Chet Raj Ojha

Interplay between Autophagy, Exosomes and HIV-1 Associated Neurological Disorders: New Insights for Diagnosis and Therapeutic Applications

The autophagy–lysosomal pathway mediates a degradative process critical in the maintenance of cellular homeostasis as well as the preservation of proper organelle function by selective removal of damaged proteins and organelles. In some situations, cells remove unwanted or damaged proteins and RNAs through the release to the extracellular environment of exosomes. Since exosomes can be transferred from one cell to another, secretion of unwanted material to the extracellular environment in exosomes may have an impact, which can be beneficial or detrimental, in neighboring cells. Exosome secretion is under the influence of the autophagic system, and stimulation of autophagy can inhibit exosomal release and vice versa. Neurons are particularly vulnerable to degeneration, especially as the brain ages, and studies indicate that imbalances in genes regulating autophagy are a common feature of many neurodegenerative diseases. Cognitive and motor disease associated with severe dementia and neuronal damage is well-documented in the brains of HIV-infected individuals. Neurodegeneration seen in the brain in HIV-1 infection is associated with dysregulation of neuronal autophagy. In this paradigm, we herein provide an overview on the role of autophagy in HIV-associated neurodegenerative disease, focusing particularly on the effect of autophagy modulation on exosomal release of HIV particles and how this interplay impacts HIV infection in the brain. Specific autophagy–regulating agents are being considered for therapeutic treatment and prevention of a broad range of human diseases. Various therapeutic strategies for modulating specific stages of autophagy and the current state of drug development for this purpose are also evaluated.

Overview on the Current Status of Zika Virus Pathogenesis and Animal Related Research

There is growing evidence that Zika virus (ZIKV) infection is linked with activation of Guillan-Barré syndrome (GBS) in adults infected with the virus and microcephaly in infants following maternal infection. With the recent outpour in publications by numerous research labs, the association between microcephaly in newborns and ZIKV has become very apparent in which large numbers of viral particles were found in the central nervous tissue of an electively aborted microcephalic ZIKV-infected fetus. However, the underlying related mechanisms remain poorly understood. Thus, development of ZIKV-infected animal models are urgently required. The need to develop drugs and vaccines of high efficacy along with efficient diagnostic tools for ZIKV treatment and management raised the demand for a very selective animal model for exploring ZIKV pathogenesis and related mechanisms. In this review, we describe recent advances in animal models developed for studying ZIKV pathogenesis and evaluating potential interventions against human infection, including during pregnancy. The current research directions and the scientific challenges ahead in developing effective vaccines and therapeutics are also discussed.

Impact of mass drug administration for elimination of lymphatic filariasis in Nepal

Background Lymphatic filariasis (LF) is a neglected tropical disease transmitted by mosquitoes. Nepal has implemented a national effort to eliminate LF by 2020 through mass drug administration (MDA) using diethylcarbamazine (DEC) and albendazole (ALB). We assessed the impact of MDAs on LF in selected districts of Nepal after the recommended six MDA rounds had been completed. Methodology and principal findings Baseline surveys were conducted in seven districts and mapping data were used as baseline in the other three districts before starting MDA in 2009. LF antigen (Ag) prevalence ranged from 1.06% to 20% among districts included in the baseline and mapping study. The number of people who received DEC and ALB were recorded during each MDA round and population-based cluster surveys were conducted at least once in each district during the life of the program. The reported MDA coverage in five districts was consistently at least 65%. Two districts achieved the targeted coverage in four out of five rounds and the rest three districts achieved the target only in the first round. A pre-transmission assessment survey (pre-TAS) was conducted in one sentinel site and at least one spot check site in each of the districts after five MDA rounds. In pre-TAS, all the sites of five districts (Pyuthan, Arghakhanchi, Kaski, Bhaktapur, and Kathmandu) and all but one spot check site of Lalitpur district had LF Ag < 2% (ranging from 0.0% to 1.99%). Transmission assessment survey (TAS) was conducted in six evaluation units (EUs) consisting of six districts qualified on pre-TAS. Though MDA coverage of 65% was not achieved in three districts (Kathmandu, Lalitpur and Bhaktapur), Nepal government in consultation with World Health Organization (WHO) decided to conduct TAS. All six EUs achieved the LF Ag threshold required to stop MDA in TAS, despite the low reported MDA coverage in those three districts. Conclusions Although Nepal has achieved significant progress towards LF elimination, five rounds of MDA were not sufficient to disrupt the transmission cycle in all districts, probably because of high baseline prevalence.

Importance of Autophagy in Mediating Human Immunodeficiency Virus (HIV) and Morphine-Induced Metabolic Dysfunction and Inflammation in Human Astrocytes

Under physiological conditions, the function of astrocytes in providing brain metabolic support is compromised under pathophysiological conditions caused by human immunodeficiency virus (HIV) and opioids. Herein, we examined the role of autophagy, a lysosomal degradation pathway important for cellular homeostasis and survival, as a potential regulatory mechanism during pathophysiological conditions in primary human astrocytes. Blocking autophagy with small interfering RNA (siRNA) targeting BECN1, but not the Autophagy-related 5 (ATG5) gene, caused a significant decrease in HIV and morphine-induced intracellular calcium release. On the contrary, inducing autophagy pharmacologically with rapamycin further enhanced calcium release and significantly reverted HIV and morphine-decreased glutamate uptake. Furthermore, siBeclin1 caused an increase in HIV-induced nitric oxide (NO) release, while viral-induced NO in astrocytes exposed to rapamycin was decreased. HIV replication was significantly attenuated in astrocytes transfected with siRNA while significantly induced in astrocytes exposed to rapamycin. Silencing with siBeclin1, but not siATG5, caused a significant decrease in HIV and morphine-induced interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) release, while secretion of IL-8 was significantly induced with rapamycin. Mechanistically, the effects of siBeclin1 in decreasing HIV-induced calcium release, viral replication, and viral-induced cytokine secretion were associated with a decrease in activation of the nuclear factor kappa B (NF-κB) pathway.

Virological and Immunological Status of the People Living with HIV/AIDS Undergoing ART Treatment in Nepal

Antiretroviral therapy (ART) has increased the life span of the people living with HIV (PLHIV), but their virological and immunological outcomes are not well documented in Nepal. The study was conducted at a tertiary care center including 826 HIV-1 seropositive individuals undergoing ART for at least six months. Plasma viral load (HIV-1 RNA) was detected by Real Time PCR and CD4+ T-lymphocyte (CD4+) counts were estimated by flow cytometry. The mean CD4+ count of patients was 501 (95% CI = 325–579) cells/cumm, but about 35% of patients had CD4+ T cell counts below 350 cells/cumm. With increasing age, average CD4+ count was found to be decreasing (p = 0.005). Of the total cases, 82 (9.92%) were found to have virological failure (viral load: >1000 copies/ml). Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV), the frequently used ART regimen in Nepal, showed virological failure in 11.34% and immunological failure in 37.17% of patients. Virological failure rate was higher among children < 15 years (14.5%) (p = 0.03); however, no association was observed between ART outcomes and gender or route of transmission. The study suggests there are still some chances of virological and immunological failures despite the success of highly active ART (HAART).

Author Correction: Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Signaling pathways and therapeutic perspectives related to environmental factors associated with multiple sclerosis: XXXX

Multiple sclerosis (MS) is an immune‐mediated demyelinating disorder of unknown etiology. Both genetic‐susceptibility and environment exposures, including vitamin D deficiency, Epstein‐Barr viral and Herpesvirus (HHV‐6) infections are strongly implicated in the activation of T cells and MS‐pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non‐pathogenic factors on the impact of MS.

Complementary Mechanisms Potentially Involved in the Pathology of Zika Virus

Zika virus (ZIKV) has emerged as a global health threat due to its neuro-teratogenic effect and wide range of transmission routes. Most recently, ZIKV infection has been linked with both autoimmune disorders in adults and neurodevelopmental disorders in newborns. Researchers are exploring potential cellular and molecular mechanisms underlying the neuro-teratogenicity and related consequences by using various in vitro cell culture methods and in vivo animal models. Though some of the putative viral entry receptors have been identified for ZIKV entry into the target cells, the exact mechanism of ZIKV entry or induced pathology are still not clear. Some of the important host cellular pathways including the toll-like receptor (TLR), autophagy, apoptosis and unfolded protein response (UPR) pathways are considered potential mechanism(s) for ZIKV induced neuroinflammation and for neurodevelopmental disorders. Since there is still a dire need for efficient treatment and vaccine to prevent ZIKV mediated disorders, a better understanding of the interaction between virus and host cellular pathways could pave the way for development of targeted therapeutic intervention. In this review, we are focusing on the recent advances and current knowledge regarding the interaction of ZIKV with abovementioned pathways so as to provide basic understanding to execute further research that could aid in the development of novel therapeutic strategy.