Neuropathologies represent a problem for HIV-1 patients, not only due to the mental and physical limitations but also because of interference with therapy adherence. In a cohort study it was observed that the neurological impairments are not a result of drug toxicity or aging but rather suggests that there must be something else acting in the brain that provokes these milder forms of impairments [14]. The HIV-1 accessory protein negative factor (Nef) has been found to be abundantly expressed by astrocytes in postmortem brain tissue from HIV-1 patients [15]. Nef is an early viral protein required for optimal HIV replication [16, 17]. Studies suggest that Nef-induced CCL2/MCP-1 expression in astrocytes contributes to infiltration of monocytes into the brain, thereby to progression of HAD [7]. It is known that Nef is constitutively present in persistently infected astrocytes [19], but hw it exits and interacts with other cells in the brain is still an emerging area of investigation. Our long term goal is to better understand the basis of this ongoing impairment and help improve the health of HIV-1 patients that are living longer but are still confronting cognitive disorders that limit their daily tasks. The objective of this proposal is to investigate the mechanism through which Nef causes neuronal damage and understand the participation of TGF? cascade in the inflammatory response. Since TGF? promotes astrogliosis after brain injury [20], we want to analyze its behavior in the presence of Nef. Our central hypothesis is that HIV-1 Nef protein alters TGF? pathway, modifying SMADs signaling while leading to increased inflammatory response and eventually neuronal damage. Our hypothesis is supported by our preliminary data and by the available literature describing the effects of Nef in the brain as well as the role of TGF? in other neuropathologies. We have designed two aims in order to study and understand neuronal fate by TGF? in the presence of Nef.
In aim1 we will quantify the expression and activity of TGF? signaling and consequent pro-inflammatory cytokines in neurons co-cultured with astrocytes transfected with Nef.
In aim2 we will study the effects of HIV-1 Nef on astrogliosis and dendritic growth in the presence and absence of TGF?. This study is significant since it aims to address some of those gaps that need to be filled in order to understand the action of Nef and its implication in learning impairment. The innovation of this project will provie understanding of how Nef causes cognitive disorders by altering TGF? signaling pathway. Insight in how SMAD proteins function when exposed to Nef will help clarify how the pathway behaves in HIV-1 patients even when they have viral loads under detectable levels.
Cognitive impairments continue to affect near 50% of HIV-1 patients, including those that maintain viral loads below detectable levels. These comorbidities threaten patients by affecting their daily functions and increasing the chances of interruption in their therapy. The HIV viral protein Nefis known to be abundantly present in astrocytes of HIV-1 patients and also to cause learning impairments. Our laboratory has published data demonstrating that Nef by itself can cause learning impairment and neuronal loss. Nevertheless, there is a gap in the field on understanding how Nef is capable of contributing to HIV neuropathologies and even less is known about the molecular mechanism Nef uses to exert this effect. In the proposed project entitled: Molecular Regulation of HIV-1 NefNeuropathogenesis by Transforming Growth Factor beta (TGF?), we aim to investigate the role of TGF? in the increased inflammation and neurotoxicity observed in the presence of Nef as well as to present a possible model for HIV Nefneuropathogenesis based on our in vitro and in vivo data. The data obtained from this study will be novel in the field and provide insight into better understanding HIV cognitive impairments and thus have important implications in targeted therapies for the patients.
| Martinez-Orengo, Neysha; Cruz, Myrella L; Velazquez, Bethzaly et al. (2018) Nurturing interest in science and understanding the role of a scientist by teaching younger students how to apply scientific thinking during daily activities. Adv Physiol Educ 42:466-472 |
