Neurotoxicity of HIV-1 Tat is attributed to its penetrating property.

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients. HIV-1 Tat protein can penetrate cell membrane freely and secrete into extracellular medium. Exo-Tat loses this penetrating property. HIV-1 Tat protein can damage the synaptic membranes contributing to the development of dementia in HIV-1 infected patients. To investigate whether the penetrating property attributes to synaptic damage in vivo, we have generated adeno-associated viruses AAV-Tat and AAV-Exo-Tat viruses. Vehicle control or AAV viruses (1 × 1012 GC/mouse in 200 µl PBS) were injected into Balb/cj mice via tail veins. The mRNA and protein expression levels in blood, brain, heart, intestine, kidney, liver, lung, muscle and spleen were determined on day 21. Intravenously injected AAV-Tat or AAV-Exo-Tat mainly infects liver and heart. Short-term expression of Tat or Exo-Tat doesn't change the expression levels of neuronal cytoskeletal marker ß3-tubulin and synaptic marker postsynaptic density 95 protein (PSD-95). Wild-type Tat, but not Exo-Tat, reduces the expression level of synaptic marker synaptophysin significantly in mice, indicating that penetrating property of HIV-1 Tat protein attributes to synaptic damage.

Variable infectivity and conserved engagement in cell-to-cell viral transfer by HIV-1 Env from Clade B transmitted founder clones.

HIV-1 transmission is usually initiated by a single viral strain called transmitted/ founder (T/F) virus. In in vitro models, HIV-1 can efficiently spread via cell-free and virological synapse (VS)-mediated cell-to-cell infection. Both modes of infection require the viral glycoprotein Envelope (Env). The efficiency with which T/F Envs initiate VS and mediate cell-to-cell infection has not been well characterized. Here we tested a panel of isogenic HIV-1 molecular clones that carry different Clade B T/F Envs. We found that despite variable infectivity among different Env clones in the two modes of infection, T/F Envs generally mediated efficient VS formation and subsequent cell-to-cell transfer. In contrast, in vitro infectivity of the T/F Env clones was more variable and strongly correlated with intrinsic fusogenicity of various Envs. We speculate that the conservation of cell-to-cell transfer by T/F Env is indicative of a biologically important function of Env.

Flavivirus NS5 associates with host-cell proteins zonula occludens-1 (ZO-1) and regulating synaptic membrane exocytosis-2 (RIMS2) via an internal PDZ binding mechanism.

Dengue virus (DENV) and tick-borne encephalitis virus (TBEV) are flaviviruses, which can cause lethal hemorrhagic fever and encephalitis, respectively. Here, we demonstrate that the TBEV-NS5 and DENV-NS5 proteins use an internal binding mechanism to target human PDZ proteins. TBEV-NS5 has high affinity to regulating synaptic membrane exocytosis-2 (RIMS2) and Scribble, whereas DENV-NS5 binds primarily to the tight junction protein zonula occludens-1 (ZO-1). Targeting of TBEV-NS5 to the plasma membrane is stabilised by ZO-1; however, DENV-NS5 co-localises with ZO-1 in the nucleus. These interactions have potential important roles in the ability of flaviviruses to manipulate cell proliferation, junction permeability and the interferon pathways.

LEDGF/p75 interferes with the formation of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro: implications for the mechanism of viral cDNA integration.

An integrase dimer can process and integrate a single HIV-1 DNA end in vitro, whereas a tetramer is required to integrate two ends. LEDGF/p75 can potently stimulate integrase activity, but its effects on half- versus full-site integration have not been investigated. Stimulation of half-site but inhibition of full-site integration is revealed here. LEDGF/p75 seems to interfere with integrase oligomerization, but does not inhibit the catalytic activity of pre-assembled complexes. We therefore speculate that LEDGF/p75 function is restricted to a point in the viral lifecycle that occurs after the formation of the preintegration synaptic complex, for example, as a chromatin-associated tethering factor.

Virus-induced neurobehavioral disorders: mechanisms and implications.

One hypothesis for the etiology of neuropsychiatric disorders proposes that viral infection contributes to the induction of neuronal system dysfunction, resulting in a wide range of behavioral abnormalities. Recent research in molecular biology supports this hypothesis and refocuses on the role of viral infection in the development of psychiatric disorders. Viral infection can induce deleterious effects in the central nervous system by direct and/or indirect pathways. Understanding the mechanisms of glial cell dysfunction caused by persistent viral infection should lead to novel insights into the development of neurobehavioral disorders, including human mental illnesses, and to the possible development of treatments.