We have discovered that an N-terminal deletion mutant of a membrane protein, CD63, (CD63DN) blocks entry of CXCR4-using, T-cell tropic human immunodeficiency virus type 1 (X4 HIV-1) by suppressing CXCR4 surface expression. This suppression was observed for CXCR4 but not for CD4, CCR5, CD25, CD71 or other tetraspanin proteins. The suppression of CXCR4 expression on the plasma membrane appeared to be caused by mislocalization of CXCR4 and exclusive transportation of CXCR4 toward intracellular organelles, mainly late endosomes/ lysosomes. Our data suggest that CXCR4 trafficking can be modified in terms of its recruitment to the plasma membrane without enhancing the degradation or arresting vesicular transport of CXCR4.

APOBEC1 (A1) is a cytidine deaminase involved in the regulation of lipids in the small intestine. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that is capable of infecting neurons in the brain, causing encephalitis. Here, we show that A1 is induced during encephalitis in neurons of rats infected with HSV-1. In cells stably expressing A1, HSV-1 infection resulted in significantly reduced virus replication compared to that in control cells. Infectivity could be restored to levels comparable to those observed for control cells if A1 expression was silenced by specific A1 short hairpin RNAs (shRNA). Moreover, cytidine deaminase activity appeared to be essential for this inhibition and led to an impaired accumulation of viral mRNA transcripts and DNA copy numbers. The sequencing of viral gene UL54 DNA, extracted from infected A1-expressing cells, revealed G-to-A and C-to-T transitions, indicating that A1 associates with HSV-1 DNA. Taken together, our results demonstrate a model in which A1 induction during encephalitis in neurons may aid in thwarting HSV-1 infection.The human apolipoprotein B-editing catalytic polypeptide (ABOBEC) family is a group of zinc-dependent DNA and RNA cytidine deaminases and consists of AID, APOBEC1 (A1), APOBEC2 (A2), seven APOBEC3s (APOBEC3A [A3A] to A3H), and APOBEC4 (A4). A1, the first APOBEC to be discovered, is known to introduce a premature stop codon into host apolipoprotein B mRNA in the gastrointestinal tract, an event critical for lipid metabolism (17,40,61). The editing by A1 is highly precise and specifically converts C to U at position 6666 of the apolipoprotein B mRNA substrate (46). Along with APOBEC1 complementation factor (ACF), these two proteins constitute the minimal required components necessary for the editing of apolipoprotein B mRNA in vitro (37).Cytidine deaminases first came into the limelight as antiviral factors after A3G was identified as a cellular restriction factor capable of inhibiting HIV-1 dissemination in the absence of HIV-1 virus infectivity factor (Vif) (56). This molecule was later shown to inhibit retrovirus infection by inducing a massive hypermutation of the murine leukemia virus (MLV) genome (23). Further detailed studies revealed that APOBEC molecules are packaged into HIV-1 virions in virus producer cells via a specific interaction with Gag and viral RNA and then exert their deaminase activity in subsequent target cells on a single-stranded DNA (ssDNA) intermediate synthesized by reverse transcriptase (3, 28, 55). Editing can lead to nonsynonymous mutations, such as premature stop codons, in critical proteins (e.g., reverse transcriptase) necessary for virus replication and infectivity, severely impairing the next round of infection (54,64). Extensive studies to assess the antiviral nature of these APOBEC enzymes have been performed across a broad range of retroviruses and hepatitis B virus (HBV) (7,35,36,42,43,50,56,58).Herpes simplex virus (HSV) is an enveloped, double-stranded DNA (dsDNA) virus and a member of the genus Alphaherpe...

Macrophages or microglial cells are the major target cells for HIV-1 infection in the brain. The infected cells release neurotoxic factors that may cause severe neuronal cell damage, especially in the basal ganglia and hippocampus. In this study, we used rat OHC to examine the region-specific neuronal cell damage caused by HIV-1-infected macrophages. When OHC was cocultured with HIV-1-infected MDM, we found that neuronal cells at the GCL of the DG were preferentially killed via apoptosis, and that projection of MF from GCL to PCL of the CA3 region was severely disturbed. We marked precursor cells around the DG region by using an EGFP-expressing retrovirus vector and found that these cells lost the ability to differentiate into neurons when exposed to HIV-1-infected MDM. In the DG, new neurons are normally incorporated into GCL or PCL, while in the presence of HIV-1-infected MDM, mature neurons failed to be incorporated into those layers. These data indicate that the neurotoxic factor(s) released from HIV-1-infected macrophages impede(s) neuronal cell repair in brain tissue. This suggests that DG is the region of the hippocampus most vulnerable to neuronal damage caused by HIV-1 infection, and that its selective vulnerability is most likely due to the highly active neurogenesis that takes place in this region.