Even in the HAART era where the viral load is below detection levels, the prevalence of HIV-1 associated neurocognitive disorders (HAND) remains high due to many reasons such as latent virus reactivation and drugs inability to efficiently cross the blood brain barrier (BBB). Therefor, it is important to understand the mechanisms leading to neuronal deregulation in HIV-1-infected patients in the HAART era. The lack of productive infection of neurons by HIV-1 suggests that viral and cellular proteins with neurotoxic activities that are released from HIV-1 infected target cells, or reservoirs cells for latent active virus, cause this neuronal deregulation. The viral protein R (Vpr) is one of the proteins encoded by HIV-1 and has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells. The mechanisms and the cellular factors used by Vpr to cause neuronal damage remain unclear. Using human neuronal cell line, SH-SY5Y, we found that Vpr can be taken up by neurons (immunohistochemistry and Western blot analysis), which gave us the rationale to measure the amount of Vpr in neurons (HPCE) (almost 100 pg). We also demonstrated that Vpr deregulates calcium homeostasis, promotes endoplasmic reticulum (ER)-calcium release and stress, activation of the oxidative stress pathway, mitochondrial dysfunction and axonal transport alteration. These effects were specifically noted with the full length Vpr but not with Vpr mutant (R73A). In search for the cellular factors involved, we performed microRNA and gene array assays using RNA collected from primary human cultures of neurons and/or SH-SY5Y-treated with recombinant Vpr protein. Interestingly, Vpr deregulates the levels of several microRNA (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. These factors were deregulated in human brain tissues of HIV-infected patients and in the brain tissues of Vpr-transgenic mice. Interestingly, these factors were also deregulated in neuronal cells treated with Tat, gp120 or supernatant collected from infected cells. Therefore, we propose a comprehensive study utilizing molecular, virological, and cellular approaches to unravel the mechanisms and identify the cellular factors used by Vpr as well as its interplay with microRNAs to cause neuronal dysfunction. These studies will be validated in an animal model (Vpr-transgenic mice). The outcome of these studies will advance the understanding of HIV-1 pathogenesis and will decipher the mechanisms used by Vpr that lead to neuronal degeneration even in the HAART era.
Typically a virus-encoded protein can function only in the infected cells. Interestingly this is no the case with HIV-1 Vpr. In HIV-1 infected individuals, soluble Vpr (extracellular and extravirion) has been demonstrated in the body fluids such as sera and CSF by ELISA methods. In addition, extracellular Vpr has also been shown in the CNS compartment by immunohistochemistry and HPCE. As Vpr is a virion-associated protein, Vpr is transferred to the host cells after virus infection. Vpr is also synthesized in the host cells as one of the proteins encoded by HIV-1 genome. The latter forms of Vpr can serve as a source for soluble Vpr. The Vpr, released from cells and virus particles, has the ability to enter adjacent cells such as neurons and to cause neuronal dysfunction by deregulating the levels of immediate early effectors such as microRNAs and their target genes that may promote HAND development. This has prompted us to assess the effect of Vpr along with microRNA on neuronal cells and their contribution in the development of neurocognitive disorders often observed in HIV-1 infected patients even in the HAART era.
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