The viral load can be controlled in the periphery of HIV-1-infected patients through consistent use of antiretroviral therapy (ART). Despite this, over 50% of HIV-infected patients are predicted to suffer from HIV-associated neurocognitive impairment (NCI). Although the pathogenesis of NCI is incompletely understood, HIV-1 transactivator of transcription (Tat) has been shown to be capable of being secreted from infected cells, and once extracellular within the central nervous system (CNS) it will induce neuronal dysregulation. Early in the infection, HIV-1 has been shown to establish a reservoir in the brain, either by entering as infected perivascular macrophages or infecting resident microglia, prior to the patient receiving ART. ART does not affect the production of Tat, which is continually made in these cells, leading to quantifiable levels of Tat in the absence of detectable viral load. Tat sequence composition varies within and between individuals due to HIV-1?s error-prone reverse transcriptase and host factors such as APOBEC3G. In the previous 5 years, we have shown that this variation is associated with NCI, as shown by our studies comparing the HIV-1 Tat protein sequence composition from impaired and non-impaired patients within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Residues associated with NCI included 59P, 74H, and 12K, while 36V, 40T, 63E, and 23T were associated with non-impairment. Effects of Tat variation can be further exemplified by Tat?s interaction with the NMDA receptor (NMDAR). This interaction can be weakened when Tat undergoes a C31S mutation, as shown in HIV-1 subtype C infections. Our preliminary data has shown that Tat genetic variants within the CARES Cohort have different predicted interaction profiles with GRIN2A, a subunit of NMDAR. Although the Tat-NMDAR interaction has been shown to be an established driver of HAND, it may not be the only factor involved in NCI in neuroHIV. Given this, we hypothesize that HIV-1 Tat genetic variation may cause differential secretion of Tat and/or affect Tat?s binding to molecular targets leading to neuronal dysfunction that underlies NCI in neuroHIV. To investigate this, we propose three Aims.
Aim 1 will determine if amino acid variations in Tat associated with NCI via peripheral blood sampling correlates to that found in the CNS and/or intact provirus.
Aim 2 will explore the impact of HIV-1 Tat genetic variation on protein-protein interactions that contribute to HAND pathogenesis.
Aim 3 will assess the contribution of HIV-1 Tat variants to NCI using an in vivo model of Tat-induced neuropathogenesis. Overall, these studies will contribute to defining the mechanism of how HIV-1 Tat polymorphisms alter interactions with neurons and ultimately affect CNS function. Successful completion of the proposed project will result in a better understanding of the etiology of HAND, potential development of diagnostic assay for HAND, and identification of novel Tat-mediated targets for treating NCI.
This proposal will build upon data from the previous funding period to understand how genetic variation in the viral accessory protein Tat affects its function and hence neuroHIV. Using complimentary in silico, in vitro, in vivo and ex vivo assays, we propose to delineate the mechanism by which Tat promotes neurotoxicity and neurocognitive impairment. Successful completion of the proposal will have implications in developing novel therapeutics to treat neurocognitive impairment and genetic diagnostic assays.
|Mele, Anthony R; Marino, Jamie; Chen, Kenneth et al. (2018) Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P2 at the epicenter. Traffic :|
|Dampier, Will; Antell, Gregory C; Aiamkitsumrit, Benjamas et al. (2017) Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status. J Neurovirol 23:113-124|
|Banerjee, Anupam; Li, Luna; Pirrone, Vanessa et al. (2017) cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells. Clin Med Insights Pathol 10:1179555717694535|
|Maubert, Monique E; Wigdahl, Brian; Nonnemacher, Michael R (2017) Opinion: Inhibition of Blood-Brain Barrier Repair as a Mechanism in HIV-1 Disease. Front Neurosci 11:228|
|Antell, Gregory C; Dampier, Will; Aiamkitsumrit, Benjamas et al. (2017) Evidence of Divergent Amino Acid Usage in Comparative Analyses of R5- and X4-Associated HIV-1 Vpr Sequences. Int J Genomics 2017:4081585|
|Strazza, Marianne; Pirrone, Vanessa; Wigdahl, Brian et al. (2016) Prolonged Morphine Exposure Induces Increased Firm Adhesion in an in Vitro Model of the Blood-Brain Barrier. Int J Mol Sci 17:|
|Azar, Ashley; Devlin, Kathryn; Mell, Joshua Chang et al. (2016) Mitochondrial Haplogroup Influences Motor Function in Long-Term HIV-1-Infected Individuals. PLoS One 11:e0163772|
|James, Tony; Nonnemacher, Michael R; Wigdahl, Brian et al. (2016) Defining the roles for Vpr in HIV-1-associated neuropathogenesis. J Neurovirol 22:403-15|
|Datta, Prasun K; Kaminski, Rafal; Hu, Wenhui et al. (2016) HIV-1 Latency and Eradication: Past, Present and Future. Curr HIV Res 14:431-441|
|Antell, Gregory C; Dampier, Will; Aiamkitsumrit, Benjamas et al. (2016) Utilization of HIV-1 envelope V3 to identify X4- and R5-specific Tat and LTR sequence signatures. Retrovirology 13:32|
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