A longitudinal characterization of sex-specific somatosensory and spatial memory deficits in HIV Tg26 heterozygous mice.

The pathogenesis of human immunodeficiency virus associated neurological disorders is still not well understood, yet is known to result in neurological declines despite combination anti-retroviral therapy. HIV-1 transgenic (Tg26) mice contain integrated non-infectious HIV-1 proviral DNA. We sought to assess the integrity of neurocognitive function and sensory systems in HIV-1 Tg26 mice using a longitudinal design, in both sexes, to examine both age- and sex-related disease progression.

Suppression of Zika Virus Infection in the Brain by the Antiretroviral Drug Rilpivirine.

Zika virus (ZIKV) infection is associated with microcephaly in neonates and Guillain-Barré syndrome in adults. ZIKV produces a class of nonstructural (NS) regulatory proteins that play a critical role in viral transcription and replication, including NS5, which possesses RNA-dependent RNA polymerase (RdRp) activity. Here we demonstrate that rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection, inhibits the enzymatic activity of NS5 and suppresses ZIKV infection and replication in primary human astrocytes.

Memory deficits, gait ataxia and neuronal loss in the hippocampus and cerebellum in mice that are heterozygous for Pur-alpha.

Pur-alpha is a highly conserved sequence-specific DNA and RNA binding protein with established roles in DNA replication, RNA translation, cell cycle regulation, and maintenance of neuronal differentiation. Prior studies have shown that mice lacking Pur-alpha (-/-) display decreased neurogenesis and impaired neuronal differentiation. We sought to examine for the first time, the behavioral phenotype and brain histopathology of mice that are heterozygous (+/-) for Pur-alpha.

Combined proteasome and Bcl-2 inhibition stimulates apoptosis and inhibits growth in EBV-transformed lymphocytes: a potential therapeutic approach to EBV-associated lymphoproliferative diseases.

Objectives: Epstein-Barr virus (EBV) transforms B-cells into immortalized lymphoblastoid cells (LCLs) by triggering signaling pathways that lead to activation of multiple transcription factors and anti-apoptotic proteins, including NF-kappaB and Bcl-2, respectively. Since proteasome inhibition suppresses NF-kappaB activity, we sought to determine whether the proteasome inhibitor, bortezomib, alone or in combination with Bcl-2 inhibition, has potential as a therapeutic strategy in EBV-driven B-cell neoplasms.

Methods: We evaluated the effects of bortezomib in LCLs in vitro, in the presence and absence of the small molecular inhibitor of Bcl-2, HA14-1, on proliferation, apoptosis, caspase activation, and expression of Bcl-2 family members, and in vivo in the severe combined immunodeficiency (SCID) model of EBV+ lymphoproliferative disease.

Systemic Bcl-2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice.

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP-1), is expressed in the majority of NPCs. LMP-1 upregulates antiapoptotic genes, including bcl-2, and Bcl-2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC.

Bcl-2 antisense (G3139, Genasense) enhances the in vitro and in vivo response of Epstein-Barr virus-associated lymphoproliferative disease to rituximab.

Bcl-2 is up-regulated by EBV in immortalized lymphoblastoid B cells and is expressed in the majority of EBV-associated lymphoproliferative diseases, including posttransplant lymphoproliferative disorder (PTLD) and AIDS-related lymphoma (ARL). Given the antiapoptotic and chemoprotective effect of Bcl-2, it represents a logical target for modulation using antisense strategies in PTLD and ARL. We previously examined the antitumor effects of a fully phosphorothioated Bcl-2 antisense oligonucleotide, G3139, in EBV(+) lymphoproliferative disease in vitro and in vivo using the human/severe combined immunodeficient (SCID) chimeric model of PTLD.