scholarly journals 12-O-Acetylphorbol-13-decanoate Potently Inhibits Cytopathic Effects of Human Immunodeficiency Virus Type 1(HIV-1), without Activation of Protein Kinase C.

1999 ◽  
Vol 47 (9) ◽  
pp. 1346-1347 ◽  
Author(s):  
Sahar EL-MEKKAWY ◽  
Meselhy R. MESELHY ◽  
Norio NAKAMURA ◽  
Masao HATTORI ◽  
Takuya KAWAHATA ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytopathic Effects ◽  
Kinase C ◽  
Immunodeficiency Virus ◽  
Hiv 1

scholarly journals Human Immunodeficiency Virus Type 1 Pathogenesis in SCID-hu Mice Correlates with Syncytium-Inducing Phenotype and Viral Replication

2000 ◽  
Vol 74 (7) ◽  
pp. 3196-3204 ◽  
Author(s):  
David Camerini ◽  
Hua-Poo Su ◽  
Graciela Gamez-Torre ◽  
Michael L. Johnson ◽  
Jerome A. Zack ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Threshold Level ◽  
Cytopathic Effects ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Entry Efficiency

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) patient isolates and molecular clones were used to analyze the determinants responsible for human CD4+ thymocyte depletion in SCID-hu mice. Non-syncytium-inducing, R5 or R3R5 HIV-1 isolates from asymptomatic infected people showed little or no human CD4+ thymocyte depletion in SCID-hu mice, while syncytium-inducing (SI), R5X4 or R3R5X4 HIV-1 isolates from the same individuals, isolated just prior to the onset of AIDS, rapidly and efficiently eliminated CD4-bearing human thymocytes. We have mapped the ability of one SI HIV-1 isolate to eliminate CD4+ human cells in SCID-hu mice to a region of the env gene including the three most amino-terminal variable regions (V1 to V3). We find that for all of the HIV-1 isolates that we studied, a nonlinear relationship exists between viral replication and the depletion of CD4+ cells. This relationship can best be described mathematically with a Hill-type plot indicating that a threshold level of viral replication, at which cytopathic effects begin to be seen, exists for HIV-1 infection of thymus/liver grafts in SCID-hu mice. This threshold level is 1 copy of viral DNA for every 11 cells (95% confidence interval = 1 copy of HIV-1 per 67 cells to 1 copy per 4 cells). Furthermore, while SI viruses more frequently achieve this level of replication, replication above this threshold level correlates best with cytopathic effects in this model system. We used GHOST cells to map the coreceptor specificity and relative entry efficiency of these early- and late-stage patient isolates of HIV-1. Our studies show that coreceptor specificity and entry efficiency are critical determinants of HIV-1 pathogenesis in vivo.

scholarly journals Human Immunodeficiency Virus Type 1 Tat Protein Activates Transcription Factor NF-κB through the Cellular Interferon-Inducible, Double-Stranded RNA-Dependent Protein Kinase, PKR

1999 ◽  
Vol 73 (8) ◽  
pp. 7080-7086 ◽  
Author(s):  
Francesca Demarchi ◽  
Maria Ines Gutierrez ◽  
Mauro Giacca
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protein Kinase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nuclear Factor Κb ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The transactivator protein of human immunodeficiency virus type 1 (HIV-1) (Tat) is a powerful activator of nuclear factor-κB (NF-κB), acting through degradation of the inhibitor IκB-α (F. Demarchi, F. d’Adda di Fagagna, A. Falaschi, and M. Giacca, J. Virol. 70:4427–4437, 1996). Here, we show that this activity of Tat requires the function of the cellular interferon-inducible protein kinase PKR. Tat-mediated NF-κB activation and transcriptional induction of the HIV-1 long terminal repeat were impaired in murine cells in which the PKR gene was knocked out. Both functions were restored by cotransfection of Tat with the cDNA for PKR. Expression of a dominant-negative mutant of PKR specifically reduced the levels of Tat transactivation in different human cell types. Activation of NF-κB by Tat required integrity of the basic domain of Tat; previous studies have indicated that this domain is necessary for specific Tat-PKR interaction.

scholarly journals Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

1999 ◽  
Vol 73 (10) ◽  
pp. 8256-8267 ◽  
Author(s):  
Jialin Zheng ◽  
Anuja Ghorpade ◽  
Douglas Niemann ◽  
Robin L. Cotter ◽  
Michael R. Thylin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protein Kinase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Damage ◽  
Neural Cell ◽  
Neural Damage ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis.

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