduction of SCFA-producing microbiota induces a reduction in the production of serotonin and other beneficial metabolites (butyrate, acetate), while the production of LPS and other endotoxins are promoted by LPS/endotoxin-producing microbiota. In the HIV infection context, immune cells are depleted and produce proinflammatory cytokines, which exert a negative influence on brain cell development and functioning. The preceding elements (LPS, endotoxins, and proinflammatory cytokines) cause abnormal functioning of the vagus nerve, which may induce a sluggish intestinal transit time (constipation) which further promotes the growth of pathogenic bacteria within the gut (George et al., 2014). Furthermore, the preceding toxic elements may then easily reach the brain through the systemic circulation. Within the brain, endotoxins, HIV-infected immune cells (microglia, astrocytes, and macrophages, which produce proinflammatory cytokines, neurotoxins, ROS, and RNS), specific pathogenic microbes (potentially less likely), and HIV viral proteins work together to further compromise neuronal integrity, resulting in neuronal damage, synapse destruction, and ultimately neuronal death (Navarathna et al., 2016; Zhu et al., 2020). The preceding events which occur during HIV infection may well be seen as the potential pathogenic mechanisms whereby the gut-brain axis induces HAND development. ROS, Reactive oxygen species; RNS, Reactive nitrogen species.