HIV Alters Gap Junction-Mediated Intercellular Communication in Human Brain Pericytes

Abstract

Despite successful control of viremia by combined antiretroviral therapy, brain infection and its resulting neurocognitive impairment remain a prevalent comorbidity in HIV infected individuals. HIV invades the brain early in the course of infection via penetration through the blood-brain barrier (BBB). While the impact of HIV on BBB astrocytes and endothelial cells is relatively well studied, the role of pericytes in BBB regulation during HIV infection remains unclear; however, it is known that a selective population of pericytes is prone to infection. In the present study, we hypothesize that injury signals are propagated from infected pericytes to neighboring cells via gap junction (GJ)-mediated intercellular communication. Among a variety of studied GJ proteins, HIV infection of human brain pericytes specifically increased expression of connexin 43 as determined by immunoblotting and immunostaining. This effect was confirmed in the brains of mice infected with EcoHIV, a mouse-specific HIV strain. In addition, HIV infection enhanced functional GJ-mediated intercellular communication in pericytes. The importance of this process was confirmed in experiments in which inhibition of GJs by carbenoxolone attenuated HIV infection. In addition to GJs, an extracellular ATP release assay revealed that HIV may also play a role in opening of connexin (Cx)-containing hemichannels (HCs). Overall, these findings indicate an important role of GJs in the propagation of HIV infection in human brain pericytes that may contribute to BBB dysfunction in brain infection and the pathogenesis of NeuroAIDS.

Alteration of cell junctions during viral infection

“…CXCR4 and CXCR5 contribute to HIV-induced CNS impairment when the BBB is compromised, which is associated with increased microvascular permeability. 84 Thus, gap junctions in pericytes mediate HIV-induced loss of BBB integrity. Additionally, although HIV infects only a small fraction of pericytes, the damage that it inflicts is amplified by gap junctions that spread viral factors to adjacent uninfected cells (Fig 2).…”

“…Pericytes in the human brain express C‐X‐C chemokine receptor type (CXCR)4 and CCR5, which are the two major co‐receptors participating in the HIV‐1 infection process. CXCR4 and CXCR5 contribute to HIV‐induced CNS impairment when the BBB is compromised, which is associated with increased microvascular permeability . Thus, gap junctions in pericytes mediate HIV‐induced loss of BBB integrity.…”

Astroglial connexins and cognition: memory formation or deterioration?

“…Apart from it, it was also shown that HIV infection may also be propagated from the infected pericytes of the blood-brain barrier to other cells through gap junction/hemichannels-mediated intercellular communication. It has been demonstrated that HIV infection increased the expression of connexin 43 on the brain pericytes and inhibition of gap junctions by carbenoxolone was shown to prevent spreading of HIV infection within the brain [76].…”

HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate

“…Pericytes have a crucial role in the formation and maintenance of the Blood Brain Barrier (BBB) integrity, and are also important mediators of neuroinflammation (Cho et al , 2017; Jansson et al , 2014; Rustenhoven et al , 2017). Their significance to BBB function is also highlighted by increased density of pericytes covering the central nervous system (CNS) vasculature, when compared to capillaries and venules in other parts of the body (Aguilera and Brekken, 2014; Armulik et al , 2010; Bell et al , 2010).…”

“…The major cells in the CNS supporting HIV-1 replication are microglia and macrophages, but the virus also has an ability to infect pericytes and astrocytes, and although at a low level, their infection was found to disrupt the integrity of the endothelial barrier (Cho et al , 2017; Churchill et al , 2006; Eugenin et al , 2011; Nakagawa et al , 2012; Thompson et al , 2011; Tornatore et al , 1994; Wiley et al , 1986). Permissiveness of pericytes to non-productive HIV-1 infection suggests that the cells might support viral latency.…”