AIDS Treatment Strategies Must Address Multi-Dimensional Nature of HIV Disease
The multiple phases of HIV disease and the many complex events that contribute to the deterioration of an HIV-infected person's immune system must all be addressed in the design of treatment strategies, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID) and chief of the NIAID Laboratory of Immunoregulation.
Dr. Fauci plans to discuss the immunologic events that occur at each stage of HIV infection and the challenges they pose for finding effective therapies in a state-of-the-science lecture, "The Immunopathogenic Mechanisms of HIV Infection," at the IXth International Conference on AIDS in Berlin on June 7 at 2:20 p.m.
HIV disease is multiphasic and multifactorial, with phases that overlap during its prolonged course," says Dr. Fauci. "Therapeutic strategies for HIV disease cannot be one- dimensional. Rather, they must take into account all the virologic and immunopathogenic processes that lead to the profound immunosuppression seen in patients with AIDS. A comprehensive approach is essential if we are to develop a truly effective treatment strategy."
Scientists now know that HIV replicates from the very early, or primary, phase of infection through the advanced phase of HIV disease when a patient's immune system is severely compromised. As reported in the March 25, 1993, Nature, Dr. Fauci and his colleagues have demonstrated that HIV is continuously present and replicating in the lymphoid tissue during HIV disease, even early in infection when a patient feels well and has no symptoms.
A true state of microbiologic latency probably does not exist at any time during the course of HIV infection," says Dr. Fauci. "We need to continue our search for combinations of safe and effective antiretrovirals that can be administered for a prolonged period of time. Although we do not yet have such drugs, the scientific rationale now exists for antiretroviral therapy throughout the course of HIV disease."
Throughout HIV infection, CD4+ T cells are progressively depleted, probably by both direct and indirect mechanisms. A healthy, uninfected person usually has 800 to 1,200 of these cells per cubic millimeter (mm3) of blood. When a person's CD4+ T cell count falls below 200/mm3, he or she becomes particularly vulnerable to opportunistic infections and cancers.
During the primary phase of infection, shortly after HIV enters the body, the virus replicates rapidly and disseminates. Large numbers of viral particles spread throughout the body, seeding themselves in various organs.
A week to a month later, the patient's immune system fights back with a vigorous response. Paradoxically, viral replication is enhanced during this period of immune activation. Large amounts of virus are produced and become trapped in specialized cells of the immune system, especially those found in the lymph nodes.
Within weeks, the immune system usually curtails the replication and spread of HIV in the bloodstream and a prolonged period of "clinical latency" ensues. In the lymph nodes, however, CD4+ T cells continue to become infected, and viral particles accumulate there.
Dr. Fauci and his colleagues have demonstrated that several naturally occurring immune proteins -- cytokines -- can stimulate laboratory cultures of cells latently infected with HIV to produce new virus. HIV may prompt production of high levels of certain cytokines, normally used by the immune system for cell-to-cell communication, contributing to the active viral replication seen in the lymph nodes during the asymptomatic period, the researchers speculate.
In the advanced stage of disease, networks of specialized cells in crucial immune organs such as the thymus and lymph nodes break down and apparently lose the ability to regenerate themselves, further compounding the suppression of the immune system caused by the decline in CD4+ T cells.
"We now know that HIV disease is characterized by phases of both immune activation and immune suppression," says Dr. Fauci. "We must further dissect the various phases of HIV disease to determine the feasibility of using agents that might block certain aspects of activation without compounding immunosuppression. We may also need to boost the immune response during the period of immunosuppression with agents that do not promote the replication and spread of HIV infection by putting the cells of the immune system into a state of total activation."
"Moreover, we must consider, when we do develop safe and effective antiretrovirals, how to reconstitute an immune system that may have lost part, or all, of its ability to regenerate itself," he adds. "The design of the next generation of drugs and vaccines to fight HIV depend on our actively and aggressively pursuing studies aimed at a further delineation of the immunopathogenic mechanisms of HIV disease."
NIAID, a component of the National Institutes of Health, supports research on allergy, immunology and infectious diseases. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
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