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Breakthrough news from 2002 HIV Conference in Barcelona, Spain

The CRISPR/Cas9 Genome Editing Methodology as a Weapon Against Human Viruses

Abstract: Viruses are a therapeutic challenge since their life cycles occur within the host cells and often utilize cellular proteins and hence it is harder to identify therapeutic targets compared to bacteria, which have their own cellular metabolism that is quite different from the host and often present unique targets such as enzymes, etc. Nevertheless, viral proteins may present useful targets for therapy, e.g., small molecule inhibitors of viral polymerases, or prevention, e.g., viral coat proteins for vaccination. However, some viruses may enter an inactive state of persistence or latency where no or very few viral proteins are produced. Thus, methodologies that are specifically able to target nucleotide sequences within viral genomes would be a useful addition to the antiviral armamentarium. Such a methodology is the clustered regulatory interspaced short palindromic repeat (CRISPR)-associated 9 (Cas9) system, which is effective, specific, and versatile and provides unprecedented control over genome editing. Here, we will discuss how CRISPR/Cas9 has been used against human viruses and future prospects for novel therapeutic approaches. ... Read more

The Contribution of Non-human Primate Models to the Development of Human Vaccines

Abstract: The non-human primates (NHPs) model in biomedical research has contributed to the study of human infectious, autoimmune, oncogenic, and neurological diseases. This review focuses on the importance of NHP models in vaccine development for tuberculosis, pertussis, Dengue, group A streptococcus (Streptococcus pyogenes) infection, HIV infection, and certain diseases in the elderly (influenza, for example). From understanding disease pathogenesis and mechanisms of protection, to assessing vaccine safety and efficacy, we discuss selected cases where the importance of the use of NHP models is highlighted. ... Read more

Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

A Feedback Regulatory Pathway Between LDL and Alpha 1 Proteinase Inhibitor in Chronic Inflammation and Infection

Abstract: Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport. ... Read more

Point-of-Care Diagnostics for HIV and Tuberculosis: Landscape, Pipeline, and Unmet Needs

Abstract: Early diagnosis and rapid initiation of treatment remains a key strategy to control both HIV and tuberculosis (TB). However, HIV and TB control programs have had completely contrasting successes, especially with the development and deployment of point-of-care (POC) diagnostics. Clinicians, researchers, and public health staff who work at the frontlines of HIV care and control have had access to an outstanding array of POC diagnostics at their disposal, including those used for screening, initial diagnosis, staging, treatment monitoring, and early infant diagnosis. The field has also advanced to consider over-the-counter, self-testing options for HIV and the use of multiplexed platforms that allow for simultaneous detection of infections associated with HIV. In sharp contrast to HIV, suboptimal and delayed diagnosis of TB has perpetuated the epidemic in many high-burden countries. Although the TB diagnostics pipeline is substantially better today than it was even five years ago, absence of a simple POC test continues to be a gaping hole in the pipeline. In this review, we compare the POC diagnostics landscape and pipelines for these two important infectious diseases, and highlight gaps and unmet needs. ... Read more

The Pathogenesis of Progressive Multifocal Leukoencephalopathy

Abstract: Interest in pathogenesis of progressive multifocal leukoencephalopathy (PML) followed the observation of the high risk for the disease in HIV infection and the recent observation of an association with a variety of newer therapeutic modalities, e.g., natalizumab, an α4β1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody. Any hypothesis of PML pathogenesis must account for a number of facts. Firstly, the causative agent JC virus is ubiquitously present, yet only a vanishingly small number of infected persons develop the disease. Secondly, disorders of cell-mediated immunity increase the risk of the disease, particularly HIV infection. Impaired innate immunity is not a risk for PML, and antibodies against JC virus are not protective. Thirdly, a latent period of several months appears necessary following the administration of natalizumab and efalizumab before PML develops. Fourthly, restoration of the immune system can arrest the PML. It is possible that infection with JC virus occurs with a form of the virus shed in the urine of as many as 40% of all adults and present in sewage worldwide. Once acquired, perhaps through an oropharyngeal route, it may replicate and disseminate. A neurotropic form of JC virus that replicates in glial tissues causes PML when immunosurveillance is impaired. There are many unanswered questions with respect to PML pathogenesis. How is virus acquired? What tissues are infected? What is the origin of the neurotropic form? When does virus enter brain? What is the role of central nervous system immunosurveillance? The lack of an animal model has made answering these questions challenging. ... Read more

Drug Profile: Emtriva

Other Names: emtricitabine.

Maker: Gilead Sciences, Inc.

Disease Treated: HIV-1 infection in adults.

Approval Status: Approved by the U.S. FDA on July 2, 2003.

Chemical/Biological Nature: EMTRIVA is a synthetic cytosine analogue. It is the (-) enantiomer of a thio analogue of cytidine. It has a fluorine in the 5-position, distinguishing it from other cytidine analogues. It has a molecular weight of 247.24 daltons.

Administration: 200 mg of EMTRIVA (one capsule) is taken orally with or without food.

Mechanism of Disease: HIV-1 infection leads to AIDS and other immunodeficiency related complications.

Mechanism of Drug ... Read more

New Drug Shown Effective in Blocking HIV Entry

A research team led by Dr. Pin-Fang Lin at Bristol-Myers Squibb, Wallingford, CT has discovered a small molecule compound that can block HIV-1’s entrance into cells (Lin, P.-F. et al., PNAS 100:11013-11018, Sep. 16, 2003). Most of the drugs currently available for treating HIV infection affect replication of viral nucleic acids or the synthesis of viral proteins.

The compound, BMS-378806, binds to the envelope protein, gp120, of HIV-1 and inhibits interactions between gp120 and the CD4 receptor molecule on CD4+ T cells, a necessary step for HIV-1 to infect host cells.

The inhibitory effect of compound BMS-378806 is selective for HIV-1. It ... Read more

Dru Profile: Fuzeon

Other Names: Enfuvirtide, T-20.

Makers: Trimeris and Roche.

Disease Treated: HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

Approval Status: FUZEON was approved by the U.S. FDA on March 13, 2003.

Chemical/Biological Nature: FUZEON is a synthetic, linear peptide comprised of 36 naturally occurring amino acids. Its N-terminus is acetylated and its C-terminus is a carboxamide. It has a molecular weight of 4,492 daltons.

Administration: 90 milligrams of FUZEON in a 1ml volume is administered by subcutaneous injection twice a day.

Mechanism of Action: FUZEON is the ... Read more

Biotechnology/Pharmaceutical Industry News: SARS gene patents, Isis antisense drug, and drug approvals

Institutions Apply Patents on SARS Genes to Make Them “Publicly Accessible”

Scientists and their institutions rush to file for their discoveries in SARS research. Canada’s British Columbia Cancer Agency Genome Sciences Centre, whose scientists led by Marco Marra first reported the SARS genome, filed patents in U.S. claiming ownership of all the genes and their applications of SARS virus. U.S. CDC, whose scientists co-discovered the virus and sequenced its genome, also submitted patent applications on all its findings. University of Hong Kong, whose scientists led by Malik Peiris were among the first to discover the SARS virus, filed patent applications on ... Read more

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