News from NIAID - November 11, 1993
National Institute of Allergy and Infectious, National Institutes of Health

* block the inappropriate activation of an HIV- infected person's immune system without worsening immune deficiency,

* selectively inhibit the inappropriate secretion of proteins called cytokines by an HIV-infected patient's immune cells or block the action of these proteins and

* reconstitute the damaged immune system of an HIV- infected person.

Investigations by Dr. Fauci and others have shown that HIV replicates from the very early, primary phase of infection through the advanced phase of HIV disease when a patient's immune system is severely compromised. "The virus itself is a primary component of the pathogenic process of HIV disease, and effective antiretroviral drugs are essential to any therapeutic strategy," says Dr. Fauci. "The development of safer and more effective antiretroviral agents appropriate for early and ongoing intervention in HIV is a crucial goal of NIAID AIDS research." However, the virus is not the only potential target of therapeutic intervention, Dr. Fauci says. Because HIV disease has phases of both immune system activation and suppression, "we must further study these phases to determine the feasibility of using agents that might block certain aspects of activation without compounding immunosuppression," he explains. "We also may need to boost the immune response during periods of immunosuppression with drugs that do not promote the replication and spread of HIV." Infection with HIV is associated with the increased production of a number of cytokines, including tumor necrosis-alpha and interleukin-6. These and some other cytokines can activate CD4+ T cells, the crucial immune cells destroyed by HIV. Activation causes increased replication of HIV in infected cells and may enhance infection of other cells. Other components of the immune system also are activated during HIV infection, with harmful consequences that may include the suicide of certain immune cells and an inability of the immune system to respond to other invaders. "Approaches such as selectively blocking cytokine secretion or action will likely have a role in the treatment of HIV-infected individuals," says Dr. Fauci. In contrast, other cytokines with key roles in the regulation of normal immune function may be secreted in decreased amounts during HIV infection. "Giving cytokines in an attempt to partially reconstitute or stimulate the defective immune system is an additional strategy being pursued at NIAID and elsewhere," says Dr. Fauci. "In ongoing research at NIAID, dramatic and sustained increases in the numbers of crucial CD4+ T cells have been observed in small numbers of HIV-infected patients treated with intermittent, intravenous doses of a cytokine called interleukin-2." Recent studies suggest that HIV destroys the lymph nodes and related organs, as well as precursor cells that develop into immune cells and the parts of the bone marrow and thymus needed for such maturing. "Spontaneous and complete regeneration of these crucial immune cells and organs is unlikely, even if virus replication could be totally blocked by an effective anti- HIV agent," Dr. Fauci says. "Therapeutic strategies in HIV disease must address the possibility of reconstituting the immune system. Thus, it is clear, based on our expanding knowledge of the pathogenic mechanisms of HIV disease, that we must take a multidimensional approach towards therapy." NIAID, a component of the National Institutes of Health, supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. NIH is an agency of the U.S. Public Health Service, Department of Health and Human Services.

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Copies of Dr. Fauci's article, "Multifactorial Nature of Human Immunodeficiency Virus Disease: Implications for Therapy," can be obtained by calling Science at (202) 326- 6440.