What will it really take to end the HIV epidemic?

Skeen, Sarah; Prince, Bridgette; Rooyen, Heidi van; Tomlinson, Mark; Swartz, Alison; Cooper, Diane; Cluver, Lucie; Davidovich, Udi; Harding, Richard; Spire, Bruno; Catalán, José; Hedge, Barbara; Sherr, Lorraine

doi:10.1080/09540121.2018.1488034

Cited by 2 publications

(1 citation statement)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is almost twenty years since the global roll out of Anti-retroviral therapy (ART) and according the UNAIDS report 2020, of the 37.9 million individuals currently living with HIV, 63% have been initiated on ART. Although we are still lagging behind the 2020 UNAIDS target [1][2][3][4], it is undeniable that ART has tremendously changed the face of the Human Immunode ciency Virus (HIV) epidemic resulting in a marked reduction in HIV associated mortality and a signi cant reduction in opportunistic infections, therefore, more people are living prolonged and more productive lives [5,6]. The current 90-90-90 strategy, ensures that all the patients who are initiated on ART are closely monitored so that they achieve viral suppression [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

Nankya¹,

Nabulime²,

Kyeyune³

et al. 2021

Preprint

View full text Add to dashboard Cite

Objective To determine the prevalence of multi-drug resistant variants among patients failing on a nucleoside reverse transcriptase inhibitor (NRTI) based regimen with a detectable viral load ≥ 1000 copies/ml among patients harboring HIV subtype A, C and D. Methods Samples were obtained from patients who were failing on an NRTI based regimen. Sanger based sequencing was performed as part of the standard of care. Mutation analysis was performed using the Stanford HIV drug Resistance database. A subset of these patient samples was further analyzed using the Next Generation Sequencing (NGS) technology and analysis of the drug resistance mutations was performed at the 20% and 1% cut off Results Analysis of the Non-nucleoside reverse transcriptase inhibitor (NNRTI) coding region revealed that the K101 and the Y181 mutations were more predominant among subtype C than subtype A and D. Although Thymidine analog mutations (TAMs) were prevalent in all subtypes, our analyses showed that these mutations occurred in significantly less proportions among subtype C infections when compared with the subtype A and D counterparts. Furthermore, the Q151M mutation complex which involves mutations in multiple domains was significantly more prominent among patients harboring subtype C variants. Analysis using NGS revealed that minority drug resistant mutations that confer multi-drug resistance (MDR) were present even in patients who exhibited a susceptible genotype based on the Sanger sequencing technique. Conclusion Although HIV-1 MDR variants occur in all subtypes, their predominance is subtype specific with TAMs being significantly more predominant among subtype A and D while the Q151M complex being significantly more predominant among patients harboring subtype C viruses. Even in patients with a susceptible genotype based on Sanger technology, minority variants are present and their evolution to full blown MDR occurs over time such that by the time they are detectable, cross resistance to other drugs has occurred in some cases.

show abstract

Section: Introductionmentioning

confidence: 99%

Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

Nankya¹,

Nabulime²,

Kyeyune³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

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

Kisaka

Ratner

Kyei

2020

J Virol

View full text Add to dashboard Cite

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.

show abstract

What will it really take to end the HIV epidemic?

Cited by 2 publications

References 16 publications

Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

Prevalence of minority Human Immunodeficiency virus multi-drug resistant mutations among patients failing a Nucleoside Reverse Transcriptase Inhibitor based regimen in Uganda

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

Contact Info

Product

Resources

About