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.
Highlights
Human immunodeficiency virus type-1 (HIV-1) currently infects approximately 36.9 million people worldwide and is a global health concern [1]
It is thought that HIV-associated neurocognitive disorder (HAND) develops due to infected leukocytes, virus, and viral proteins trafficking through a compromised blood-brain barrier (BBB), and establishing a neuroinflammatory environment in the central nervous system (CNS)
In a recent report, in a transgenic mice expressing full length HIV-1 provirus cloned from the lymphocytes of an HIV-1-infected patient, HIV infection systemically increased lipopolysaccharide (LPS) levels, that yields the BBB to be more susceptible to disruption by LPS, thereby increasing the ability of monocytes to enter the brain [64]
Summary
Human immunodeficiency virus type-1 (HIV-1) currently infects approximately 36.9 million people worldwide and is a global health concern [1]. The advent of combination antiretroviral therapy (cART) has played a pivotal role in reducing viral load and has dramatically decreased the death rate from HIV and acquired immune deficiency syndrome (AIDS) [2]. The central nervous system (CNS) is a major target for HIV, such that the virus enters the CNS early and remains for the duration of the infection [3]. The bloodbrain barrier (BBB) serves to protect the CNS by separating it from peripheral blood [4]. BBB dysfunction, a hallmark of HIV-induced inflammatory response in the CNS, culminates in neurocognitive deficits ranging from mild to severe forms, known as HIV associated.
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