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Breakthrough news from 2002 HIV Conference in Barcelona, Spain


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

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

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

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

Mechanism of resiliency shown by HIV-positive “long-term non-progressors”

About 1-2% of people infected with HIV stop the infection from progressing into AIDS for as long as 20 years and counting. A research team led by Drs. David Ho and Linqi Zhang of the Aaron Diamond AIDS Research Center in New York City thought they know why, at least partially, and described their findings in Science (epub ahead of print, Sept. 26, 2002).

The scientists discovered that three protein molecules, α-defensins 1, 2, and 3, played the anti-HIV role and prevented these HIV-carriers from progressing to AIDS. CD8 T cells and neutrophils produced the three defensins. It is unclear as ... Read more

A novel therapeutic HIV/AIDS vaccine to be tested in humans

Scientists and clinicians from Italy and the U.S. are going to begin human trials of a therapeutic HIV/AIDS vaccine combined with the anti-HIV drugs.

This vaccine is a novel DNA-based vaccine that contains most of the HIV proteins. “In this way we guarantee a wide spectrum of action, and do not target a specific protein,” Dr. Franco Lori told Reuters. Dr. Juliana Lisiewicz, Dr. Lori’s colleague and co-founder of the Research Institute for Genetic and Human Therapy based in both Washington, DC and Pavia, Italy, presented the details of the study at the Barcelona HIV Conference.

The vaccine, which was applied onto ... Read more

HLA's key role in T cell-mediated cytotoxicity confers individualized defense against HIV

It is well known that HIV can escape from antibody responses, sometimes entirely, by mutating the envelope proteins. But whether HIV can escape from cytotoxic T cell (CTL) responses has not been firmly established. In addition, individuals’ HLA (human leukocyte antigen) genes differ and the impact that the distinct HLA types impose on HIV’s mutation and evolution at the population level remains largely unknown.

HLA class I molecules, i.e., the human major histocompatibility complex (MHC) class I molecules, impose restrictions on the epitopes CTLs recognize via their T cell receptors. CTLs recognize antigenic epitopes (antigenic determinants) in complex with HLA class ... Read more

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