Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Free Radic Biol Med ; 147: 102-113, 2020 02 01.
Article in English | MEDLINE | ID: mdl-31863909

ABSTRACT

Redox imbalance results in damage to cellular macromolecules and interferes with signaling pathways, leading to an inflammatory cellular and tissue environment. As such, the cellular oxidative environment is tightly regulated by several redox-modulating pathways. Many viruses have evolved intricate mechanisms to manipulate these pathways for their benefit, including HIV-1, which requires a pro-oxidant cellular environment for optimal replication. One such virulence factor responsible for modulating the redox environment is the HIV Transactivator of transcription (Tat). Tat is of particular interest as it is actively secreted by infected cells and internalized by uninfected bystander cells where it can elicit pro-oxidant effects resulting in inflammation and damage. Previously, we demonstrated that Tat regulates basal expression of Superoxide Dismutase 2 (sod2) by altering the binding of the Sp-transcription factors at regions relatively near (approx. -210 nucleotides) upstream of the transcriptional start site. Now, using in silico analysis and a series of sod2 promoter reporter constructs, we have identified putative clusters of Sp-binding sites located further upstream of the proximal sod2 promoter, between nucleotides -3400 to -210, and tested their effect on basal transcription and for their sensitivity to HIV-1 Tat. In this report, we demonstrate that under basal conditions, maximal transcription requires a cluster of Sp-binding sites in the -584 nucleotide region, which is extremely sensitive to Tat. Using chromatin immunoprecipitation (ChIP) we demonstrate that Tat results in altered occupancy of Sp1 and Sp3 at this distal Tat-sensitive regulatory element and strongly stimulated endogenous expression of SOD2 in human pulmonary artery endothelial cells (HPAEC). We also report altered expression of Sp1 and Sp3 in Tat-expressing HPAEC as well as in the lungs of HIV-1 infected humanized mice. Lastly, Tat co-immunoprecipitated with endogenous Sp3 but not Sp1 and did not alter the acetylation state of Sp3. Thus, here, we have defined a novel and important cis-acting factor in HIV-1 Tat-mediated regulation of SOD2, demonstrated that modulation of Sp1 and Sp3 activity by Tat promotes SOD2 expression in primary human pulmonary artery endothelial cells and determined that pulmonary levels of Sp3 as well as SOD2 are increased in the lungs of a mouse model of HIV infection.


Subject(s)
Endothelial Cells , HIV Infections , Animals , Binding Sites , Endothelial Cells/metabolism , Gene Products, tat , HIV Infections/genetics , Humans , Mice , Protein Binding , Pulmonary Artery/metabolism , Sp1 Transcription Factor/genetics , Sp1 Transcription Factor/metabolism , Sp3 Transcription Factor , Superoxide Dismutase , tat Gene Products, Human Immunodeficiency Virus
2.
AIDS Res Hum Retroviruses ; 34(9): 794-803, 2018 09.
Article in English | MEDLINE | ID: mdl-29905080

ABSTRACT

HIV type 1 (HIV-1) envelope glycoproteins (Env) mediate virus entry and are the target of neutralizing antibodies. Binding of the metastable HIV-1 Env trimer to the CD4 receptor triggers structural rearrangements that mediate Env conformational transitions from a closed conformation to a more open state through an intermediate step. Recent studies have revealed new insights on the dynamics, regulation, and molecular mechanisms of Env transitions along the entry pathway. In this study, we provide an overview of the current knowledge on Env conformational dynamics and the relationship between Env conformational states and neutralization selectivity of the broadly neutralizing antibodies that develop in 10%-20% of infected individuals and may provide guidance for the development of an effective HIV-1 vaccine.


Subject(s)
Antibodies, Neutralizing/immunology , Glycoproteins/immunology , HIV Antibodies/immunology , HIV Envelope Protein gp120/immunology , HIV Infections/immunology , HIV-1/immunology , CD4 Antigens/immunology , HIV Seropositivity/immunology , Humans , Protein Conformation , Virus Internalization , env Gene Products, Human Immunodeficiency Virus/immunology
SELECTION OF CITATIONS
SEARCH DETAIL
...