scholarly journals Circulating Fibroblast Growth Factor-2 precipitates HIV-nephropathy in mice

2021 ◽  
Author(s):  
Jharna R. Das ◽  
Marina Jerebtsova ◽  
Pingtao Tang ◽  
Jinliang Li ◽  
Jing Yu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Kidney Failure ◽  
High Plasma ◽  
Antiretroviral Drugs ◽  
Vegf Receptor ◽  
Living With Hiv ◽  
Circulating Levels ◽  
Renal Expression ◽  
Hiv 1

Over 80% of all children living with HIV reside in Africa and are at risk of developing HIV-associated nephropathy (HIVAN). Once HIVAN is established in children, it is difficult to revert its progression to chronic kidney failure even using antiretroviral drugs. Therefore, new therapeutic strategies are needed. Previous studies showed that the risk of developing HIVAN increases in children with high circulating levels of FGF-2, but it is unclear whether FGF-2 per se precipitates HIVAN. To unravel the role of circulating FGF-2 in childhood HIVAN, we used the HIV-Tg26 mouse model of HIVAN. Briefly, we demonstrated that circulating FGF-2 was preferentially recruited in the kidney of HIV-Tg26 mice with renal disease, and precipitated HIVAN in young mice without pre-existing kidney disease by activating the pERK pathway in renal epithelial cells without previously inducing the expression of HIV-1 genes. Wild type mice injected with recombinant adenoviral FGF-2 vectors (rAd-FGF-2) carrying a secreted form of human FGF-2 developed transient and reversible HIVAN-like lesions, including proteinuria and glomerular enlargement. HIV-Tg26 mice injected with rAd-FGF-2 developed more significant proliferative and pro-fibrotic inflammatory lesions, similar to those seen in childhood HIVAN. These lesions were partially reversed in mice treated with the FGF/VEGF receptor tyrosine kinase inhibitor PD173074. In conclusion, we developed a new FGF-2-inducible model of childhood HIVAN, and showed that high circulating levels of FGF-2 precipitated HIVAN without inducing the renal expression of HIV-genes. These findings suggest that high plasma FGF-2 levels may be an independent risk factor for precipitating HIVAN in young children.

scholarly journals Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

2016 ◽  
Vol 1 (1) ◽  
pp. 41 ◽  
Author(s):  
Said A. Hassounah ◽  
Thibault Mesplède ◽  
Mark A. Wainberg
Keyword(s):  
Nonhuman Primates ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Humanized Mouse ◽  
Hiv Replication ◽  
Hiv Therapy ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

Since the discovery of the first inhibitors of HIV replication, drug resistance has been a major problem in HIV therapy, due, in part, to the high mutation rate of HIV. Therefore, the development of a predictive animal model is important to identify impending resistance mutations and to possibly inform treatment decisions. Significant advances have been made possible through use of nonhuman primates infected by SIV, SHIV, and stHIV-1, and use of humanized mouse models of HIV-1 infections. In this review, we describe some of the findings from animal models used for the preclinical testing of integrase strand transfer inhibitors as well as other antiretroviral drugs. These models have led to important findings about the potential role of integrase strand transfer inhibitors in both the prevention and treatment of HIV-1 infection.

Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment

2021 ◽  
Author(s):  
Thibaut Gelé ◽  
Antoine Chéret ◽  
Alicia Castro Gordon ◽  
Lionelle Nkam ◽  
Valérie Furlan ◽  
...  
Keyword(s):  
Real Life ◽  
Antiretroviral Drugs ◽  
People Living With Hiv ◽  
Hiv Cure ◽  
Crucial Component ◽  
Total Plasma Concentration ◽  
Tenofovir Alafenamide ◽  
Living With Hiv ◽  
Csf Concentration ◽  
Hiv 1

Abstract Objectives The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. Methods Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). Results Twenty-four patients (nine women) were enrolled. The age was 45 (26–68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6–9.6), 84.4 (28.6–337.4) and 1.6 (0.7–4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%–82%) versus 0.33% (0.11%–0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). Conclusions We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age.

scholarly journals Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency

2018 ◽  
Vol 63 (2) ◽  
pp. e01744-18 ◽  
Author(s):  
Benni Vargas ◽  
Nicholas S. Giacobbi ◽  
Anwesha Sanyal ◽  
Narasimhan J. Venkatachari ◽  
Feng Han ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Kinase C ◽  
Wide Range ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried out in the absence or presence of three mechanistically distinct latency-reversing agents (LRAs), namely, prostratin, panobinostat, and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked the reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these, danusertib, an Aurora kinase inhibitor, and PF-3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40 to 147 nM for danusertib (selectivity indices, >150) and from 0.1 to 1 nM for PF-3758309 (selectivity indices, >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity or the maintenance of HIV-1 latency and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.

scholarly journals Understanding the role of resilience resources, antiretroviral therapy initiation, and HIV-1 RNA suppression among people living with HIV in South Africa

AIDS ◽  
2019 ◽  
Vol 33 ◽  
pp. S71-S79 ◽  
Author(s):  
Ingrid T. Katz ◽  
Laura M. Bogart ◽  
Janan J. Dietrich ◽  
Hannah H. Leslie ◽  
Hari S. Iyer ◽  
...  
Keyword(s):  
South Africa ◽  
Antiretroviral Therapy ◽  
People Living With Hiv ◽  
Therapy Initiation ◽  
Living With Hiv ◽  
Hiv 1

scholarly journals Role of Divalent Cations in HIV-1 Replication and Pathogenicity

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 471
Author(s):  
Nabab Khan ◽  
Xuesong Chen ◽  
Jonathan D. Geiger
Keyword(s):  
Divalent Cations ◽  
Dietary Supplementation ◽  
Review Literature ◽  
Host Factors ◽  
People Living With Hiv ◽  
Immunodeficiency Virus ◽  
Living With Hiv ◽  
Hiv 1

Divalent cations are essential for life and are fundamentally important coordinators of cellular metabolism, cell growth, host-pathogen interactions, and cell death. Specifically, for human immunodeficiency virus type-1 (HIV-1), divalent cations are required for interactions between viral and host factors that govern HIV-1 replication and pathogenicity. Homeostatic regulation of divalent cations’ levels and actions appear to change as HIV-1 infection progresses and as changes occur between HIV-1 and the host. In people living with HIV-1, dietary supplementation with divalent cations may increase HIV-1 replication, whereas cation chelation may suppress HIV-1 replication and decrease disease progression. Here, we review literature on the roles of zinc (Zn2+), iron (Fe2+), manganese (Mn2+), magnesium (Mg2+), selenium (Se2+), and copper (Cu2+) in HIV-1 replication and pathogenicity, as well as evidence that divalent cation levels and actions may be targeted therapeutically in people living with HIV-1.

Role of testosterone in regulating the growth of mice from lines selected for low vs high plasma insulin-like growth factor-I concentrations

1989 ◽  
Vol 121 (5) ◽  
pp. 686-690 ◽  
Author(s):  
Rafat A. Siddiqui ◽  
Stuart N. McCutcheon ◽  
Duncan D. S. Mackenzie ◽  
Hugh T. Blair ◽  
J. Eldon Ormsby ◽  
...  
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
High Plasma ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Pubertal Growth ◽  
Igf I ◽  
Growth Factor I ◽  
Circulating Levels

Abstract. A study was undertaken to investigate the role of testosterone in regulating growth and circulating levels of insulin-like growth factor-I in male mice from lines divergently selected on the basis of plasma IGF-I. Controls of each lines were sham-operated at 10 days of age and treated with peanut oil from day 14 to day 70. A second group, which was castrated at 10 days and treated with testosterone enanthate (0.5 μg · (g body weight) −1 · day−1) from day 14 to 70, did not differ from controls in body weight but had higher plasma IGF-I concentrations. Delaying testosterone therapy until day 42 in a third group retarded growth, with body weights being significantly lower than those of other two groups from days 35 to 56. However, plasma IGF-I levels in this group were not different from those of controls. Effects of line and treatment were additive. It is concluded that the greater pubertal growth of high-line compared to low-line males is not due to greater stimulation of circulating IGF-I by testosterone. Furthermore, testosterone does not appear to influence pubertal growth by acting on circulating levels of IGF-I.

scholarly journals Insights into the Gene Expression Profiles of Active and Restricted Red/Green-HIV+ Human Astrocytes: Implications for Shock or Lock Therapies in the Brain

2020 ◽  
Vol 94 (6) ◽  
Author(s):  
Venkata Viswanadh Edara ◽  
Anuja Ghorpade ◽  
Kathleen Borgmann
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Neurocognitive Disorders ◽  
Antiretroviral Drugs ◽  
Gene Expression Patterns ◽  
People Living With Hiv ◽  
Human Astrocytes ◽  
Living With Hiv ◽  
Hiv 1

ABSTRACT A significant number of people living with human immunodeficiency virus type 1 (HIV-1) suffer from HIV-associated neurocognitive disorders (HAND). Many previous studies investigating HIV in astrocytes as a heterogenous population have established the relevance of astrocytes to HIV-associated neuropathogenesis. However, these studies were unable to differentiate the state of infection, i.e., active or latent, or to evaluate how this affects astrocyte biology. In this study, the pseudotyped doubly labeled fluorescent reporter red/green (R/G)-HIV-1 was used to identify and enrich restricted and active populations of HIV+ astrocytes based on the viral promoter activity. Here, we report that the majority of human astrocytes restricted R/G-HIV-1 gene expression early during infection and were resistant to reactivation by vorinostat and interleukin 1β. However, actively infected astrocytes were inducible, leading to increased expression of viral proteins upon reactivation. R/G-HIV-1 infection also significantly decreased the cell proliferation and glutamate clearance ability of astrocytes, which may contribute to excitotoxicity. Moreover, transcriptome analyses to compare gene expression patterns of astrocyte harboring active versus restricted long terminal repeats (LTRs) revealed that the gene expression patterns were similar and that the active population demonstrated more widespread and robust changes. Our data suggest that harboring the HIV genome profoundly alters astrocyte biology and that strategies that keep the virus latent (e.g., block and lock) or those that reactivate the latent virus (e.g., shock and kill) would be detrimental to astrocyte function and possibly augment their contributions to HAND. IMPORTANCE More than 36 million people are living with HIV-1 worldwide, and despite antiretroviral therapy, 30 to 50% of the people living with HIV-1 suffer from mild to moderate neurocognitive disorders. HIV-1 reservoirs in the central nervous system (CNS) are challenging to address due to low penetration of antiretroviral drugs, lack of resident T cells, and permanent integration of provirus into neural cells such as microglia and astrocytes. Several studies have shown astrocyte dysfunction during HIV-1 infection. However, little is known about how HIV-1 latency affects their function. The significance of our research is in identifying that the majority of HIV+ astrocytes restrict HIV expression and were resistant to reactivation. Further, simply harboring the HIV genome profoundly altered astrocyte biology, resulting in a proinflammatory phenotype and functional changes. In this context, therapeutic strategies to reactivate or silence astrocyte HIV reservoirs, without excising proviral DNA, will likely lead to detrimental neuropathological outcomes during HIV CNS infection.

scholarly journals S100A8 and S100A9, biomarkers of SARS-Cov-2-infected patients, suppress HIV replication in primary macrophages

2021 ◽  
Author(s):  
Raphael M. Oguariri ◽  
Terrence W. Brann ◽  
Joseph W. Adelsberger ◽  
Qian Chen ◽  
Suranjana Goswami ◽  
...  
Keyword(s):  
Cell Types ◽  
People Living With Hiv ◽  
Hiv Replication ◽  
Viral Loads ◽  
Novel Biomarkers ◽  
Immunocompromised Status ◽  
Living With Hiv ◽  
Hiv 1 ◽  
Pro Inflammatory Cytokines

S100A8 and S100A9 are members of the Alarmin family; these proteins are abundantly expressed in neutrophils and form a heterodimer complex. Recently, both proteins were identified as novel biomarkers of SARS-CoV-2 infection and were shown to play key roles in inducing an aggressive inflammatory response by mediating the release of large amounts of pro-inflammatory cytokines, called the cytokine storm. Although co-infection with SARS-CoV-2 in people living with HIV-1 may result in an immunocompromised status, the role of the S100A8/A9 complex in HIV-1 replication in primary T cells and macrophages is still unclear. Here, we evaluated the roles of the proteins in HIV replication to elucidate their functions. We found that the complex had no impact on virus replication in both cell types; however, the subunits of S100A8 and S100A9 inhibits HIV in macrophages. These findings provide important insights into the regulation of HIV viral loads during SARS-CoV-2 co-infection.

scholarly journals Crucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection

2021 ◽  
Vol 9 (12) ◽  
pp. 2537
Author(s):  
Ana Borrajo ◽  
Valentina Svicher ◽  
Romina Salpini ◽  
Michele Pellegrino ◽  
Stefano Aquaro
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
People Living With Hiv ◽  
Viral Reservoirs ◽  
Virus Eradication ◽  
The Central Nervous System ◽  
Neurological Research ◽  
Living With Hiv ◽  
Hiv 1

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

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