New AIDS treatment strategies must address the multiple phases and numerous immunological events of HIV disease, says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID).
Dr. Fauci plans to discuss the complex processes that lead to the deterioration of an HIV-infected person's immune system, and the challenges they pose for developing effective therapies in a state-of-the-science lecture, The Immunopathogenesis of HIV-1 Infection, at the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in New Orleans on Monday, October 18 at 8:00 a.m. Dr. Fauci's presentation is part of an AIDS colloquium cosponsored by ICAAC and the Infectious Diseases Society of America.
HIV disease is extraordinarily complex," says Dr. Fauci. "The disease has many components and is characterized by multiple and overlapping phases of active viral replication, inappropriate immune activation, elevated secretion of immune system proteins called cytokines, and immune deficiency. This complexity suggests that therapeutic strategies for the treatment of people with HIV must be multidimensional and comprehensive, addressing all of HIV's known pathogenic mechanisms."
Unfortunately," he adds, "the current generation of anti-HIV agents is only partially and temporarily effective in suppressing viral replication and is hampered by problems of toxicity and drug resistance. An important focus of the NIAID AIDS research effort is using our growing understanding of the HIV disease process to develop new therapies and interventions for all stages of HIV disease."
Once it enters the body, HIV replicates rapidly and disseminates. During this early, acute phase of infection, large numbers of viral particles spread throughout the body, seeding themselves in various organs, particularly lymphoid tissues such as the lymph nodes, spleen, tonsils and adenoids. Three to six weeks after exposure to the virus, up to 70 percent of HIV- infected individuals suffer flu-like symptoms related to the acute infection, such as fever, malaise, sore throat, headaches and swollen lymph nodes.
After several weeks, the patient's immune system fights back: B cells produce antibodies that neutralize some of the free virus and killer T cells destroy many HIV-infected cells. Then, the individual generally goes into a symptomless stage of infection lasting an average of 10 years. The immune system deteriorates slowly during this period as the number of crucial immune cells in the bloodstream, known as CD4+ T cells. These cells become infected in increasingly large numbers, and viral particles accumulate, both in infected cells and as free virus.
A true state of microbiological latency probably does not exist at any time during the course of HIV infection," explains Dr. Fauci.
Many Cd4+ T cells in the lymphoid organs probably are activated by the increased secretion of certain cytokines such as tumor necrosis factor-alpha and interleukin-6. Activation allows uninfected cells to be more easily infected and causes increased replication of HIV in infected cells. Other components of the immune system also are chronically activated, with negative consequences that may include the suicide of cells by a process known as programmed cell death and an inability of the immune system to respond to other invaders.
We now know that HIV disease has phases of activation and suppression of the immune system," says Dr. Fauci. "We must further dissect these phases to determine the feasibility of using agents that might block certain aspects of activation without compounding immunosuppression. We also may need to boost the immune response during periods of immunosuppression with agents that do not promote the replication and spread of HIV."
Ultimately HIV overwhelms the lymphoid organs. The FDC networks break down in late-stage disease and virus-trapping is impaired, allowing spillover of large quantities of virus into the bloodstream.
"The destruction of the lymph node structure seen late in HIV disease may preclude a successful immune response against not only HIV but other pathogens as well, and heralds the onset of the opportunistic infections and cancers that characterize AIDS," says Dr. Fauci.
Recent evidence suggests that HIV also destroys precursor cells and the microenvironment in the bone marrow and the thymus needed for the development of mature immune cells. These organs may lose their ability to regenerate, further compounding the suppression of the immune system caused by the loss of the FDC networks and the decline in levels of CD4+ T cells.
"We must consider, even 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," says Dr. Fauci. "The design of the next generation of drugs and vaccines to fight HIV depends on our actively and aggressively pursuing studies to further delineate the immunopathogenic mechanisms of HIV disease."