scholarly journals Inhibition of HIV Replication by Host Cellular Factors

10.5772/60795 ◽  
2015 ◽  
Author(s):  
J.M. Azevedo-Pereira ◽  
Pedro Canhão ◽  
Marta Calado ◽  
Quirina Santos-Costa ◽  
Pedro Barroca
Keyword(s):  
Hiv Replication ◽  
Cellular Factors

scholarly journals Identification and Optimization of Thienopyridine Carboxamides as Inhibitors of HIV Regulatory Complexes

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Robert L. Nakamura ◽  
Mark A. Burlingame ◽  
Shumin Yang ◽  
David C. Crosby ◽  
Dale J. Talbot ◽  
...  
Keyword(s):  
Viral Latency ◽  
Screening Strategy ◽  
Hiv Replication ◽  
Single Digit ◽  
New Class ◽  
Structure Activity ◽  
Cellular Factors ◽  
Small Molecule Library ◽  
A Cell

ABSTRACT Viral regulatory complexes perform critical functions during virus replication and are important targets for therapeutic intervention. In HIV, the Tat and Rev proteins form complexes with multiple viral and cellular factors to direct transcription and export of the viral RNA. These complexes are composed of many proteins and are dynamic, making them difficult to fully recapitulate in vitro. Therefore, we developed a cell-based reporter assay to monitor the assembly of viral complexes for inhibitor screening. We screened a small-molecule library and identified multiple hits that inhibit the activity of the viral complexes. A subsequent chemistry effort was focused on a thieno[2,3-b]pyridine scaffold, examples of which inhibited HIV replication and the emergence from viral latency. Notable aspects of the effort to determine the structure-activity relationship (SAR) include migration to the regioisomeric thieno[2,3-c]pyridine ring system and the identification of analogs with single-digit nanomolar activity in both reporter and HIV infectivity assays, an improvement of >100-fold in potency over the original hits. These results validate the screening strategy employed and reveal a promising lead series for the development of a new class of HIV therapeutics.

scholarly journals The Dual-Specificity Kinase DYRK1A Modulates the Levels of Cyclin L2 To Control HIV Replication in Macrophages

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Javan K. Kisaka ◽  
Lee Ratner ◽  
George B. Kyei
Keyword(s):  
Public Health Problem ◽  
Critical Factor ◽  
Major Public Health Problem ◽  
Hiv Replication ◽  
Viral Reservoirs ◽  
Dual Specificity ◽  
Cellular Factors ◽  
Latently Infected ◽  
Hiv Eradication ◽  
Hiv 1

ABSTRACT HIV replication in macrophages contributes to the latent viral reservoirs, which are considered the main barrier to HIV eradication. Few cellular factors that facilitate HIV replication in latently infected cells are known. We previously identified cyclin L2 as a critical factor required by HIV-1 and found that depletion of cyclin L2 attenuates HIV-1 replication in macrophages. Here we demonstrate that cyclin L2 promotes HIV-1 replication through interactions with the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). Cyclin L2 and DYRK1A were colocalized in the nucleus and were found together in immunoprecipitation experiments. Knockdown or inhibition of DYRK1A increased HIV-1 replication in macrophages, while depletion of cyclin L2 decreased HIV-1 replication. Furthermore, depletion of DYRK1A increased expression levels of cyclin L2. DYRK1A is a proline-directed kinase that phosphorylates cyclin L2 at serine residues. Mutations of cyclin L2 at serine residues preceding proline significantly stabilized cyclin L2 and increased HIV-1 replication in macrophages. Thus, we propose that DYRK1A controls cyclin L2 expression, leading to restriction of HIV replication in macrophages. IMPORTANCE HIV continues to be a major public health problem worldwide, with over 36 million people living with the virus. Although antiretroviral therapy (ART) can control the virus, it does not provide cure. The virus hides in the genomes of long-lived cells, such as resting CD4+ T cells and differentiated macrophages. To get a cure for HIV, it is important to identify and characterize the cellular factors that control HIV multiplication in these reservoir cells. Previous work showed that cyclin L2 is required for HIV replication in macrophages. However, how cyclin L2 is regulated in macrophages is unknown. Here we show that the protein DYRK1A interacts with and phosphorylates cyclin L2. Phosphorylation makes cyclin L2 amenable to cellular degradation, leading to restriction of HIV replication in macrophages.

scholarly journals Leukocyte extract reduces HIV replication and modulates cellular factors involved in HIV infection: therapeutic meant

2010 ◽  
Vol 13 (Suppl 4) ◽  
pp. P226
Author(s):  
C Fernandez-Ortega ◽  
D Casillas ◽  
M Dubed ◽  
L Navea ◽  
A Ramirez ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Hiv Replication ◽  
Cellular Factors

Ultrastructural observations of human monocytes infected with HIV-1

1991 ◽  
Vol 49 ◽  
pp. 108-109
Author(s):  
James K. Koehler ◽  
Steven G. Reed ◽  
Joao S. Silva
Keyword(s):  
Gradient Centrifugation ◽  
Virus Production ◽  
Human Monocyte ◽  
Red Cross ◽  
Human Monocytes ◽  
Blood Monocytes ◽  
Hiv Replication ◽  
Electron Microscopic ◽  
Ultrastructural Studies ◽  
Hiv 1

As part of a larger study involving the co-infection of human monocyte cultures with HIV and protozoan parasites, electron microscopic observations were made on the course of HIV replication and infection in these cells. Although several ultrastructural studies of the cytopathology associated with HIV infection have appeared, few studies have shown the details of virus production in “normal,” human monocytes/macrophages, one of the natural targets of the virus, and suspected of being a locus of quiescent virus during its long latent period. In this report, we detail some of the interactions of developing virons with the membranes and organelles of the monocyte host.Peripheral blood monocytes were prepared from buffy coats (Portland Red Cross) by Percoll gradient centrifugation, followed by adherence to cover slips. 90-95% pure monocytes were cultured in RPMI with 5% non-activated human AB serum for four days and infected with 100 TCID50/ml of HIV-1 for four hours, washed and incubated in fresh medium for 14 days.

Sign in / Sign up

Export Citation Format

Share Document