Novel nanoformulation to mitigate co-effects of drugs of abuse and HIV-1 infection: towards the treatment of NeuroAIDS.

Drug abuse (e.g., methamphetamine-Meth or cocaine-Coc) is one of the major risk factors for becoming infected with HIV-1, and studies show that in combination, drug abuse and HIV-1 lead to significantly greater damage to CNS.

Gene-expression reversal of lncRNAs and associated mRNAs expression in active vs latent HIV infection.

Interplay between lncRNAs and mRNAs is rapidly emerging as a key epigenetic mechanism in controlling various cell functions. HIV can actively infect and/or can persist latently for years by manipulating host epigenetics; however, its molecular essence remains undiscovered in entirety. Here for the first time, we delineate the influence of HIV on global lncRNAs expression in monocytic cells lines.

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection.

Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood-brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity.

Effect of Cocaine on HIV Infection and Inflammasome Gene Expression Profile in HIV Infected Macrophages.

We have observed significantly increased HIV infection in HIV infected macrophages in the presence of cocaine that could be due to the downregulation of BST2 restriction factor in these cells. In human inflammasome PCR array, among different involved in inflammasome formation, in HIV infected macrophages in the presence of cocaine, we have observed significant upregulation of NLRP3, AIM2 genes and downstream genes IL-1β and PTGS2. Whereas negative regulatory gene MEFV was upregulated, CD40LG and PYDC1 were significantly downregulated.

Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis.

Therapeutical Neurotargeting via Magnetic Nanocarrier: Implications to Opiate-Induced Neuropathogenesis and NeuroAIDS.

Magnetite (Fe3O4) is the most commonly and extensively explored magnetic nanoparticles (MNPs) for drug-targeting and imaging in the field of biomedicine. Nevertheless, its potential application as safe and effective drug-carrier for CNS (Central Nervous System) anomalies is very limited. Previous studies have shown an entangled epidemic of opioid use and HIV infection and increased neuropathogenesis.

Interaction of drugs of abuse and microRNA with HIV: a brief review.

MicroRNAs (miRNAs), the post-transcriptional regulators of gene expression, play key roles in modulating many cellular processes. The changes in the expression profiles of several specific miRNAs affect the interactions between miRNA and their targets in various illnesses, including addiction, HIV, cancer etc. The presence of anti-HIV-1 microRNAs (which regulate the level of infectivity of HIV-1) have been validated in the cells which are the primary targets of HIV infection.

Preparation and characterization of anti-HIV nanodrug targeted to microfold cell of gut-associated lymphoid tissue.

The human immunodeficiency virus 1 (HIV-1) still remains one of the leading life-threatening diseases in the world. The introduction of highly active antiretroviral therapy has significantly reduced disease morbidity and mortality. However, most of the drugs have variable penetrance into viral reservoir sites, including gut-associated lymphoid tissue (GALT).

Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1)-facilitated HIV restriction in astrocytes is regulated by miRNA-181a.

Background: Although highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality in HIV patients, virus continues to reside in the central nervous system (CNS) reservoir. Hence, a complete eradication of virus remains a challenge. HIV productively infects microglia/macrophages, but astrocytes are generally restricted to HIV infection.

Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder.

Background: HIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported.

Enhanced blood-brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation.

The blood-brain barrier (BBB) is considered as the primary impediment barrier for most drugs. Delivering therapeutic agents to the brain is still a big challenge to date. In our study, a dual mechanism, receptor mediation combined with external non-invasive magnetic force, was incorporated into ferrous magnet-based liposomes for BBB transmigration enhancement.

Towards nanomedicines for neuroAIDS.

Although highly active antiretroviral therapy (HAART) has resulted in remarkable decline in the morbidity and mortality in AIDS patients, controlling HIV infections still remain a global health priority. HIV access to the CNS serves as the natural viral preserve because most antiretroviral (ARV) drugs possess inadequate or zero delivery across the brain barriers. Thus, development of target-specific, effective, safe, and controllable drug-delivery approach is an important health priority for global elimination of AIDS progression.

Cocaine enhances HIV-1 infectivity in monocyte derived dendritic cells by suppressing microRNA-155.

Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation.

Immune activation is associated with increased gut microbial translocation in treatment-naive, HIV-infected children in a resource-limited setting.

Background: Gut damage resulting in microbial translocation (MT) is considered a major cause of immune activation (IA) in HIV infection, but data in children are limited, particularly in the absence of antiretroviral therapy.

Methods: Sixty perinatally HIV-infected, antiretroviral therapy-naive children, aged 2-12 years, were evaluated for plasma levels of lipopolysaccharide, DNA sequences encoding bacterial 16 second ribosomal DNA (16S rDNA) and soluble CD14 concurrently with markers of CD4 and CD8 T-cell IA and immune exhaustion (IE), CD4 counts, and plasma viral load. At study entry, participants were classified into immune categories (ICs): IC1 (CD4% > 25), IC2 (CD4% 15-25), and IC3 (CD4% < 15).

Defective dendritic cell response to Toll-like receptor 7/8 agonists in perinatally HIV-infected children.

Understanding the defects in innate immunity associated with perinatal HIV infection is a prerequisite for effective antiretroviral treatment. We therefore compared the innate immune response [dendritic cell (DC) phenotype and function] in peripheral blood by flow cytometry at baseline and 12 months in HIV-infected children to determine the defect associated with perinatal HIV infection. As compared with controls, patients had decreased numbers of total DCs including plasmacytoid (p)DCs and myeloid (m)DCs and impaired function based on induction of maturation markers (CD83, CD80, CCR7) and cytokines tumor necrosis factor-α and interferon-α (exclusive to pDC) upon stimulation with the TLR7/8 agonist Resiquimod.

Targeted brain derived neurotropic factors (BDNF) delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: an in-vitro study.

Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element-binding (CREB) expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF), which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction.

Inhibitors of HIV-1 entry and integration: recent developments and impact on treatment.

Advances in the drug development against HIV-1 have lead to the identification of new compounds which could be used to target cellular entry and nuclear integration of virus in addition to drugs that commonly target reverse transcriptase and protease. These additional targets have added a new dimension to fight against HIV. Cellular entry of HIV is a multistep procedure involving a range of cellular and molecular interactions between virus envelope protein and receptors expressed on the surface of the target cells, thus providing many opportunities to block infection.

Silicone nanoparticles do not induce immune responses by naïve human peripheral blood mononuclear cells: implications in breast implants.

Background: Several studies have reported adverse immunological effects of silicone due to their ability to induce proinflammatory molecules, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In recent years, use of nanoparticles has been under fast development for therapeutic drug targeting, diagnostic imaging, and immune response in various fields of nanomedicine. The authors hypothesize that immune responses induced by in vivo use of silicone materials can be reduced or eliminated by the use of nanosilicone.

Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder.

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV.

Increased gut microbial translocation in HIV-infected children persists in virologic responders and virologic failures after antiretroviral therapy.

Background: Gut microbial translocation (MT) is considered a major cause of immune activation (IA) and failure of immune reconstitution in HIV infection. This study investigated the relationship of virus replication, IA, CD4 counts and MT in HIV-infected children.

Methods: Lipopolysaccharide, bacterial 16S ribosomal DNA (16SrDNA) and soluble CD14 (sCD14) levels were determined in prospectively collected, stored plasma samples from the Pediatric AIDS Clinical Trials Group Protocol P338, a 48-week study initiated in 1997 to compare efficacy of dual nucleosides with a ritonavir-containing regimen.

MicroRNA: implications in HIV, a brief overview.

MicroRNAs (miRNAs) are 20-22 nucleotide length noncoding RNA molecules that represent key regulators of many normal cellular functions. miRNAs undergo two processing steps which transform a long primary transcript into the mature miRNA. Available literatures demonstrate the association between alterations in the expression of miRNAs and the progression of numerous human disorders.

Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients.

Background: Mechanisms underlying the failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood.

Objective: To investigate innate immune factors regulating B-cell function in HIV-infected persons and to correlate them with serologic responses to H1N1/09 vaccine.

Methods: We evaluated immunologic characteristics of 17 HIV-infected patients and 8 healthy controls (HCs) at 0, 7, and 28 days (designated T0, T1, and T2) following a single 15-μg dose of nonadjuvanted H1N1/09 influenza vaccine by using flow cytometry, ELISpot, and ELISA.

Upregulation of IL-21 receptor on B cells and IL-21 secretion distinguishes novel 2009 H1N1 vaccine responders from nonresponders among HIV-infected persons on combination antiretroviral therapy.

Mechanisms underlying failure of novel 2009 H1N1 influenza vaccine-induced Ab responses in HIV-infected persons are poorly understood. This study prospectively evaluated 16 HIV-infected patients on combination antiretroviral therapy and eight healthy controls (HC) who received a single 15 μg dose of nonadjuvanted novel 2009 H1N1 influenza vaccine during the 2009 H1N1 epidemic. Peripheral blood was collected at baseline (T0) and at 7 d (T1) and 28 d (T2) postvaccination for evaluation of immune responses.

Optimization of storage and shipment of cryopreserved peripheral blood mononuclear cells from HIV-infected and uninfected individuals for ELISPOT assays.

Functional immunologic assays using cryopreserved peripheral blood mononuclear cells (PBMC) are influenced by blood processing, storage and shipment. The objective of this study was to compare the viability, recovery and ELISPOT results of PBMC stored and shipped in liquid nitrogen (LN/LN) or stored in LN and shipped on dry ice (LN/DI) or stored at -70°C for 3 to 12 weeks and shipped on DI (70/DI 3 to 12); and to assess the effect of donor HIV infection status on the interaction between storage/shipment and the outcome measures. PBMC from 12 HIV-infected and 12 uninfected donors showed that LN/LN conferred higher viability and recovery than LN/DI or 70/DI 3, 6, 9 or 12.