The HIV virus responsible for AIDS provides a tough challenge to researchers who want to understand it and minimize its effects.
New tools and technologies have brought scientific teams in sight of the ultimate goal of developing an effective vaccine
|by Peter Gwynne and Gary Heebner
|•||THE IMMUNE REACTION|
|•||HOW HIV WREAKS HAVOC|
|•||FROM HIV TO AIDS|
|•||ANTIBODIES WITH ATTITUDE|
|•||NO ANXIETY OVER SEPARATION|
|•||METHODS OF MONITORING|
|•||ISSUES OF SUSCEPTIBILITY|
|•||TECHNOLOGIES FOR TREATMENT|
|•||THE PROMISE OF VACCINES|
|•||FOCUS ON THE FUTURE|
Attacking the Ultimate Invader/Evader
Just over a month ago, the medical world marked the 20th anniversary of the report that first identified the strange and apparently fatal disease that we now know as AIDS (for acquired immunodeficiency syndrome). During the 1980s the worldwide scientific and medical community struggled to understand the nature of the disease, to track down the human immunodeficiency virus (HIV) responsible for it, and to develop rudimentary treatments — an effort that continued throughout the 1990s.
In the meantime, AIDS has continued to destroy lives. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that 36.1 million individuals around the world were living with HIV infections or full-blown AIDS at the end of last year. In 2000 alone HIV/AIDS caused the deaths of approximately 3 million individuals, making a cumulative death toll of 21.8 million by year's end. UNAIDS' figures also indicate that roughly one in every 100 adults between the ages of 15 and 49 is now infected with HIV. More than 80 percent of all adult HIV infections have resulted from heterosexual intercourse.
Throughout the past decade the scientific and medical communities have sought better understanding of the HIV virus in hopes of developing more effective therapies, possibly including vaccines for individuals not exposed to the virus and for AIDS patients. Policy makers realize that they have a long road to travel before they begin to think about having this disease in check. "You not only have the effect of the virus infecting the cell," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID). "The HIV envelope itself is an extraordinary entity in its ability to have an aberrant effect on the immune system. In addition to being a disease of immune deficiency, it is a disease of aberrant immune system activations. These effects are really quite profound. Unfortunately for the human species HIV/AIDS is proving to be an extraordinary experiment of nature with regard to its effects on the immune system."
Marie Chow, professor of microbiology and immunology at the University of Arkansas, expands that thought. "Certainly other viruses have had some effects on immune systems before, but we never saw anything as devastating as the HIV," she explains. That devastation is amplified by HIV's ability to destroy the immune system. "The virus has been very difficult to pin down. HIV is making a precision surgical hit, knocking out the cells that direct and regulate the immune response," Chow continues. "AIDS victims succumb to diseases caused by other fungal, parasitic, bacterial, and viral infections owing to the loss of T cell function from the underlying HIV infection. On the one hand we're still learning so much about the immune system and how it works. But at the same time we can't defer research on HIV therapeutics and vaccine development until we understand how to help the immune system combat infections. It is really guerilla warfare at several levels, developing treatments and therapies for the variety of different infections seen in AIDS patients that are symptoms of the HIV infection itself."
Multidisciplinary approaches, involving collaborations between basic researchers and clinicians and among research scientists with different skills, have become mandatory for that effort and for treating the conditions that the virus causes. "HIV has forced us to deal with this disease on multiple fronts with individuals who have different backgrounds," says Chow.
Researchers and clinicians working in multidisciplinary teams have made steady progress in countering the virus. For example, the research effort that isolated the HIV virus and then sequenced and cloned its various genes to express its proteins led about a decade ago to protease inhibitors. "This class of drugs has been shown to be extraordinarily efficient when used with other drugs," says Fauci. "To me this is a classical example of the translation from basic research to clinical benefit."
Drug cocktails containing protease inhibitors have significantly extended the lives of many patients. And the search for other effective forms of chemical therapy continues. "What we would like to see from a new class of drugs is the same impact as protease inhibitors," says Richard Colonno, vice president of infectious disease discovery at pharmaceutical company Bristol-Myers Squibb. "We're seeing similar inhibition levels with the new class of entry inhibitors. New drugs will give patients an expanded set of options for combining drugs and avoiding long-term toxicity."
Behavioral concepts have also proved valuable for individual patients. For example, interrupted therapy permits individual patients to take occasional breaks from their drug regimens, giving them some relief from the often devastating side effects that those regimens cause. A team at the Lifespan/Tufts/Brown Center for AIDS Research (CFAR) is refining a project that pays neighbors to deliver AIDS treatments to patients who have difficulty reaching a hospital or doctor's office for therapy. "So far we've achieved results in terms of reducing viral loads far better than before," says Charles Carpenter, committee chair of CFAR and professor of medicine at Brown University. "We're also looking at nutrition. In women the body-mass index correlates positively with the length of time before the patient gets serious symptoms after being infected."
All those approaches lack one essential element. While they slow down the progress of HIV infection or full-blown AIDS, they do not result in a reconstitution of HIV-specific immunity. So the search is on for a vaccine — or perhaps several vaccines — that will confer at least some immunity to the virus. Vaccines can be used in an attempt to prevent initial infection or to slow progression of disease if a person becomes infected despite having been vaccinated. In addition, vaccine trials have been initiated in people who are already infected in an attempt to boost HIV-specific immunity.
To date approximately 30 vaccines against HIV have been tested, most in phase 1 or phase 2 trials to determine their safety and immunogenicity. Only one vaccine candidate, made by VaxGen, Inc., has gone on to phase 3 efficacy trials, which will probably not be completed for some time. Development of an HIV vaccine has become a very high priority in AIDS research. The National Institutes of Health expects to spend $282 million on research into vaccines this year, one-eighth of its entire AIDS budget. Several pharmaceutical companies have also entered the arena.
Within the past few months the effort has started to show definite promise. "Vaccines provide another example of how in-the-trenches basic research is showing us light at the end of a tunnel that was very dark for a long time," says Fauci. "Right now we feel certainly more optimistic than we felt a year ago about the possibility of developing an HIV vaccine."
The research has application beyond AIDS. "The natural experiment of HIV is really teaching us more about the human immune system than many decades of animal research," says Fauci. "HIV has, in a grossly horrific way, given us clues to how the immune system works," echoes Chow.
The immune system consists of a series of mechanisms that work together to protect the host from any number of foreign invaders. Together, these systems protect the body against potentially deadly attackers. Thus whenever a pathogen invades the body it elicits an almost immediate response from the innate immune system. This produces a rather unspecific defense against any pathogen. This defense includes barriers such as skin, the cilia in mucous membranes that sweep away airborne invaders, and tears, secretions, and saliva whose enzymes can destroy bacteria and other pathogens.
When this first line of defense fails to prevent an invader from entering the human body, a more specific set of responses can be evoked. The adaptive immune system mounts a specific response against a foreign molecule or antigen. It involves both B cells and T cells.
B cells originate in the bone marrow and circulate in the bloodstream. They are white blood cells that produce antibodies whose purpose is to interact with foreign particles or antigens; an antigen is a molecule that can elicit the production of antibodies (Abs) to a specific antigen (Ag). Antibodies generally recognize only one antigenic determinant, in a process known as the lock and key phenomenon. T cells, meanwhile, form in the thymus. The two main varieties are helper T cells that help other immune cells in their functions and cytotoxic T cells that kill damaged or foreign cells in the body.
When a foreign particle or organism enters the body, the immune system goes from alert status to active duty. Both B cells and T cells respond to the threat and eliminate the foreign substance from the host's body. If the invader is located in the bloodstream or outside the individual cells of the body, the B cells take charge. They bind to the foreign particle, an action that prompts another series of events which ends with the elimination of the Ab-Ag complex. If, on the other hand, the pathogen enters a cell, as viruses do, the body responds by activating cytotoxic T cells. These cells circulate in the bloodstream and lymph system and eliminate the foreign body by killing the host cell that is infected with the foreign agent.
HIV is a kind of retrovirus, a term that refers to the ability to copy its RNA genome into DNA rather than taking the reverse direction. The core of HIV contains several proteins including reverse transcriptase which converts the viral RNA into DNA that can then be integrated into the host's genome.
Interestingly, these viral enzymes have allowed molecular biologists to produce complementary DNA from the messenger RNA taken from a living cell. This has become a very important tool in studying the families of proteins expressed in a cell, the field now referred to as proteomics. Several suppliers, among them Ambion, Promega, New England Biolabs, and Roche, provide this type of molecular biology enzyme to help researchers in their efforts to produce high quality copies of cDNA. RT-PCR, the reverse transcriptase polymerase chain reaction, is based on this unique enzyme's ability to copy RNA into its counterpart DNA.
The general structure of the virus resembles that of other viruses. It has a membrane or viral envelope that it takes from the membrane of a human cell when a newly formed virus particle exits the host cell. This membrane surrounds a core of proteins and two single strands of RNA, each of which codes for the virus's nine genes. The viral envelope contains several proteins from the host cell as well as 72 copies of a complex HIV protein that protrudes from the surface of the viral envelope. Efforts to develop a vaccine for HIV have involved these envelope proteins.
Scientists have slowly elucidated the functions of the nine viral genes. Some contain information for making structural proteins while others code for regulatory proteins that control the ability of HIV to infect a cell, replicate its genome, and cause disease.
HIV wreaks its havoc by more than conventional viral action. One of the HIV envelope proteins, gp120, recognizes a receptor on helper T cells called CD4 and can physically bind to it. A normal membrane component of a helper T cell, the CD4 protein also acts as a specific receptor for HIV. The virus can also infect other cells such as macrophages and phagocytes. By interacting with CD4 on helper T cells, HIV specifically infects the very cells needed to activate both the B cell and the cytotoxic T cell responses. Without helper T cells, the body cannot produce antibodies effectively. Worse, cells that contain HIV can no longer be properly eliminated through the action of cytotoxic T cells. By blocking these critical defense mechanisms HIV can multiply and spread to other T cells, until the population of helper T cells diminishes.
Researchers established fairly quickly that the CD4 receptor plays a key role in HIV infection. But they also realized that the process must also involve other receptors. Eventually research teams identified a second co-receptor that HIV commonly uses to enter cells. Known as CCR-5, this normally associates with body proteins known as chemokines that send chemical messages to cells, directing them to sites of inflammation. Another co-receptor for the virus is CXCR4. This normally associates with a chemokine or chemokines different from those associated with CCR-5.
Several companies, including BD Biosciences, PerkinElmer Life Sciences, R&D Systems, and Research Diagnostics, specialize in providing products for chemokine research. That research has already shown that individuals who produce larger amounts of chemokines tend to be more resistant to HIV infection; the chemokines interfere with the virus's binding to the receptors. Furthermore, some individuals with mutations that alter the CCR-5 receptor appear to possess resistance to HIV infection.
The battle between the virus and the host's immune system continues for some time. The body responds to this assault by producing more T cells. Some of these will mature to become helper T cells that the virus ultimately infects, eliminating them from the struggle. In fact the battle may continue for several years before the human body finally succumbs to the virus. By this time the body seems to have lost its ability to produce any more T cells. Because of this loss of helper T cells, the body eventually loses all ability to fight off even the weakest of foreign organisms — organisms that would not normally pose any serious threat to the host. This acquired immunodeficient condition is referred to as AIDS.
Molecular biology has revealed another disturbing facet of the HIV virus: It can hide effectively in the genetic components of cells. "It's still somewhat of a mystery why the immune system is incapable of completely clearing the virus from the body, even in individuals doing well on treatment," says Fauci. "In every individual we look at, including those being adequately treated who have levels of the virus below detectability, it's inevitable that the virus can bounce back. That has been an extraordinary challenge."
The other major difficulty faced by HIV/AIDS researchers stems from the mercurial nature of HIV. "Like other viruses with RNA genomes, HIV readily mutates to generate new virus variants that contain subtle differences from the original virus but are now resistant to the drug's action. Yet once the HIV genes in their DNA forms are integrated, these variants are as stable as other cellular genes and the cell expresses the viral genes as if they were cellular genes," says Chow. "That presents a particular challenge if you're trying to develop an effective therapeutic agent. The acquired immune response is driven by the ability to differentiate between host and foreign [or viral gene] form. But because the HIV virus is so mutable, that's much more difficult. Basically mutations in the virus nullify what you're trying to develop."
Life scientists have carried out intensive research on the HIV virus since the mid-1980s. Many laboratories worldwide have contributed to the clear understanding of the virus's structure and the mechanisms that make the virus so elusive to the natural immune system. Their work has relied on a series of research tools that range from specialized antibodies to robotic systems.
Antibodies have become familiar to generations of life scientists. The scientists use a relatively simple procedure to produce the basic variety: Inject an animal with antigenic material, allow for an immune response to develop, and then harvest the circulating antibodies present in the animal's blood. These polyclonal antibodies arise from a variety of B cells that produce different antibodies against different epitopes of the immunizing antigen.
Polyclonal antibodies are inexpensive to produce. Just as important, large quantities (up to 10 milligrams per milliliter) can be produced from the serum of an immunized animal. They also offer a realistic example of the immune response since polyclonal antibodies represent the entire antigen-specific antibody population in an animal. Polyclonal antibodies have the disadvantage of a limited supply, however; they can be harvested only from the animal used in the immunization.
Producing monoclonal antibodies involves a more complicated process. Scientists immunize an animal with an antigen as in the case of polyclonal antibodies. The difference occurs once the immune response develops. At that point the scientific team removes the animal's spleen. The cells in the spleen ultimately develop into mature, antibody-producing B cells that are, however, incapable of replicating and hence unable to be cultured invitro. Scientists get around that problem by fusing the spleen cells with "immortal" myeloma cells that can replicate in culture for an extended period of time. The team then screens the resulting fused cells (hybridomas) with an ELISA assay to identify the cells that produce the antibody of interest. That cell is then isolated and cloned; it will produce large amounts of a single (monoclonal) antibody directed against the original antigen for virtually an indefinite period of time.
This hybridoma cell line can be frozen and stored for long periods of time, thereby providing the research team with a constant supply of a specific antibody. Polyclonal and monoclonal antibodies are available from several companies. They include Alexis Corporation, BD Biosciences, Calbiochem-Novabiochem, Chemicon International, Sigma-Aldrich, and Zymed Laboratories.
Antibodies tagged with labels such as fluorescein and other molecules that allow the antibodies to be visualized find widespread use in identifying and locating specific proteins in or on a cell. Antibody-based probes are ideal for identifying specific cell populations based on differences in their cell surface proteins or markers. These antibodies can also be used in histochemical applications, in which a cell is fixed in paraffin and sections of it stained with antibody for a specific molecule. To identify the tagged cells scientists rely on microscopy, fluorescent readers, or flow cytometers. Molecular Probes provides many of the fluorescent labels used with antibodies.
Antibodies find a role in another aspect of HIV/AIDS research: cell separation. Researchers can use the great diversity and specificity of antibodies to separate one type of cell from another. Typically they attach a specific antibody to a chromatography column; the antibody recognizes a particular antigen in the cells under investigation. By binding to those antigens the antibody pulls the targeted cells out of the mixture. T cells are often selected for and enriched using these antibodies. Pierce Chemical and R&D Systems, among other firms, offer a number of products for cell separation.
An alternative method of sorting cells involves covalently binding magnetic particles to antibodies specific to a particular cell of interest. A mixture of cells is then incubated in a solution with the magnetic antibodies. Next, the entire reaction mixture is exposed to a magnetic field, which retains the magnetic beads and separates out the cells of interest. Removing the magnet frees up the cells again. Several companies, including Dynal, Miltenyi Biotech, and Polysciences, have developed cell separation products based on magnetic particles. As an added advantage, some of the magnetic materials naturally degrade without adversely affecting cell function.
Flow cytometers developed by BD Biosciences and other companies, meanwhile, can measure differences in fluorescence with much greater accuracy than the human eye. Flow cytometry has faced limitations on its use in the past because of the difficulty of sorting and collecting enough cells for subsequent biochemical analysis. Now, however, the polymerase chain reaction permits scientists to use even a single cell as the starting material to amplify its DNA for biochemical analysis.
By using several antibodies tagged with different fluorescent labels, scientists can measure several variables in a cell population simultaneously. Cells can be identified and then sorted into different aliquots via the sorting capability of a flow cytometer. This multiparametric method eliminates several separate runs to measure more than one parameter. Companies such as BD Biosciences offer complete lines of antibodies for use with flow cytometry. "The flow cytometer is the ideal tool for AIDS researchers looking at subsets of T cells because it allows you to look at many cell types at the same time," explains Skip Maino, the company's scientific director for biological research and development.
In a related context, robotics can increase the productivity in many immunological and diagnostic procedures by fully automating an otherwise manual and labor intensive process. Hamilton Company has developed several systems for automating routine laboratory procedures. Beckman Coulter has designed a robotic system called Biomek FX System for high- throughput screening (HTS). TECAN has developed the GENESIS workstation, a robotic system that can perform HTS assays including pipetting, plate washing, incubation, and plate reading. And Tropix, a division of Applied Biosystems, offers several HTS systems for both live-cell and biochemical assays. All these systems constantly drive toward increased sensitivity that enables scientists to detect smaller samples, to use smaller amounts of reagents, and — by demanding less input by individual team members — to increase laboratory productivity.
The diagnosis of HIV infections has evolved over the past years from Ab-based ELISA assays to ultrasensitive assays based on the detection of viral RNA, DNA, or other specific molecules. The current molecular based assays can measure HIV circulating in a person's blood down to levels that were undetectable just a few years ago. Several of these diagnostic assays depend on RT-PCR to amplify the number of copies of HIV RNA to a detectable level for the assay.
Roche has developed an HIV test called Amplicor HIV-1 Monitor UltraSensitive Method. This test, approved by the U.S. Food and Drug Administration for clinical diagnostic use in 1999, can detect viral levels down to 50 copies per milliliter of plasma, a proportion previously undetectable. Other companies such as Chiron Corporation and Organon Technika have developed kits for measuring HIV in blood or plasma.
Ambion RNA Diagnostics focuses on products and services for the clinical investigator, including standards and controls for nucleic acid assays that monitor patient HIV viral loads. Many standards and controls for HIV clinical assays use naked RNA. "Naked RNA is easily degraded by ribonucleases and tends to hydrolyze over time," points out Ambion's Cindy WalkerPeach, director of diagnostic manufacturing. Last year the company launched a system, Armored RNA, based on protecting an RNA molecule from degradation by surrounding it with a phage coat protein complex. "Because the sequence mutation rate for the HIV is so high, it is important for researchers to have access to the myriad of potential sequences to study. This system allows the investigator to define any number of protected RNA sequences as potential targets for assay and vaccine development studies," says WalkerPeach. Roche Molecular Biochemicals, Abbott Laboratories, Gen-Probe, and others have licensed the technology.
Tests generally rely on blood samples. But Calypte Biomedical Corporation has taken a different approach. It has developed an FDA licensed urine test for the HIV antibody that has also shown promise in trials in Uganda. "We were able to identify people (who wouldn't have given blood) with HIV virus via a urine sample," explains Toby Gottfried, Calypte's director of research and development. "Our test may not be as accurate as a blood test, but it is a great alternative for patients who otherwise would not be tested at all." Scientists from Johns Hopkins University using the test in concert with educational advice have been able to make an impact on the epidemic in Uganda and have started a promising effort in Thailand. Another method of avoiding the necessity to take blood samples is an oral mucosa test for the HIV virus developed by Orasure.
Several companies offer reagents and other products for the specific purpose of monitoring HIV and AIDS. "Our general products for the area are aimed at scientists who want to do viral culture work," says Jim Hengst of Zeptometrix Corporation. "We supply ELISA kits for the detection of HIV, simian immunodeficiency virus, and related viruses. We also provide interleukin 2 to help the viruses grow." Similarly Cell Sciences, Inc. markets ELISA kits to detect cytokines and chemokines. "And we can custom produce chemokines and other biologically active molecules that our customers can then modify," adds president Irwin Libeskind. "They can change the natural sequence into something that is in their scientific design for them to test."
Another small company, BioErgonomics, Inc., has worked with AIDS researchers since its founding in 1993. "The first thing I did was fly to Washington to meet AIDS clinical trial groups," recalls Daniel Collins, the firm's cofounder, executive vice president, and chief scientific officer. The company actually grew out of the field of flow cytometry. "Most of our technology uses it as a platform," explains Collins. "That's useful because flow cytometry is an extremely sensitive instrument and it naturally multiplexes things. We have multiplex cytokine assays that are very rapid and sensitive, much better than ELISA assays, and capable of being done in a fraction of the time that other assays take. Based on a similar flow cytometry platform, BioE has developed an extremely sensitive assay that can simultaneously detect the HIV/AIDS virus and the presence of antibody against the virus. Unlike current ELISA assays, detection of the virus is done without interference by the antibody and detection of the antibody is done without interference by the virus. This allows very early detection of infection and actual monitoring of viral load."
That type of assay addresses a major aim of AIDS researchers: monitoring patients' progress. The initial approach involved counting the number of CD4 cells in patients' blood samples. "Right from the early stages we had CD4 as the benchmark for monitoring," says Amitabh Gaur, director of the custom technology team at BD Biosciences. "Our method of true count monitors the numbers for AIDS/HIV infections." The company has recently started to adapt work on cytokine flow cytometry by Louis Picker of the University of Oregon that permits researchers to characterize single antigen specific T cells. "We can show that an HIV antigen specific T cell is a CD4 rather than a CD8 or a particular type of memory T cell," explains Maino.
Beyond monitoring, researchers increasingly try to develop methods of measuring individual patients' susceptibility to HIV/AIDS and to specific treatments for the condition. Thus scientific teams have tried for several years to detect single nucleotide polymorphisms (SNPs). These natural genetic variations may be the basis for determining whether an individual is more likely to develop a particular disease. They may also be of great value in determining how a patient will respond to drug therapy. "Certain individuals are susceptible to AIDS and others not so, according to their genotype," points out Steve Hurt, director of receptor ligand biology at PerkinElmer Life Sciences. "We have introduced the first in a series of products for SNP detection — a nonradioactive kit based on detection of fluorescence polarization."
PerkinElmer is not alone. The SNP Consortium, formed by several companies worldwide, has the goal of promoting the identification of a large number of SNPs.
Applied Biosystems Group recently announced that it is in the final stages of clinical trials for a product that can tell physicians whether or not specific drugs would work with a particular HIV-infected patient. This could eliminate much of the trial and error associated with AIDS treatment. "Our ViroSeq HIV-1 genotyping system is designed to give an indication of the resistance of the HIV to the drugs that the patient is taking," says Eric Shulse, director of molecular diagnostics at Applied Biosystems. "Even with multiple drug cocktails a patient's HIV can become resistant to the drugs. Our test is used to give an indication of that resistance. It helps physicians to determine whether a patient is noncompliant on a particular drug treatment and to identify the drug to which the patient has become resistant."
Within the next month the company plans to submit tests of the system to the FDA. If it gains FDA approval, the test could reach the market next year. In fact, says Shulse, home brew versions of the test are already available today from large reference laboratories that have standardized on Applied Biosystems' technology.
Therapies for AIDS have progressed over the last several years as research teams have learned more about the mechanisms of HIV infection and AIDS. Many of the technologies used in developing therapeutics for AIDS and other important diseases will be addressed at the upcoming Drug Discovery Technology Conference in Boston, Massachusetts, on August 12 to 17, 2001 (seeaccompanyingitem, Getting Up to Date on Drug Discovery).
The first drugs available to treat HIV infections were the nucleoside reverse transcriptase inhibitors or NRTIs. HIV undergoes reverse transcription when it converts its genetic material (RNA) into DNA so that it can integrate this genetic material into the host's DNA genome. NRTIs block this step, preventing HIV reproduction. The first company to offer these inhibitors was GlaxoWellcome (now GlaxoSmithKline) with its AZT drug.
Protease inhibitors came later. These drugs target the protease enzyme, which cuts long polypeptide chains into the smaller segments essential for viral reproduction. By preventing the formation of the smaller, active forms of polypeptides, the drug family prevents the virus from reproducing.
The pharmaceutical industry continues to pursue a new generation of protease inhibitors. "We have a protease inhibitor in phase 3 trials that can be taken once a day and does not appear to elevate cholesterol levels as other protease inhibitors do," says Bristol-Myers Squibb's Colonno. "We're very hopeful that this will result in greater compliance and tolerance over the long term." Why does this therapy keep patients' cholesterol levels low? "We're working on that," says Colonno. "It's a very big plus."
Other treatments use cytokines, the body's own chemical messengers, to increase the immune system's response to HIV. Different cytokines transmit different messages to immune cells. Some, for example, can activate a cell to multiply while others can send a cell into the form of death known as apoptosis. One of the best known cytokines for AIDS treatment is interleukin 2 (IL-2, or Aldesleukin) produced by Chiron Corporation.
Further in the future, pharmaceutical firms see the possibility of treatment via gene therapy. Cell Genesys, in fact, has already developed an AIDS gene therapy protocol. The treatment first involves collecting CD4 and CD8 cells from an HIV-infected individual. The cells are then genetically modified to recognize and kill HIV-infected cells. Next they are cultured to increase the number of affector cells, and finally they are reinfused back into the same patient. As Cell Genesys conceives its strategy, physicians would use gene therapy in conjunction with antiviral drugs.
GETTING UP TO DATE ON DRUG DISCOVERY
For scientists and executives interested in treatments for AIDS and other diseases, the Drug Discovery Technology 2001 congress will offer the opportunity to get up to date on the entire process of drug discovery, including cutting edge science, fundamental pharmaceutical technologies, and the ever-changing business of drug development. The event, in Boston's Seaport Hotel & World Trade Center, will take place between August 12 and 17. Key technical symposia include those on Cutting-Edge Technologies, Genomics and Target Validation, Screening and Assay Development, Chemical Biology & New Paradigms in Medicinal Chemistry, and Infrastructure for the Drug Discovery Factory. The event will feature more than 100 presentations by speakers, more than 300 exhibit booths, and over 40 launches of new products. You can obtain more information at the event's web page, www.drugdisc.com. Alternatively, contact Michael Keenan at IBC USA Conferences, 1 Research Drive, Suite 400A, P.O. Box 5195, Westborough, MA 01581. Telephone: 508-616-5550, extension 288.
The most promising new approach to AIDS therapy focuses on the traditional approach to protection against infectious diseases. "Everyone's eye is on the vaccine question," says Calypte's Gottfried.
Researchers developing vaccines for HIV have less lofty ambitions than their colleagues dealing with other infectious diseases. They recognize that the ultimate target of preventing infection by HIV is almost certainly beyond their skill in the next few years. Instead, they aim to develop a vaccine, or better yet several vaccines, that will slow down the rate at which the HIV virus spreads in patients. "The field has deviated a little from the initial goal of developing a vaccine that causes sterilizing immunity toward one focused on the issues of adequate suppression of the virus," explains William Blattner, head of the Institute of Human Virology, Epidemiology and Prevention Division at the University of Maryland Biotechnology Institute. The institute works on both preventative and therapeutic vaccines.
The most advanced vaccine candidate, VaxGen's AIDSVAX, consists of the gp120 envelope protein. Produced in mammalian cells, this is designed to prevent infection in individuals who have not been exposed to the virus. The vaccine is undergoing phase 3 efficacy trials in the United States and Thailand.
Immune Response Corporation takes a different approach. It has designed its Remune product in collaboration with Agouron Pharmaceuticals (a Pfizer company) as a therapeutic vaccine to enhance the immune systems of individuals already infected with the virus. "Remune is depleted of the gp120 envelope protein of the virus, so that, in a way, we're trying to focus the immune system on the more conserved parts of HIV-1," says Ron Moss, vice president of medical and scientific affairs. "We've observed in our clinical trials that we can stimulate T helper cell responses in some patients. We're at the point where we're trying to see whether the T helper responses correlate with clinical disease progression and whether these additional immune responses decrease the failure rate of patients on antiviral drug therapy." BD Biosciences and others provide reagents and assay services to monitor the functional T cell response following vaccinations with candidate vaccines.
Other organizations are carrying out development that should eventually find use in treating AIDS. AlleCure, for example, is a relatively new biotechnology company that focuses on the development and commercialization of vaccines and other therapies designed to affect the immune system. "Our platform system allows us to precisely modulate the immune system and desensitize any individual against any allergen," says president and CEO Stephen McCormack. That platform could eventually find use in delivering vaccines to AIDS patients.
The devastating consequences of AIDS and other immune disorders have certainly made the public more aware of the importance of the study of the immune system and its role in medicine. The development of better and more specific drugs has also helped to control the progress of AIDS. The possibility of developing an effective vaccine against this virus brings the hope of limiting the spread of AIDS in the future.
Research on AIDS has provided fresh insights for scientists trying to understand other forms of illness. "CD4 assays, the development of exquisitely sensitive assays for the HIV virus in both plasma and tissue, new adjuvants, and new vectors for vaccines: All these technologies would probably have come along anyway, but the compelling need for the study of AIDS has made the process more rapid," says Fauci of NIAID. "It's going to be extremely beneficial for other diseases."
The main target of scientists in academic and industrial laboratories who are studying AIDS and many other immune-related disorders, however, is the hope of finding treatments and cures. Their understanding of the human immune system and how it relates to several diseases such as AIDS, lymphomas, and leukemia remains very limited. "HIV is one incredibly hard virus to study because it affects the physiology of the immune network," declares the University of Arkansas's Chow. "It calls for an interactive effort from a network of investigators from all the basic sciences. No single perspective or field will be able to make an adequate effort or progress."
Nevertheless, with continued efforts from researchers and the manufacturers who supply the tools to make such research possible, the scientific community will enhance progress in the war against the ultimate invader. "We're trying to accelerate the process," says Blattner of the Institute of Human Virology in Baltimore. "We're in the faces of the lab people and they're in our faces to make sure that these products move forward."
Peter Gwynne is a freelance science writer based on Cape Cod, Massachusetts, U.S.A. Gary Heebner is president of Cell Associates, a scientific consulting firm in Chesterfield, Missouri, U.S.A.
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