Viral entry into the host and possible immune reaction The human immunodeficiency virus (HIV) and AIDS HIV-infected subjects have major defects in their immune system Possible vaccine approaches Beware of potentially harmful auto-antibodies The innovative Mymetics AIDS preventive vaccine approach Literature Cited Glossary Glossary A B C D E G H I K L M O P R S T V                 AIDS Acquired Immune Deficiency Syndrome. AIDS is the most severe manifestation of infection with the Human Immunodeficiency Virus (HIV). According to the Centers for Disease Control and Prevention (CDC), a CD4+T cell count at or below 200 cells per microliter (normal range from 500 to 1,500 cells per microliter) in addition to opportunistic infection and or neoplasm (cancers) in the presence of HIV infection constitutes an AIDS diagnosis. ANTIBODIES Molecules in the blood or secretory fluids that tag, destroy, or neutralize bacteria, viruses, or other harmful toxins. They are members of a class of proteins known as immunoglobulins, which are produced and secreted by B-lymphocytes in response to stimulation by antigens. An antibody is specific to an antigen. AUTOIMMUNE DISEASE A condition that results when the immune system responds against a person's own tissues, cells or proteins. B CELLS B-lymphocytes. One of the two major classes of lymphocytes. B lymphocytes are blood cells of the immune system, derived from the bone marrow and spleen, and involved in the production of antibodies. During infection, these cells are transformed into plasmocyte cells that produce large quantities of antibody directed against specific proteins or pathogens. When antibodies bind to foreign proteins, such as those that occur naturally on the surfaces of bacteria, they mark the foreign cells for consumption by other cells of the immune system. This transformation occurs through interactions with various types of T cells and other components of the immune system. In persons living with AIDS, HIV damages the functional ability of both the B and the T lymphocytes, with the T lymphocytes being most affected. BIOTECHNOLOGY Use of living organisms or their products to make or modify a substance. This includes recombinant DNA techniques (genetic engineering) and hybridoma technology (monoclonal antibody production). 2. Industrial application of the results of biological research, particularly in fields such as recombinant DNA or gene-splicing, which permits the production of synthetic hormones or enzymes by combining genetic material from different species. CCR5 Cell surface molecule on target cells, which is needed along with the primary receptor, the CD4 molecule, in order to fuse with the cell membrane of an immune system cell. Researchers have found that the strains of HIV most often transmitted from person to person require the CCR5 molecule and CD4 molecule in order for HIV to enter the cell. In addition to its role in fusion, CCR5 is a receptor for certain immune-signaling molecules called chemokines. CD4+ CELLS 1. A type of T cell involved in protecting against viral, fungal, and protozoal infections. These cells normally orchestrate the immune response, signaling other cells in the immune system to perform their special functions. Also known as T helper cells. 2. A specialized subtype of T cell, also known as a regulatory/suppressor CD4+CD25+ T cell. The main function of CD4+ cells is to control and prevent autoreactive cells from expanding during the host's entire life. These immune cells may also shut down the immune response after it has effectively wiped out invading organisms. 3. CD4 stands for cluster designation 4, a type of molecule found on certain T cells. Cells with this molecule are known as CD4-positive (or CD4+) cells. HIV targets this molecule on these cells. 4. Destruction of CD4+ T lymphocytes is the major cause of the immunodeficiency observed in AIDS, and decreasing CD4+ T lymphocyte levels appear to be the most accurate indicator for increased risk of opportunistic infections. As CD4 counts fall, the total T cell level can remain fairly constant through the course of HIV disease, because of a concomitant increase in the CD8+ T cells. The ratio of CD4+ to CD8+ T cells is therefore an important measure of disease progression. CD8+ CELLS 1. Protein embedded in the cell membrane of suppressor T lymphocytes. Also called cytotoxic T cells. Some CD8+ cells recognize and kill cancerous cells and those cells infected by intracellular pathogens (some bacteria, viruses, and mycoplasma). CD8+ cells are called cytotoxic T lymphocytes. 2. Sensitive to high concentrations of circulating lymphokines (especially IL-2), CD8+ cells release their own lymphokines when an immune response has achieved its goal, signaling all other participants in the immune response to cease their coordinated attack. A number of B-lymphocytes remain in circulation in order to fend off a possible repeat attack by the same organism. CELL-MEDIATED IMMUNITY A branch of the immune system that exists primarily to deal with viruses which are more insidious than bacteria because they invade the host (e.g., human) cells, where they can hide from the antibody-making cells of the immune system. In cell-mediated immunity, specific defense cells, such as killer T cells, macrophages, and other white blood cells rather than by antibodies, form the primary defense against foreign material. CHEMOKINES Studies of the relationship between HIV and these immune system chemicals have elucidated the complex exchanges that take place when HIV and white blood cells meet. Chemokines are intracellular messenger molecules secreted by cells whose major function is to attract immune cells to sites of infection. Recent research has shown that HIV-1 needs access to chemokine receptors on the cell surface to infect the cell. Several chemokines - called RANTES, MIP-1a and MIP-1b - interfere with HIV replication by occupying these receptors. Findings suggest that one mechanism these molecules use to suppress HIV infectivity is to block the process of fusion used by the virus to enter cells. CLINICAL TRIAL A scientifically designed and executed investigation of the effects of a drug (or vaccine) administered to human subjects. The goal is to define the safety, clinical efficacy, and pharmacological effects (including toxicity, side effects, incompatibilities, or interactions) of the drug. The U.S. government, through the FDA, requires strict testing of all new drugs and vaccines prior to their approval for use as therapeutic agents. CO-RECEPTORS A group of proteins that have been found to block the entry of HIV into immune cells. COMBINATION THERAPY Two or more drugs or treatments used together to achieve optimum results against HIV infection and/or AIDS. Combination therapy may offer advantages over single-drug therapies by being more effective in decreasing viral load. An example of combination therapy would be the use of two nucleoside analog drugs (such as 3TC and AZT) plus either a protease inhibitor or an inhibitor peptide / antibody (HAART). CXCR4 A cell surface molecule that acts as a cofactor or co-receptor for the entry of HIV into immune system cells. Early in the epidemic, CD4 molecules were found to be the primary receptor for HIV on immune system cells. Later on, it was shown that a second molecule, CXCR4, is also required for fusion and entry of certain strains of HIV into cells. New studies indicate a multistage interplay between HIV and two receptors on white blood cells. After binding to the CD4 receptor, the virus fuses with a second receptor, CXCR4, which normally binds to chemokines. This double clasp may then signal the receptors to move the virus into the cell. CYTOKINES Cytokines act as chemical messengers between cells and can stimulate or inhibit the growth and activity of various immune cells. HIV replication is regulated by a delicate balance among the body's own cytokines. By altering that balance one can influence the replication of the virus in the test tube and potentially even in the body. CYTOMEGALOVIRUS A herpesvirus that causes an AIDS-defining illness. CTL Cytotoxic T-lymphocyte. A lymphocyte that is able to kill foreign cells marked for destruction by the cellular immune system. DISSEMINATED Signals spread of a disease throughout the body. DRUG RESISTANCE The ability of some disease-causing microorganisms, such as bacteria, viruses, and mycoplasma, to adapt themselves, grow and multiply even in the presence of drugs that usually kill them. EFFICACY The ability of a drug or treatment to produce a result regardless of dosage. A drug passes efficacy trials if it is effective at the dose tested and against the illness for which it is prescribed. In the procedure mandated by the FDA, Phase II clinical trials gauge efficacy at certain doses, and Phase III trials confirm it. ENV An HIV gene that codes for the protein gp160, the precursor of the envelope proteins gp120 and gp41. ENVELOPE In virology, a protein-studded covering that packages the virus's genetic information. The outer coat, or envelope, of HIV is composed of two layers of fat-like molecules called lipids taken from the membranes of human cells. Embedded in the envelope are numerous cellular proteins, as well as mushroom-shaped HIV proteins that protrude from the surface. Each mushroom is thought to consist of a cap made of three glycoprotein molecules called gp120, and a stem consisting of three gp41 molecules embedded in the envelope. The virus uses these proteins to attach to and infect cells. EPITOPE A unique shape or marker carried on an antigen surface that triggers a corresponding antibody or cellular response. GLYCOPROTEIN A conjugated protein in which the non-protein group is a carbohydrate (e.g., a sugar molecule). GP160 (Glycoprotein-160) A precursor of HIV envelope proteins that includes both gp41 and gp120. GP120 (Glycoprotein-120) A protein that protrudes from the surface of HIV and binds to CD4+ T cells. In a two-step process that allows HIV to breach the membrane of T cells, the gp120-CD4 complex refolds to reveal a second structure that binds to CC CCR5, one of several chemokine co-receptors used by the virus to gain entry into T cells. GP41 (Glycoprotein-41) A protein embedded in the outer envelope of HIV. Plays a key role in HIV's infection of CD4+ T cells by facilitating the fusion of the viral envelope and the cell membrane. HAART Highly Active Antiretroviral Therapy; See COMBINATION THERAPY. HELPER T CELLS Lymphocytes bearing the CD4 marker that are responsible for many immune system functions, including turning antibody production on and off. HEPATITIS An inflammation of the liver. May be caused by bacterial or viral infection, parasitic infestation, alcohol, drugs, toxins, or transfusion of incompatible blood. Although many cases of hepatitis are not a serious threat to health, the disease can become chronic and can sometimes lead to liver failure and death. There are four major types of viral hepatitis: (a) hepatitis A, caused by infection with the hepatitis A virus, which is spread by fecal-oral contact; (b) hepatitis B, caused by infection with the hepatitis B virus (HBV), which is most commonly passed on to a partner during intercourse, especially during anal sex, as well as through sharing of drug needles; (c) non-A, non-B hepatitis, caused by the hepatitis C virus, which appears to be spread through sexual contact as well as through sharing of drug needles (another type of non-A, non-B hepatitis is caused by the hepatitis E virus, principally spread through contaminated water); (d) delta hepatitis, which occurs only in persons who are already infected with HBV and is caused by the HDV virus; most cases of delta hepatitis occur among people who are frequently exposed to blood and blood products such as persons with hemophilia. HERPES VIRUSES A group of viruses that includes herpes simplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), human herpes virus type 6 (HHV-6), and HHV-8, a herpes virus associated with Kaposi's sarcoma. HIV DISEASE The natural course of HIV infection is through the mucosal surface, where HIV finds susceptible T cells. Then, HIV-infected T cells migrate to the proximal lymph nodes, the first site at which there is truly massive production of the virus. This leads to a burst of massive viremia with wide dissemination of the virus to lymphoid organs. The resulting immune response to suppress the virus is only partially successful and some viruses escape. Eventually, this results in high viral turnover that leads to destruction of the immune system. HIV disease is, therefore, characterized by a gradual deterioration of immune function. During the course of infection, crucial immune cells, called CD4+ T cells, are disabled and killed, and their numbers progressively decline. The decline of the immune system leads to AIDS, the final stage of HIV infection. HIV-1 & HIV-2 The human immunodeficiency virus (HIV) belongs to the retrovirus family (Retroviridae), so called because they contain the reverse transcriptase enzyme that copies viral RNA back into DNA (the reverse of what usually occurs in nature: DNA is copied into RNA). The viral DNA is then integrated into the infected cell. This cell may either become an HIV factory, producing thousands of new viruses, or a latent infected cell (no virus production). Retroviruses include three main groups: 1) spumaviruses; 2) oncoviruses that are often associated with cancers; and 3) lentiviruses that cause slowly evolving pathologies, e.g. AIDS-associated lentiviruses. HIV belongs to this third group, the lentivirus (Lentiviridae), and causes a slow evolving disease named Acquired Immunodeficiency Syndrome (AIDS). HIV infection is characterized by the inability of the host immune system to mount an efficient immune response capable of neutralizing the HIV. Therefore, HIV is still replicating and spreading in the infected host, affecting and killing numerous cells of the immune system, leading to the life-threatening later stages of the disease. Two strains of HIV capable of causing AIDS have been identified, HIV-1 and HIV-2. HIV-2 is usually not as virulent as HIV-1. The genetic material of these two strains is approximately 60% identical. HIV-1 is found worldwide (pandemic), while HIV-2 seems to be more limited to certain areas of Africa (epidemic). Along with HLTV-1 and HLTV-2 (oncoviruses linked to human leukemia), HIV-1 and HIV-2 are the only retroviruses that cause known diseases in humans. Other AIDS-associated lentiviruses that cause diseases in animals include: FIV (Feline Immunodeficiency Virus causing AIDS in felines), SIV (Simian Immuno Deficiency Virus causing AIDS in monkeys) and BIV (Bovine Immuno Deficiency Virus causing AIDS in bovines). HTLV-1 Human T cell Lymphotropic Virus Type I. HTLV-I and HTLV-II, like all retroviruses, are single-stranded RNA viruses containing a genome that replicates through a DNA intermediate. This unique life cycle is made possible by the presence of a virally encoded enzyme, reverse transcriptase, which converts a single-stranded viral RNA into a double-stranded DNA provirus that can then be integrated into the host genome. HTLV-I has an affinity for T lymphocytes; it appears to be the causative agent of certain T cell leukemias, T cell lymphomas, and HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-II Human T cell lymphotropic Virus Type II. A virus closely related to HTLV-I, shares 60 percent genomic homology (structural similarity) with HTLV-I. Found predominantly in injection drug users and Native Americans, as well as Caribbean and South American Indian groups. HTLV-II has not been clearly linked to any disease but has been associated with several cases of myelopathy/tropical spastic paraparesis-like neurological disease. HUMORAL IMMUNITY The branch of the immune system that relies primarily on antibodies. IMMUNE DEFICIENCY A breakdown or inability of certain parts of the immune system to function, thereby making people susceptible to certain diseases that they would not ordinarily develop. IMMUNE RESPONSE The activity of the immune system against foreign substances. IMMUNE SYSTEM The body's complicated natural defense against disruption caused by invading foreign agents (e.g., microbes, viruses). There are two aspects of the immune system's response to disease: innate and acquired. The innate part of the response is mobilized very quickly in response to infection and does not depend on recognizing specific proteins or antigens foreign to an individual's normal tissue. It includes complement, macrophages, dendritic cells and granulocytes. The acquired, or learned, immune response arises when dendritic cells and macrophages present pieces of antigen to lymphocytes, which are genetically programmed to recognize very specific amino acid sequences. The ultimate result is the creation of cloned populations of antibody-producing B cells and cytotoxic T lymphocytes primed to respond to a unique pathogen. IMMUNITY A natural or acquired resistance to a specific disease. Immunity may be partial or complete, long-lasting or temporary. IMMUNIZATION Administration of antigenic components of an infectious agent to stimulate a protective immune response. IL-2 Interleukine-2 (IL-2) is a small protein of 133 amino acids mostly produced by T cells. IL-2 is considered one of the most important messenger of the immune system. IL-2 helps to coordinate the immune response, in addition to be crucial for the generation of new T cells. IMMUNODOMINANT Area of an antigen (ex. protein) corresponding to a short sequence of amino acids that is preferentially recognized by the immune system over the other regions of the antigen. This preferentially recognized immunodominant area may activate the immune system to produce antibodies or cytotoxic T cells (CD8+ T cells). IN VITRO ("In glass.") An artificial environment created outside a living organism (e.g., a test tube or culture plate) used in experimental research to study a disease or process. IN VIVO ("In life.") Studies conducted within living organisms (e.g., animal or human studies). INFECTION The state or condition where the body (or part of the body) is invaded by an infectious agent (e.g., a bacterium, fungus, or virus), which multiplies and produces an injurious effect (active infection). As related to HIV: Infection typically begins when HIV encounters a CD4+ cell. The HIV surface protein gp120 binds tightly to the CD4 molecule on the cell's surface. The viral envelope and the cell membrane fuse, a process governed by gp41, another surface protein. The viral core, containing HIV's RNA, proteins and enzymes, is released into the cell. ISOLATE An individual (as a spore or a single organism), viable part of an organism (as a cell), or a strain that has been separated (as from diseased tissue, contaminated water or the air) from the whole. Also, a pure culture produced from such an isolate or a particular strain of HIV taken from a patient. KILLER T CELLS Because viruses lurk inside host (e.g., human) cells where antibodies cannot reach them, the only way they can be eliminated is by killing the infected host cell. To do this, the immune system uses a kind of white blood cell, called killer T cells. These cells act only when they encounter another cell that carries a "marker" (i.e., a protein) that links it to a foreign protein - that of the invading virus. Killer T cells can themselves become infected by HIV or other viruses, or transformed by cancer. Also known as cytotoxic T cells (or cytotoxic T lymphocytes). LATENCY An inactive or resting period during a disease process. Clinical latency is an asymptomatic period in the early years of HIV infection. The period of latency is characterized in the peripheral blood by near normal CD4 counts. Recent research indicates that HIV remains quite active in the lymph nodes during this period. Cellular latency is the period after HIV has integrated its genome into a cell's DNA but has not yet begun to replicate. LENTIVIRUS "Slow" virus characterized by a long interval between infection and the onset of symptoms. HIV is a lentivirus, as is the simian immunodeficiency virus (SIV) that infects nonhuman primates, as is feline immunodeficiency virus (FIV) that infects cats. LEUKOCYTES Any of the various white blood cells that together make up the immune system. Neutrophils, lymphocytes, and monocytes are all leukocytes. LIPOSOMES Small artificial membranes (50-200 um) produced in laboratory that may mimic the lipidic membrane of cells, viruses, bacteria, parasites, or others. Liposomes are usually constituted of cholesterol and different phospholipids in various ratios, according to the need. Liposomes are often used to anchor proteins, incorporate peptides or coat pharmaceutical products for improving delivery and half-life of the molecules in the host. LYMPH NODES Small, bean-sized organs of the immune system, distributed widely throughout the body. Lymph fluid is filtered through the lymph nodes in which all types of lymphocytes take up temporary residence. Antigens that enter the body find their way into lymph or blood and are filtered out by the lymph nodes or spleen respectively, for attack by the immune system. LYMPH A transparent, slightly yellow fluid that carries lymphocytes. Lymph is derived from tissue fluids collected from all parts of the body and is returned to the blood via lymphatic vessels. LYMPHOID ORGANS Include tonsils, adenoids, lymph nodes, spleen, thymus, and other tissues. These organs act as the body's filtering system, trapping invaders (i.e., foreign particles, e.g., bacteria and viruses) and presenting them to squadrons of immune cells that congregate there. Within these lymphoid tissues, immune activity is concentrated in regions called germinal centers, where the thread-like tentacles of follicular dendritic cells (FDCs) form networks that trap invaders. LYMPHOKINES 1. These molecules are products of the lymphatic cells that stimulate the production of disease-fighting agents and the activities of other lymphatic cells. Among the lymphokines are gamma interferon (IFN-g) and interleukin-2 (IL-2). 2. Non-antibody mediators of immune responses, released by activated lymphocytes. MEMORY T CELLS A subset of T lymphocytes that have been exposed to specific antigens and can then proliferate (i.e., reproduce) during subsequent immune system encounters with the same antigen. MONOCLONAL ANTIBODIES Antibodies produced in the laboratory by a hybridoma or antibody-producing cell source for a specific antigen. Monoclonal antibodies are useful as tools for identifying specific protein molecules. MUTATION As related to HIV: During the course of HIV disease, HIV strains may emerge in an infected individual that differ widely in their ability to infect and kill different cell types, as well as in their rate of replication. Of course, HIV does not mutate into another type of virus. ONCOVIRUS Virus that belongs to the retrovirus family. The oncovirus sub-group is often associated with tumors and leukemia. PEPTIDES Biochemical formed by the linkage of several amino acids to form a chain. Longer chains are called proteins. The amino acids are coupled by a peptide bond, a special linkage in which the nitrogen atom of one amino acid binds to the carboxyl carbon atom of another. PHASE I TRIALS Involve the initial introduction of an investigational new drug into humans. Phase I trials are closely monitored and may be conducted in patients or healthy volunteers. The studies are designed to determine the metabolism and pharmacological actions of the drug in humans, safety, side effects associated with increasing doses, and if possible, early evidence of effectiveness. The trials can also include studies of structure-activity relationships, mechanisms of action in humans, use of the investigational drug as a research tool to explore biological phenomena or disease processes. The total number of patients included in Phase I studies varies but is generally in the range of 20 to 80. Sufficient information should be obtained in the trial to permit design of well-controlled, scientifically valid Phase II studies. PHASE II TRIALS Include controlled clinical studies of effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study, and determination of common, short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and usually involve no more than several hundred patients. These trials often seek to determine the optimum dose level for entry into Phase III testing. PHASE III TRIALS Expanded controlled and uncontrolled studies. They are performed after preliminary evidence of drug effectiveness has been obtained. Phase III trials are intended to gather additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide adequate basis for physician labeling. These studies usually include anywhere from several hundred to several thousand subjects. PHASE IV TRIALS Studies most often carried out after licensure of a drug. Generally, a Phase IV trial is a randomized, controlled trial that is designed to further evaluate the long-term safety and efficacy of a drug for a given indication. Phase IV trials are important in evaluating AIDS drugs because many drugs for HIV infection have been given accelerated approval with small amounts of clinical data about the drugs' effectiveness. PRECLINICAL Refers to the testing of experimental drugs in the test tube or in animals — the testing that occurs before trials in humans may be carried out. RECEPTOR A molecule on the surface of a cell that serves as a recognition or binding site for antigens, antibodies, or other cellular or immunological components. REGULATORY T CELLS T cells that direct other immune cells to perform special functions. The chief regulatory cell, the CD4+CD25+ T cell is a primary target for HIV. RESISTANCE Reduction in a pathogen's sensitivity to a particular drug. Resistance is thought to result usually from a genetic mutation. In HIV, such mutations can change the structure of viral enzymes and proteins so that an antiviral drug can no longer bind with them as well as it used to. Resistance detected by searching a pathogen's genetic makeup for mutations thought to confer lower susceptibility is called “genotypic resistance.” Resistance found by successfully growing laboratory cultures of the pathogen in the presence of a drug is called “phenotypic resistance.” RETROVIRUS A type of virus that, when not infecting a cell, stores its genetic information on a single-stranded RNA molecule instead of the more usual double-stranded DNA. HIV is an example of a retrovirus. After a retrovirus penetrates a cell, it constructs a DNA-based version of its genes using a special enzyme called reverse transcriptase. This DNA then becomes part of the host cell's genetic material. SIV Simian Immunodeficiency Virus. SIV is a HIV-like virus that infects monkeys, chimpanzees, and other nonhuman primates. THERAPEUTIC HIV VACCINE A vaccine designed to boost the immune response to HIV in persons already infected with the virus. A therapeutic vaccine is different from a preventive vaccine, which is designed to prevent a disease from becoming established in a person. TRANSCYTOSIS Mechanism by which a molecule or a pathogen like HIV may enter through one side of a cell and then migrate across the cell to exit on the other side. By this mechanism, HIV can cross the mucosa surface (ex. vaginal or anal mucosa) to gain access to the CD4+ T cells underneath and infect them. TRIMER / TRIMERIC To form a trimeric protein or a trimer, three individual proteins must be assembled together. This association may involve identical or different protein sub-units, and can be transient or permanent, all depending on the type of proteins. The native gp41 present on the surface of HIV is thought to exist in part as trimers from the association of three identical gp41 proteins (homotrimers). VIRUSES Viruses are small non-cellular organisms that act as parasites. They latch on to host cells within the body for their chemical energy and ability to reproduce. Viruses enter the body and attack at the cellular level. They typically approach a host cell and then attach themselves to it. Once attached, the virus penetrates the host cell and seizes control of the host cell's machinery involved in DNA replication and/or protein synthesis. It then uses this machinery to reproduce itself rapidly. This replication results in more viruses, each determined to hunt and attack more host cells. The host cells that have been attacked typically die.