ABSTRACT

An important aspect of the pathophysiology of human immunodeficiency virus type-1 (HIV-1) infection is the ability of the virus to replicate in non-dividing cells. HIV-1 matrix (MA), the amino-terminal domain of the Pr55 gag polyprotein (Pr55), bears a nuclear localization signal that promotes localization of the viral preintegration complex to the nucleus of non-dividing cells following virus entry. However, late during infection, MA, as part of Pr55, directs unspliced viral RNA to the plasma membrane, the site of virus assembly. How MA can mediate these two opposing targeting functions is not understood. Here we demonstrate that MA has a previously undescribed nuclear export activity. Although MA lacks the canonical leucine-rich nuclear export signal, nuclear export is mediated through the conserved Crm1p pathway and functions in both mammalian cells and yeast. A mutation that disrupts the MA nuclear export signal (MA-M4) mislocalizes Pr55 and genomic viral RNA to the nucleus, thereby severely impairing viral replication. Furthermore, we show that MA-M4 can act in a dominant-negative fashion to mislocalize genomic viral RNA even in the presence of wild-type MA. We conclude that the MA nuclear export signal is required to counteract the MA nuclear localization signal, thus ensuring the cytoplasmic availability of the components required for virion assembly.

Objectives:To determine the risk factors and incidence of cerebral infarction associated with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome. Methods:The Mayo Clinic dysproteinemia database was queried to identify patients with coded diagnosis of POEMS syndrome. Patients with cerebral infarction, occurring after the onset of POEMS-related symptoms, were selected. A retrospective observational study design was used to evaluate potential predictors of stroke in patients with POEMS syndrome.Results: A total of 9 patients (10%; 95% confidence interval 5.4 -17.9) with cerebral infarction were identified (2 women, 22%). Traditional stroke risk factors were not significantly different between the stroke and nonstroke subgroups, but hematologic abnormalities such as elevated platelet count and bone marrow plasmacytosis differed between the 2 groups. Cerebral infarction occurrence after successful treatment of the underlying condition was not observed. CT and MRI data demonstrated a wide spectrum of infarct topography in these patients. Common stroke etiologies comprised suspected vascular structural abnormalities leading to vessel dissection and stenosis, in addition to embolism from a proximal source.

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