Modeling HIV-1 Induced Neuroinflammation in Mice: Role of Platelets in Mediating Blood-Brain Barrier Dysfunction

Abstract

The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND) is increasing. In these individuals, the integrity of the blood-brain barrier (BBB) is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L) is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT) mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1). As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND.

Platelets should be at the Frontline: HIV Researchers and Care Providers Needs a lot of Sticky Notes

“…We further demonstrated that altered platelets have a remarkable ability to damage and cross the blood brain barrier [20]. This is not unexpected, since platelets are the source of multiple pro-inflammatory substances, including TNF, IL-6 and CD40, which are known for altering the BBB [18][19][20][21][22][23]. Besides their role in pathogenesis, platelets might also play a key role in the regulation of brain function.…”

“…Yet the mechanisms of such a dysfunction are still under investigation [18][19][20][21][22][23]. Our group started by documenting the close relationship between thrombocytopenia, a condition characterized by low platelets, and cognitive alterations [19].…”

“…Platelets carry serotonin, platelet activating factor, brain derived neurotrophic factor, thymus and activation-regulated chemokine, monoamine oxidase, and arachidonic acid products which may negatively impact cognition and mood [18]. All these factors confer platelets a prominent role in maintaining cognitive status [17][18][19][20][21][22]. Beyond that, a recent analyses of the Multicenter AIDS Cohort Study structural brain imaging sub-study discovered a positive significant relationship between platelet decline and reduced gray matter.…”

Persistent EcoHIV infection induces nigral degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated mice

“…Taken together, it appeared prudent to use species-specific substitutes for studies of innate and adaptive immunity. Thus, EcoHIV infection of conventional immunocompetent mice was used to address this question (Hadas et al , 2007; He et al , 2014; Jones et al , 2016; Potash et al , 2005). …”

“…EcoHIV infection mimics HIV and offers a testing paradigm for studies of virus-induced neurodegeneration (Hadas et al , 2007; He et al , 2014; Potash et al , 2005). Notably, EcoHIV enters and establishes an infection in the mouse brain as early as 3 weeks after viral exposure and can alter BBB permeability by 2 weeks (Jones et al , 2016). Infected brains express inflammatory factors and mediators such as C3a, IL-1B, STAT-1, and IL-6 indicating an active infection and anti-viral response (Potash et al , 2005).…”