Molecular Mechanisms of Neurodegenerative Diseases Induced by Human Retroviruses: A Review

Abstract

PROBLEM STATEMENT: Infection with retroviruses such as human immunodeficiency virus type 1 (HIV-1) and human T cell leukemia virus type 1 (HTLV-1) have been shown to lead to neurodegenerative diseases such as HIV-associated dementia (HAD) or neuroAIDS and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), respectively. APPROACH: HIV-1-induced neurologic disease is associated with an influx of HIV-infected monocytic cells across the blood-brain barrier. Following neuroinvasion, HIV-1 and viral proteins, in addition to cellular mediators released from infected and uninfected cells participate in astrocytic and neuronal dysregulation, leading to mild to severe neurocognitive disorders. RESULTS: The molecular architecture of viral regulatory components including the Long Terminal Repeat (LTR), genes encoding the viral proteins Tat, Vpr and Nef as well as the envelope gene encoding gp120 and gp41 have been implicated in 'indirect' mechanisms of neuronal injury, mechanisms which are likely responsible for the majority of CNS damage induced by HIV-1 infection. The neuropathogenesis of HAM/TSP is linked, in part, with both intra-and extracellular effectors functions of the viral transactivator protein Tax and likely other viral proteins. Tax is traditionally known to localize in the nucleus of infected cells serving as a regulator of both viral and cellular gene expression. CONCLUSION/RECOMMENDATIONS: However, recent evidence has suggested that Tax may also accumulate in the cytoplasm and be released from the infected cell through regulated cellular secretion processes. Once in the extracellular environment, Tax may cause functional alterations in cells of the peripheral blood, lymphoid organs and the central nervous system. These extracellular biological activities of Tax are likely very relevant to the neuropathogenesis of HTLV-1 and represent attractive targets for therapeutic intervention.

Fig. 1

Mechanism of HIV-1-induced neurodegeneration. Neurodegeneration caused by HIV-1 infection is the result of both direct infection of cells, as well as the release of HIV-1 proteins that cause additional neurodegeneration. Infected perivascular macrophages and microglia, in addition to producing more infectious virus, can also release these viral proteins. These proteins include Tat, Env (120 and gp41) and Vpr; (a) Tat (represented as ●) exhibits effects on both infected and uninfected cells, because secreted Tat can be taken up by neighboring cells. Tat has been demonstrated to play a role in oxidative stress-dependent apoptosis of neurons (represented by black cells). It has also been shown that Tat can cause excitotoxicity in neurons by activating the NMDAR; (b) Env (represented as △) also plays both a direct and indirect role in neurodegeneration. The Env protein gp120 has been shown to interact with both CCR5 and CXCR4 expressed on the surface of neurons and glial cells and subsequently induce neuronal apoptosis. Macrophages and microglia activated by gp120 secrete various proinflammatory factors including cytokines, chemokines and arachidonic acid, resulting in neuronal damage; (c) Vpr (represented as grey ◆) has been shown to increase viral transcription and production in cells of the monocyte/macrophage lineage. Extracellular Vpr has also been demonstrated to induce apoptosis in undifferentiated and mature neuronal precursor cells; (d) Nef (represented as grey ■) within the brain has been shown to be predominantly in astrocytes. Stable expression of Nef may alter the growth properties of astrocytes. Nef also demonstrates direct neurotoxicity. When cells of the monocyte-macrophage lineage are exposed to Nef, proinflammatory mediators are released

Fig. 2

Overview of the HTLV-1 LTR regulation as it relates to HAM/TSP pathogenesis. The progressive stages of HAM/TSP are characterized by the presence of activated CD4⁺ and CD8⁺ T cells and macrophages in demyelinating lesions. At these sites an array of proinflammatory cytokines are produced facilitating further recruitment of inflammatory cells into the CNS. CD4⁺ T cells represent the chief source of viral gene expression and along with the help of antigen presenting cells such as dendritic cells activate CD8⁺ T cells. HTLV-1-specific CD8⁺ T cells traffic to and accumulate within the CNS throughout the course of neurologic disease. Therefore, the presence of activated HTLV-1-specific CD8⁺ CTL and macrophage populations in the CNS may result in the maintenance of a persistent CTL response against infected cells expressing viral antigens and proinflammatory cytokine-mediated bystander damage. During this process, differentiation of infected bone marrow progenitor cells lead to HTLV-1 genomic activation and an increased viral gene expression mediated by Tax-CREB dimer formation and the cell type-specific activity of different transcription factors such as AP-1, C/EBP and Sp1/Sp3. BM, bone marrow; CNS; central nervous system; PB, peripheral blood; PD, proviral DNA; PR, proviral replication; DC, dendritic cell

Fig. 3

Components of the cellular secretory pathway important for nucleocytoplsmic shuttling, endoplasmic reticulum to golgi transport and post-golgi transport to the plasma membrane. While NTF p97 may facilitate nuclear import of Tax, CRM1 and calreticulin may facilitate its export through the nuclear pore complex. Tax is likely targeted to the secretory pathway by being transported into the Endoplasmic Reticulum (ER). Once in the ER, Tax likely moves to the Golgi by inclusion into COPII vesicles. Amino acid signals within Tax including ³³⁰DHE³³² and ³¹²YTNI³¹⁵ were shown to be important for targeting Tax to the Golgi. A portion of Tax may also be returned to the ER via retrograde transport by inclusion into COPI vesicles. In the Golgi, Tax is likely included into secretory vesicles through its interaction with SCAMPs and vSNAREs including SNAP23