Potent dual block to HIV-1 infection using lentiviral vectors expressing fusion inhibitor peptide mC46- and Vif-resistant APOBEC3G.

Gene therapy strategies that effectively inhibit HIV-1 replication are needed to reduce the requirement for lifelong antiviral therapy and potentially achieve a functional cure. We previously designed self-activating lentiviral vectors that efficiently delivered and expressed a Vif-resistant mutant of APOBEC3G (A3G-D128K) to T cells, which potently inhibited HIV-1 replication and spread with no detectable virus. Here, we developed vectors that express A3G-D128K, membrane-associated fusion inhibitor peptide mC46, and O-methylguanine-DNA-methyltransferase (MGMT) selectable marker for selection of transduced CD34 hematopoietic stem and progenitor cells.

Hemagglutinin destabilization in H3N2 vaccine reference viruses skews antigenicity and prevents airborne transmission in ferrets.

During influenza virus entry, the hemagglutinin (HA) protein binds receptors and causes membrane fusion after endosomal acid activation. To improve vaccine efficiency and pandemic risk assessment for currently-dominant H3N2 influenza viruses, we investigated HA stability of 6 vaccine reference viruses and 42 circulating viruses. Recent vaccine reference viruses had destabilized HA proteins due to egg-adaptive mutation HA1-L194P.

Swine H1N1 Influenza Virus Variants with Enhanced Polymerase Activity and HA Stability Promote Airborne Transmission in Ferrets.

Understanding how animal influenza A viruses (IAVs) acquire airborne transmissibility in humans and ferrets is needed to prepare for and respond to pandemics. Here, we investigated in ferrets the replication and transmission of swine H1N1 isolates P4 and G15, whose majority population had decreased polymerase activity and poor hemagglutinin (HA) stability, respectively. For both isolates, a minor variant was selected and transmitted in ferrets.

Relationship between hemagglutinin stability and influenza virus persistence after exposure to low pH or supraphysiological heating.

The hemagglutinin (HA) surface glycoprotein is triggered by endosomal low pH to cause membrane fusion during influenza A virus (IAV) entry yet must remain sufficiently stable to avoid premature activation during virion transit between cells and hosts. HA activation pH and/or virion inactivation pH values less than pH 5.6 are thought to be required for IAV airborne transmissibility and human pandemic potential.

Reduced-Beclin1-Expressing Mice Infected with Zika-R103451 and Viral-Associated Pathology during Pregnancy.

Here, we used a mouse model with defective autophagy to further decipher the role of Beclin1 in the infection and disease of Zika virus (ZIKV)-R103451. Hemizygous () and wild-type () pregnant mice were transiently immunocompromised using the anti-interferon alpha/beta receptor subunit 1 monoclonal antibody MAR1-5A3. Despite a low mortality rate among the infected dams, 25% of offspring were smaller in size and had smaller, underdeveloped brains.

Morphine counteracts the antiviral effect of antiretroviral drugs and causes upregulation of p62/SQSTM1 and histone-modifying enzymes in HIV-infected astrocytes.

Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure.

Toll-like receptor 3 regulates Zika virus infection and associated host inflammatory response in primary human astrocytes.

The connection between Zika virus (ZIKV) and neurodevelopmental defects is widely recognized, although the mechanisms underlying the infectivity and pathology in primary human glial cells are poorly understood. Here we show that three isolated strains of ZIKV, an African strain MR766 (Uganda) and two closely related Asian strains R103451 (Honduras) and PRVABC59 (Puerto Rico) productively infect primary human astrocytes, although Asian strains showed a higher infectivity rate and increased cell death when compared to the African strain. Inhibition of AXL receptor significantly attenuated viral entry of MR766 and PRVABC59 and to a lesser extend R103451, suggesting an important role of TAM receptors in ZIKV cell entry, irrespective of lineage.

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 cell culture methods and animal models.

Critical Role of Beclin1 in HIV Tat and Morphine-Induced Inflammation and Calcium Release in Glial Cells from Autophagy Deficient Mouse.

We previously showed that autophagy is an important component in human immunodeficiency virus (HIV) replication and in the combined morphine-induced neuroinflammation in human astrocytes and microglia. Here we further studied the consequences of autophagy using glial cells of mice partially lacking the essential autophagy gene Atg6 (Beclin1) exposed to HIV Tat and morphine. Tat is known to cause an inflammatory response, increase calcium release, and possibly interact with autophagy pathway proteins.

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.

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 , but not the Autophagy-related 5 () gene, caused a significant decrease in HIV and morphine-induced intracellular calcium release.

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.

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.

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

We previously reported that activation of the host autophagic protein, Beclin1, by HIV-1 infection represents an essential mechanism in controlling HIV replication and viral-induced inflammatory responses in microglial cells. Existing antiretroviral therapeutic approaches have been limited in their ability to cross the blood-brain barrier effectively and recognize and selectively eliminate persistent HIV-infected brain reservoirs. In the present study and for the first time, the bio-distribution and efficacy of noninvasive intranasal delivery of small interfering RNA (siRNA) against the Beclin1 gene using the cationic linear polyethylenimines (PEI) as a gene carrier was investigated in adult mouse brain.

Mammalian microRNA: an important modulator of host-pathogen interactions in human viral infections.

MicroRNAs (miRNAs), which are small non-coding RNAs expressed by almost all metazoans, have key roles in the regulation of cell differentiation, organism development and gene expression. Thousands of miRNAs regulating approximately 60 % of the total human genome have been identified. They regulate genetic expression either by direct cleavage or by translational repression of the target mRNAs recognized through partial complementary base pairing.

Evaluation of SD Bioline HIV/syphilis Duo rapid test kits in Nepal.

Background: Accurate and prompt diagnosis of HIV and syphilis simultaneously has reinforcing effect on their control program because of their prevalent co-infection. Availability of a simple user-friendly two-pronged and affordable detection tools brings down the cost of health care. They are important in the antenatal clinics, with added opportunity for intervention and prevention of mother to child transmission.

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.

Lower respiratory tract infections among HIV positive and control group in Nepal.

Lower respiratory tract infections (LRTIs) are the most frequent respiratory diseases among HIV infected patients and are frequently the first clinical manifestations of the HIV infections. LRTIs are common not only among the HIV seropositive cases but also the commonest domiciliary and nosocomial infections among the general population. The present study was carried out to determine the comparative prevalence of common bacterial and fungal organism among the HIV positive and control population.