Etiology and Pathogenesis
Research progress in this area includes:
NIH-sponsored investigations have led to significant advances in the understanding of HIV and how it causes disease. These studies facilitated the identification of HIV as the causative agent of AIDS, the development of a highly sensitive diagnostic test for HIV infection, delineation of some of the mechanisms of immune dysfunction, the elucidation of the role of the structural and regulatory gene products of HIV, and the delineation of the cytopathic effects of HIV infection. Insight gained from these studies is crucial for the development of potential therapeutic agents and vaccines that will result in the control, treatment, and prevention of HIV infection and its sequelae.
By use of sophisticated molecular and cellular biology techniques, scientists are uncovering the detailed processes responsible for virus growth and escape from the immune response. The mechanisms for generation of HIV antigenic variation are being defined, and the role of this variation in disease progression is being identified. Additionally, the cellular factors involved in regulation and expression of viral genes are being delineated. Specific NIH-sponsored research programs focus on mechanisms of viral and immune pathogenesis. The Centers for AIDS Research (CFARs) and investigator-initiated research grants, some of which have been awarded through the Mechanisms of AIDS Pathogenesis initiative, target basic research studies in these areas. Such studies provide the knowledge base for drug and vaccine development, funded in part through the National Cooperative Vaccine Development Groups, the National Cooperative Drug Discovery Groups, and the Strategic Program for Innovative Research on AIDS Therapies. Efforts in AIDS research are facilitated by the NIH AIDS Research and Reference Reagent Program, which provides essential AIDS-related reagents to qualified researchers worldwide.
Ongoing research at the molecular, cellular, and organ-system levels is elucidating the pathogenic mechanisms of HIV infection. Recent studies have shown that newly infected patients experience a high rate of viral replication and that, in an as yet unpredictable manner, their immune systems undergo changes that continue until the development of AIDS. Research at the cellular and molecular levels includes studies of the mechanisms by which HIV enters and infects various cell types; the interaction between the viral regulatory elements and infected cells that appears to be directed at maintaining a persistent infection; the mechanisms of inappropriate immune activation; the net balance among various types of immune cells and the immunomodulatory growth factors expressed by those cell types; and the viral- and host-mediated mechanisms that influence the level of viral expression seen in successive stages of HIV disease.
Studies have shown that HIV infection is active in the lymphoid tissue throughout clinical latency and that accumulation, or trapping, of virus in the lymph nodes may provide a site for transmission of HIV to uninfected immune cells as well as contribute to the destruction of the architecture of the lymphoid tissues. In addition, NIH-supported investigators demonstrated that significant levels of virus are present in plasma during all stages of HIV infection, including the clinically asymptomatic phase, and that active virus replication is directly linked to the destruction of T cell populations in infected individuals. This new understanding of the magnitude and kinetics of HIV replication in vivo has great implications for understanding and potentially overcoming the obstacle to effective antiviral therapy that is posed by the development of viral variants that are resistant to the inhibitory effects of antiviral drugs. The quantitation of HIV in plasma provides a new, direct virologic end point for monitoring virtually all infected people and may be of particular utility in assessing antiviral efficacy in clinical studies, especially in early-stage disease, where conventional virologic markers are often negative. In addition to measuring viral burden, NIH-sponsored research is demonstrating the breadth and specificity of the anti-HIV immune response as a possible factor in a longer period of clinical latency. This research reinforces the importance of understanding both the generation of HIV genetic variation and the host immune response that struggles to control the infection.
To further the understanding of the interaction between the virus and host immune system response, the NIH is placing particular importance on the study of the in vivo effects of HIV infection. NIH-sponsored longitudinal cohort studies constitute a major resource for this type of pathogenesis research. Specific cohorts, such as long-term nonprogressors, HIV-exposed but uninfected individuals, and rapid progressors, will provide clues for treatment and vaccine research by helping to characterize immune response profiles and provide information on correlates of immunity. In addition, the resources developed in these cohort studies and the NIH, NIAID, Division of AIDS Treatment Research Initiative are being used to identify and assess individuals experiencing acute infection for virologic, immunologic, and pathogenic studies. These cohort studies provide a powerful tool for clinical/laboratory correlative studies and serve as the basis for effective therapeutic intervention studies.
In vivo research into mechanisms of viral immunopathogenesis also utilizes animal models. All the available animal models contribute to our understanding of disease mechanisms. Continued support of in vivo research is a high priority at the NIH.
There are hypotheses regarding AIDS pathogenesis in which factors, either genetic, environmental, or other infectious agents, in addition to HIV infection, may promote specific disease manifestations. For example, a novel herpesvirus has been identified in Kaposi's sarcoma tissues and may prove to be the causative agent of this malignancy. Other such factors, often referred to as "cofactors," may enhance or retard HIV transmission and/or alter the rate of progression from HIV infection to the development of symptomatic disease.
The biologic determinants of infectiousness and susceptibility are important areas currently under investigation. Specific attention is being given to the possible correlation between the level of cell-free or cell-associated virus in blood, semen, urine, cervical/vaginal secretions, or oral fluids and the probability of transmission. In addition, NIH-funded research also is studying factors such as the cellular and molecular aspects of mucosal immunity, viral and host genetic factors, and other infectious agents and STDs as cofactors and their impact on HIV susceptibility and transmission.
In response to the changing demographics of the disease, studies have been designed to elucidate the pathogenic mechanisms more commonly observed in women, children, and adolescents with HIV infection. As part of this effort, the NIH supports a number of epidemiologic cohort studies specifically focused on women and adolescents. The study of patient samples and data generated by these cohorts is providing critical information about the course of the disease in these populations. These NIH-sponsored cohort studies represent an important scientific link between epidemiology and basic research into the pathogenic mechanisms of HIV disease.
In the area of maternal-fetal transmission, studies have demonstrated that the transmission rate of HIV from mother to infant is between 20 and 35 percent. A recently completed large clinical trial has determined that administration of zidovudine during gestation and labor and to the infant after birth significantly reduces the rate of HIV transmission. An ongoing clinical trial is evaluating hyperimmune anti-HIV immunoglobulin (HIVIG) for blocking or reducing maternal-fetal transmission. However, crucial issues associated with maternal-fetal transmission remain, including the specific mechanisms involved and the time distribution at the point at which HIV transmission occurs between mother and infant; whether specific strains (monocytotropic or lymphocytotropic) of the virus are more likely to be transmitted; delineation of the role of maternal immunity in prevention of transmission to the fetus; and the role of cofactors such as substance abuse and other infections.
Since HIV infection is known to affect the functioning of virtually all the organ systems within the body, current basic and clinical research studies are focused on examining the progression of disease in the various systems, including the interactions between HIV and the normal cellular functions of specific cell types.
Since its recognition, AIDS has had a close association with a broad spectrum of cancers, including Kaposi's sarcoma (KS), lymphomas, cervical carcinomas, anogenital carcinomas, and hepatitis B-related hepatocellular carcinomas. The proportions of malignancies and their incidence rates are increasing as the development of effective antiretroviral therapies and prophylaxis against opportunistic infections leads to prolonged survival of HIV-infected patients in the immunodeficient state. NIH-sponsored investigators have demonstrated a striking relationship between profound cellular immunodeficiency, manifested by the depletion of CD4 lymphocytes, and the development of non-Hodgkin's lymphoma (NHL). Studies of AIDS-related KS have uncovered the crucial roles of a cancer-associated herpesvirus, various angiogenic growth factors, and HIV-related factors in disease pathogenesis. Elucidation of the interactive components involved in the pathogenesis of the various AIDS-associated cancers is now beginning to translate into clinical trials of multimodal therapies that are designed to interdict the effects of multiple factors and cofactors. The identification of pathogenic factors will also serve as targets for disease prevention and treatment.
NIH-sponsored studies of the neuropathogenesis of HIV infection are enhancing our understanding of the profound impact of HIV disease on both the central and peripheral nervous systems. New techniques in the molecular detection of HIV, as well as recent research on cellular genes and development of primate models of HIV encephalopathy, have focused on possible mechanisms of neuronal dysfunction due to toxic cytokines and viral products. These investigations will help provide for a better understanding of the molecular and cellular changes underlying CNS disease. Studies also will continue to identify the link between HIV-associated neuropathology and neuropsychological impairment. In addition, experimental models of HIV/CNS disease have been established in primates, felines, and rodents. These models can be utilized to investigate various aspects of HIV/CNS disease in humans and are expected to be employed in the future for testing therapies for HIV/CNS disease.
NIH-sponsored research on the pathogenesis of the opportunistic infections (OIs) involves the study of a diverse group of bacteria, viruses, protozoa, and fungi. Efforts are under way to define the interactions between Mycobacterium tuberculosis and HIV at the cellular level and in HIV-infected people. Additional OIs of high priority under study are CMV infection, infectious causes of wasting, Mycobacterium avium infection, and infection by pathogenic fungi. Many of these agents also cause disease in non-immunosuppressed individuals. Studies are also examining the OIs that may be the cause of increased morbidity and mortality in women and an overall acceleration of HIV pathogenesis. Since the OIs remain the principal cause of death for HIV-infected people, understanding the mechanisms of pathogenesis of these organisms will contribute to improved quality of life as well as a better understanding of how to treat and prevent these diseases.
Wasting contributes significantly to the debilitation, morbidity, and mortality in AIDS. Ongoing studies have shown the etiology of wasting in HIV infection to be complex and multifactorial. Resting energy expenditure is chronically elevated in HIV infection, in part due to disturbances in lipid metabolism. OIs are associated with episodes of rapid weight loss, as appetite is suppressed and caloric intake cannot meet the increased metabolic demands. Elucidation of the factors contributing to wasting will allow effective therapies to be tailored to the specific mechanisms by which wasting occurs, with the potential for prolonging life and enhancing its quality in patients with HIV infection. The mechanisms by which wasting may alter immune function and increase susceptibility to OIs are also under investigation.
Gastrointestinal dysfunction, particularly diarrhea and malabsorption, is common in HIV infection. Ongoing studies are distinguishing the contributions of opportunistic infections, acquired deficiencies in intestinal enzymes, tumor involvement, and direct intestinal infection with HIV and identifying the specific nature of the resulting enteropathy and malabsorption. The endocrine and immune systems share a common set of signals. Characterization of the endocrine alterations associated with HIV infection and AIDS and their potential effects on immune function is ongoing.
HIV-associated heart disease (HIVHD) also represents a cause of morbidity and mortality in seropositive children and adults. Additional ongoing studies are examining the pulmonary effects of HIV infection, elucidating the basis of HIV-associated nephropathy, and delineating the early cutaneous manifestations of HIV infection.
The results of studies concerned with the etiology and pathogenesis of HIV infection and AIDS have major implications for basic biomedical and clinical research in non-AIDS areas. Basic studies on mechanisms of viral replication provide insight into all life processes, and studies on transcription, RNA processing, and translation provide information about mechanisms controlling cellular gene expression and oncogenesis. To date, research into the mechanisms of action of HIV gene products, particularly the regulatory functions provided by the tat and rev proteins, has provided new insights into the fundamental processes by which normal human cells produce and process RNA and proteins. Further, as AIDS is a disease primarily of the immune system, understanding the function and dysfunction of the immune system will contribute to increased knowledge of other immune system diseases as well as to knowledge required for development of an HIV vaccine. The studies of HIV disease also illuminate mechanisms of other immunodeficiency states. This points to the need to understand the normal developmental details of the immune system to help define the processes that are disrupted in AIDS. This will also provide valuable information on how to improve all viral vaccines. Also, information concerning the blood-brain barrier will provide the basis for the development of therapeutics for other disorders of the central nervous system, and the development of targeted drug design strategies will have implications for a wide variety of therapeutics for other diseases. In addition, results of these studies will continue to provide important information for the development of diagnostic assays to preserve the safety of the Nation's blood supply. The increasing understanding of mechanisms of maternal-fetal transmission and the development of pathogenesis-based interventions to abrogate such transmission will have important societal impact. In sum, the applications of knowledge of etiology and pathogenesis of HIV disease will serve as the building blocks for the design of therapeutic and preventive strategies.
Etiology and pathogenesis research sits in a pivotal position in the pathway from basic and epidemiologic observations to clinical intervention. The multi-dimensional flow of information among each of these disciplines will generate new principles that cut across and inform all aspects of HIV-related research. The NIH is committed to fostering new links across these areas to facilitate progress. Among these cross-cutting issues are the development and standardization of assays and animal models and the sharing of, and access to, patient specimens and information data bases. For example, studies of developmental immunobiology and neurobiology will synergize with HIV therapeutics and prevention research in both adults and children. Animal models are critical for preclinical antiretroviral drug and HIV vaccine development. The development of reliable and accurate biomarkers to quantitate disease activity is crucial for epidemiologic studies as well as for the purpose of measuring the effects of specific interventions. Essential to each of these research areas is the efficient acquisition, careful storage, and broad availability of relevant patient and research animal materials. To this end, the NIH will work to integrate the investigative effort of investigators in diverse disciplines to foster a broad-based collaborative research portfolio.
For more information on Etiology and Pathogenesis HIV/AIDS-related research at the NIH, contact:
Mark Feinberg, M.D., Ph.D.
Office of AIDS Research, NIH
Building 31, Room 4C06
Bethesda, MD 20892
(301) 496-4564 TELEPHONE
(301) 496-4843 FAX
Last Update: October 4, 1996
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