Biomedical subjects

Andrew I Dayton

Publications and source records attributed to Andrew I Dayton.

7 recordsLinked to original sources

PubMed2006

Beyond open access: open discourse, the next great equalizer.

The internet is expanding the realm of scientific publishing to include free and open public debate of published papers. Journals are beginning to support web posting of comments on their published articles and independent organizations are providing centralized web sites for posting comments about any published article. The trend promises to give one and all access to read and contribute to cutting edge scientific criticism and debate.

Internet↗

PubMed2006

HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro.

We report a novel mechanism, involving up-regulation of the interleukin (IL)-7 cytokine receptor, by which human immunodeficiency virus (HIV) enhances its own production in monocyte-derived macrophages (MDM) in vitro. HIV-1 infection or treatment of MDM cultures with exogenous HIV-1 Tat(86) protein up-regulates the IL-7 receptor (IL-7R) alpha-chain at the levels of steady-state RNA, protein, and functional IL-7R on the cell surface (as measured by ligand-induced receptor signaling). This IL-7R up-regulation is associated with increased amounts of HIV-1 virions in the supernatants of infected MDM cultures treated with exogenous IL-7 cytokine. The overall effect of IL-7 stimulation on HIV replication in MDM culture supernatants is typically in the range of one log and greater. The results are consistent with a model in which HIV infection produces the Tat protein, which in turn up-regulates IL-7R in a paracrine manner. This results in increased IL-7R signaling in response to the IL-7 cytokine, which ultimately promotes early events in HIV replication, including binding/entry and possibly other steps prior to reverse transcription. The results suggest that the effects of IL-7 on HIV replication in MDM should be considered when analyzing and designing clinical trials involving treatment of patients with IL-7 or Tat vaccines.

Cells, Cultured↗

PubMed2006

Monocytes-macrophages are a potential target in human infection with West Nile virus through blood transfusion.

BACKGROUND: West Nile virus (WNV) transmission by transfusion was documented in 2002. Approximately 80 percent of WNV infections are asymptomatic and 1 percent develop severe neurological illness. In animals, Langerhans-dendritic cells support initial viral replication, followed by replication in lymphoid tissues and dissemination to organs and possibly to the CNS. The cellular tropism of WNV infection after transfusion and the particular human blood cells that sustain viral replication remain largely unknown. Whether primary monocyte-derived macrophages (MDMs) support WNV infection-replication and produce infectious virions, with an in vitro system, was investigated. STUDY DESIGN AND METHODS: Elutriated monocytes (CD33+/CD14+) from suitable blood donors were cultured in the presence of macrophage-colony-stimulating factor, infected with WNV-NY99 at different time points, washed, and cultivated for up to 47 days. Supernatants were tested for WNV replication by TaqMan reverse transcription-polymerase chain reaction (RT-PCR), with primers for the envelope and/or 3'NC regions, and by cDNA-PCR to detect WNV minus-strand RNA and for the presence of functional virions by infectivity assays in Vero cells. RESULTS: RT-PCR TaqMan of supernatants demonstrated productive infection of MDMs. Viral load reached 2 to 5 log above baseline in 3 to 6 days and then declined, with detectable viral replication persisting for up to 47 days. WNV minus-strand RNA was detected in Day 4 cultures, indicating active viral replication. Infected MDM cultures showed no cytopathic changes. Supernatants that were TaqMan-positive for the presence of WNV-infected Vero cells and produced cytopathic effects within 3 to 5 days of culture. CONCLUSION: The susceptibility of monocytes-macrophages to productive infection in vitro is compatible with a potential role in initial WNV replication and propagation after transmission by transfusion.

Cells, Cultured↗

PubMed2005

Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1.

Human immunodeficiency virus type 1 viral protein R (Vpr) is required for viral pathogenesis and has been implicated in T-cell apoptosis through its activation of caspase 3 and caspase 9 and perturbation of mitochondrial membrane potential. To understand better Vpr-mitochondria interaction, we report here the identification of antiapoptotic mitochondrial protein HAX-1 as a novel Vpr target. We show that Vpr and HAX-1 physically associate with each other. Overexpression of Vpr in cells dislocates HAX-1 from its normal residence in mitochondria and creates mitochondrion instability and cell death. Conversely, overexpression of HAX-1 suppressed the proapoptotic activity of Vpr.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Within you, without you: HIV-1 Rev and RNA export.

Nucleo-cytoplasmic transport of RNA is one of many cellular pathways whose illumination has progressed hand in hand with understanding of retroviral mechanisms. A recent paper in Cell reports the involvement of an RNA helicase in the pathway by which HIV exports partially spliced and unspliced RNA out of the nucleus. This suggests the ubiquity of RNA helicases in RNA export from the nucleus, and has novel mechanistic implications.

Anti-HIV Agents↗

PubMed2004

Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection.

Correct endoproteolytic maturation of gp160 is essential for the infectivity of human immunodeficiency virus type 1. This processing of human immunodeficiency virus-1 envelope protein, gp160, into gp120 and gp41 has been attributed to the activity of the cellular subtilisin-like proprotein convertase furin. The prototypic furin recognition cleavage site is Arg-X-Arg/Lys-Arg. Arg-Arg-Arg-Arg-Arg-Arg or longer iterations of polyarginine have been shown to be competitive inhibitors of substrate cleavage by furin. Here, we tested polyarginine for inhibition of productive human immunodeficiency virus-1-infection in T-cell lines, primary peripheral blood mononuclear cells, and macrophages. We found that polyarginine inhibited significantly human immunodeficiency virus-1 replication at concentrations that were benign to cell cultures ex vivo and mice in vivo. Using a fluorogenic assay, we demonstrated that polyarginine potently inhibited substrate-specific proteolytic cleavage by furin. Moreover, we verified that authentic processing of human immunodeficiency virus-1 gp160 synthesized in human cells from an infectious human immunodeficiency virus-1 (HIV-1) molecular clone was effectively blocked by polyarginine. Taken together, our data support that inhibitors of proteolytic processing of gp160 may be useful for combating human immunodeficiency virus-1 and that polyarginine represents a lead example of such inhibitors.

Animals↗

PubMedDate not supplied

Bcl-2 upregulation by HIV-1 Tat during infection of primary human macrophages in culture.

The ability of cells of the human monocyte/macrophage lineage to host HIV-1 replication while resisting cell death is believed to significantly contribute to their ability to serve as a reservoir for viral replication in the host. Although macrophages are generally resistant to apoptosis, interruption of anti-apoptotic pathways can render them susceptible to apoptosis. Here we report that HIV-1(BAL )infection of primary human monocyte-derived macrophages (MDM) upregulates the mRNA and protein levels of the anti-apoptic gene, Bcl-2. Furthermore, this upregulation can be quantitatively mimicked by treating MDM with soluble HIV-1 Tat-86 protein. These results suggest that in infecting cells of the monocyte/macrophage lineage, HIV-1 may be benefiting from additional protection against apoptosis caused by specific upregulation of cellular anti-apoptotic genes.

Apoptosis↗