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HIV / AIDS

HIV / AIDS

HIV / AIDS

Description
 HIV - the Human Immunodeficiency Virus - is a virus that kills your body"s "CD4 cells." CD4 cells (also called T-helper cells) help your body fight off infection and disease. AIDS - the Acquired Immunodeficiency Syndrome - is a disease you get when HIV destroys your body"s immune system. Normally, your immune system helps you fight off illness. When your immune system fails you can become very sick and can die.

Who is at Risk?
 Anyone can get HIV. HIV can be passed from person to person if someone with HIV infection has unprotected sex - sex without a condom - with someone who has HIV, or shares drug injection needles with another person. If a couple have anal intercourse the risk of infection is greater than with vaginal intercourse. HIV also can be passed from a mother to her baby when she is pregnant, when she delivers the baby, or if she breast-feeds her baby. Some health-care workers have become infected with HIV by being stuck with needles containing HIV-infected blood.

Source: Centers for Disease Control and Prevention, AVERT

Hope for AIDS Vaccine Rises after TSRI Scientists Discover Antibody
 The search for an AIDS vaccine has taken a step forward with TSRI scientists determining the structure of an antibody that can neutralize the virus. The antibody, called 2G12, was first isolated from an AIDS patient a decade ago, and binds to HIV to prevent it from infecting human cells. TSRI professors Ian A. Wilson, D. Phil., and Dennis R. Burton, Ph.D. found an unusual configuration of the 2G12 antibody that had never been seen before. This discovery provides the opportunity to design new vaccine candidates to stimulate the body to make 2G12-like antibodies and destroy HIV before it can establish an infection. HIV has generally proven to be remarkably resistant to neutralization by antibodies so that detailed understanding of how such an antibody works is considered a significant advance.

HIV/AIDS affects about 42 million people worldwide and results in more than 4 million deaths annually. It is generally accepted that the best way to halt the pandemic is through the development of an effective vaccine. The current work will likely take several years to come to fruition but raises hope that such a vaccine may be feasible.

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A Simple Strategy for Blocking HIV Transmission Proves Effective in Pre-clinical Trials
 An international team of researchers recently announced the promising results of a preclinical study on a chemical called PSC-RANTES to block male-to-female sexual transmission of human immunodeficiency virus (HIV). In a recent issue of Science, the team reports how a topical microbicide with a high enough concentration of PSC-RANTES prevented HIV transmission to female rhesus macaques that were challenged with high doses of a modified form of HIV. Donald Mosier, M.D., Ph.D., a professor of immunology at TSRI is a member of the research team. PSC-RANTES works by targeting a protein in the body called C-C chemokine receptor 5 (CCR5) - the receptor on human cells to which HIV binds. HIV needs CCR5 in order to achieve infection of any given cell.

In order for the virus to be transmitted during heterosexual intercourse - the number one way the virus is spread in many parts of the world - the virus must attach to CCR5 in cells within the vaginal mucosa. When these cells are protected with PSC-RANTES, however, the virus cannot attach to them. To date, more than 20 million people have died from HIV. In the United States, 40,000 people are infected with HIV each year - more than one person every 15 minutes. If, in the future, a topical mibrobicide containing PSC-RANTES proves to be effective in humans in the context of clinical trials, it would be a boon to worldwide efforts to contain and curtail the global HIV epidemic because such a microbicide would be broadly efficacious against the many HIV strains that exist in the world. Virtually all HIV strains use the CCR5 receptor. Completely blocking CCR5 would block 99 percent of HIV transmission worldwide.

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Attachment Receptors and Hot Spots For HIV Infection
 Attachment receptors have been shown in recent years to enhance the entry of HIV into cells and can have a profound impact on HIV pathogenesis. TSRI Associate Professor Philippe Gallay, Ph.D. has been studying the attachment of the virus to cells and looks toward using these host proteins as a guide for drug design. Gallay is particularly interested in a class of attachment receptors called heparin sulfate proteoglycans, which are proteins expressed on the surface of human cells that bear sugar chains known as heparin sulfates. Heparan sulfate proteoglycans are important players in the pathology of HIV because when their sugar chains are removed, the virus cannot infect a main in vivo cell target, the macrophage. A main goal of Gallay"s laboratory is to understand how and why HIV requires these receptors to successfully enter into and infect human cells.

Gallay and members of his laboratory have also recently published a paper describing the primary importance of a member of the heparin sulfate proteoglycan family called syndecan. They found that syndecan via its sugar chains captures HIV onto the surface of endothelial cells. Interestingly, HIV captured by syndecan retains its infectivity for several weeks, whereas uncaptured virus loses its infectivity already after a single day. Importantly, viruses captured by syndecan on the endothelium can infect cells that circulate in the bloodstream. To place this finding in its proper context, the total surface area of the endothelial lining of the vasculature is estimated to be at least 600 square meters; this suggests that the endothelium may represent an abundant, if not the major HIV reservoir in the body. This mode of transmission provided by syndecans richly expressed on the capillaries, where the velocity of the blood flow is tranquil, may also represent hot spots for HIV replication.

Gallay is attempting to generate drugs that prevent the interaction between HIV and the heparin sulfate proteoglycan receptor, hoping to identify novel anti-viral agents to combat AIDS.

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A Vaccine Factory Inside Each Cell
 TSRI Associate Professor Bruce Torbett, Ph.D. is developing and testing a gene delivery technique that may someday be used to deliver genes into cells, providing a high level of protection against HIV or cancer. The technique involves treating hematopoietic stem cells (HSC). These are the pluripotent granddaddy of all blood cells, located in the bone marrow, that develop into lymphocytes, platelets, erythrocytes, and red blood cells. The basic idea is to give these cells genes that will allow them to resist an HIV infection, then implant them into tissue where they can freely grow, develop, and resist HIV infection. The same approach may be used to inhibit cells from becoming cancerous.

Using a crippled version of HIV as a gene delivery vector/vehicle that can no longer spread in human cells and cause disease, Torbett"s group has shown that human stem cells can be given the gene for green fluorescent protein from jelly fish, and all cells developed from these stem cells express the protein. One vector would take out the patient"s bone marrow, remove the stem cells and infect them with the intrabody gene using the HIV vector, then return the cells to the patient. The stem cells would then develop into dendritic cells and blood cells, including cells that HIV infects, such as macrophages and T-cells. These progeny cells, then, would be effectively resistant to HIV. Having a selective advantage over the wild type cells, they would repopulate the body. The intrabodies would then do what antiretroviral drugs have done for years: keep the virus in check. The idea is to keep the viral level low, protect the T-cells, and allow the immune system to do its job and control the infection. This approach could one day be used as a vaccine to protect people from being infected. Inserting HIV intrabody genes is only one of several applications of Torbett"s work to control cellular function. Another promising application is the treatment of a certain type of cancer called acute myeloid leukemia (AML), a common form of acute leukemia in adults.

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AIDS and the Brain
 HIV, like all lentiviruses, is a neurotropic virus and infects cells of the central nervous system (CNS) early in the course of infection. As in other tissues in the body, HIV injures or kills these cells and spreads to infect others. Infected macrophages and microglial cells may be more active than non-infected ones and may overproduce chemokines and cytokines as part of a natural immune response. These molecules may disrupt the function of the other, third-party cells - such as neurons - that get caught in the crossfire. HIV has a deleterious effect on the brain that can lead to subtle and pronounced complications and these complications may become more prevalent even though we are finding new ways of treating the virus elsewhere in the body. About one quarter to one third of all AIDS patients suffer from some form of CNS disorder in the course of their infection. TSRI Professor Howard Fox, M.D., Ph.D., and his colleagues are seeking to discover why these disorders do not disappear with therapy.

The HIV virus migrates to the lymphatic tissues and to the brain via white blood cells. These infected cells become activated and secrete nitric oxide, increasing blood-brain barrier permeability and allowing them through. Macrophages and microglia in the brain and throughout the cerebrospinal fluid are then infected. HIV may long remain dormant in these cells after it inserts itself into their genome. Basic hypothalamic functions are affected throughout the course of an infection and cognitive responses may become delayed. Fox and his colleagues are exploring a number of new possibilities for addressing the inability to treat HIV-infected brains, including the study of brain-penetrating antiretrovirals. In order to further research into the cause, prevention, and treatment of HIV infection in the brain, Fox has organized the Scripps NeuroAIDS Preclinical Studies center, funded through a $10 million grant from the National Institutes of Mental Health. Center scientists will develop novel in vitro molecular and cellular assays and new molecules to test. They will correlate all possible therapeutics and cognitive and behavioral markers in animal models, measuring the effects of rampant chemokine and cytokine production.

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Inhibitor Effective against Broad Range of HIV Proteases
 For the last several years, the greatest weapons doctors have had for treating HIV infections have been antiretroviral drugs that tightly bind specific enzymes necessary for replication and infection - the protease and reverse transcriptase inhibitors, for instance. Highly active antiretroviral therapy (HAART), which combines both classes of drugs together into one treatment, has proven particularly effective, as demonstrated by the decline in AIDS mortality in the United States in the last few years. However, the last few years have also witnessed the rise of drug-resistant strains of HIV in patients on HAART. Because HIV"s genome is short and composed only of the essentials it needs for replication and infectivity, it lacks the luxury of a proofreading mechanism - which mammals, for instance, use to ensure fidelity in cell replication and division. The fidelity of HIV is so low that it makes an average of one mistake every time it replicates. And because it replicates so much in an infected host, mutant variants quickly arise.

These variants are often resistant to HAART drugs but are still able to replicate. The drugs lose and the infection wins. As a result, more and more inhibitors have been designed in recent years, alongside a plethora of combinations and dosage schedules that aim to maximize the effectiveness of the drug. TSRI Professor Chi-Huey Wong, Ph.D., has designed an inhibitor with broad activity rather than specific. This inhibitor, which targets the viral protease that HIV uses to assemble infectious virions, is ten-fold less active than some of the weakest HIV protease inhibitors on the market, but it is active against almost all variants of the viral enzyme. Mutations in the protease are less likely to knock out its effectiveness. In preliminary studies, the inhibitor is effective against a broad range of similar proteases from a range of HIV and related viruses in cell culture assays, and further studies are being pursued.

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FIV A Good Model for Studying HIV-type Infections
 TSRI Professor John Elder, Ph.D., has studied feline immunodeficiency virus (FIV) since the mid-1980s. FIV was discovered in California in 1986. Elder and his colleagues extract DNA from infected blood lymphocytes, chop it up with enzymes, insert the DNA pieces into a phage (a virus that infects bacteria), and then infects the bacteria with the phage. Elder and his colleagues found one piece of DNA that contained what looked to be the whole virus. They then took that piece of DNA and used it to transfect cells. When they observed those cells, they found that they were productively replicating the virus, which they then isolated so they could sequence it.

Building on this initial work, Elder and his colleagues have been able to characterize the genomic organization of FIV and, significantly, to compare it to that of its cousin HIV. FIV and HIV have a lot in common, which makes FIV a good model for studying an HIV-type infection. Both are members of the lenti (slow) virus family and they contain many of the same characteristic genes and proteins. FIV, much like its human cousin HIV, has an RNA genome of around 10,000 bases that is packaged in a protein and lipid capsid and coat. HIV and FIV both code for a number of structural genes, which encapsulate the RNA and are produced by a gene called gag. Elder and his collaborators are trying to make more broad-based inhibitors of the two viruses, and also look at the development of vaccines in HIV and FIV.

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FIGHTAIDS@HOME
 A large TSRI research consortium is beginning to use resistant HIV protease to develop methodologies for drug evolution. Led by Professor Arthur Olson, Ph.D., the group seeks to establish a drug design "cycle" aimed at developing, testing, and refining novel approaches to making specific inhibitors of HIV protease that would be capable of limiting or eliminating drug resistance. The group is trying to understand resistance by looking at what happens as the virus changes in response to protease inhibitors. They are looking to identify the sequential protease transition mutants and to understand their most basic to advanced biology, including sequence, biochemical reactivity, and structure. The researchers are also looking at resistance as a phenomenon - how it can be predicted to how it can be countered.

Rather than aiming solely to make the next useful AIDS drug - which is naturally one goal of all the investigators - the team is seeking to bring all of the knowledge and technology to bear on developing a methodology that will allow them to understand something much more complex. In particular, the researchers are focusing on active site mutations.

The FightAIDS@Home project, a distributed computer project, is integral to the research consortium that Olson leads. Any person with a computer and an internet connection can sign up by logging onto http://fightaidsathome.scripps.edu/ and downloading the program. Once the program is installed on the individual"s computer, it is designed to conduct some set of calculations that may be one tiny part of a larger computation. The computations basically take a known or candidate drug and simulate docking it into the HIV protease enzyme. The program runs so that the computations take place without disturbing normal computer use, running when the machine is not in use and until the computation is finished.

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Structure of H.I.V. Capsid Protein Reveals Potential Weakness of Inner Core of Virus
 Scientists at The Scripps Research Institute have published a detailed molecular model of the full-length HIV CA protein - a viral protein that forms a cone-shaped shell around the genome of HIV. This structure reveals a never-before-seen molecular interaction that may be a weakness at the core of the virus. CA plays a crucial role in the lifecycle of HIV because it forms a protein shell inside infectious particles, providing a scaffold that organizes important components of the virus. The new CA structure has clinical implications and may help scientists develop new drugs for treating HIV. Scripps Research Professor Mark Yeager, M.D., Ph.D., led the study. There are several effective drugs and methods for treating and preventing HIV infections, but there is an ongoing need for new therapy due to the shear enormity of the disease and the emergence of drug resistance.

HIV infections can be successfully managed for years with a variety of existing drugs known as antiretrovirals, which interfere with critical parts of the viral lifecycle. Interfering with some of these stages can prevent the virus from replicating, integrating its genome into the cell's DNA, or processing new infectious viral particles. Doctors often prescribe a regimen of several antiretrovirals from different classes for people living with HIV because AIDS drugs with different mechanisms of action are more effective in combination than when taken alone. Finding new drugs with new mechanisms of action is important because HIV constantly mutates and may become resistant to existing drugs. In general, the capsid (the protein coat that covers the core of a virion) is an attractive target because it plays a crucial role in the viral lifecycle. It packages and organizes the HIV genome, and this is necessary for the virus to transmit and replicate efficiently. If chemical compounds could target the CA protein, scientists might be able to prevent the protein's assembly into capsid shells and thereby block infectivity of HIV. Capsid inhibitors would be a novel class of drugs that would complement existing pharmaceuticals.

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