Knowledge about the complex responses of the human body to HIV, which differ from individual to individual and play a major role in the progression of HIV disease, is the necessary foundation for understanding the pathogenesis of AIDS and for developing effective therapeutic interventions, according to 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 "Host Factors in the Pathogenesis of HIV Disease" during a plenary presentation on Monday, Aug. 8, at 9 a.m. Japan Time, at the Tenth International Conference on AIDS in Yokohama, Japan.
His talk will include new findings regarding the complex role played by several naturally occurring immune proteins called cytokines, the host responses of HIV-infected people whose disease does not progress and certain immunologic events associated with primary infection.
By intensive study of lymph nodes from patients with HIV infection, Dr. Fauci and his colleagues have characterized more precisely how immune responses, cellular activation, cytokine secretion and immunopathogenicity contribute to the multifactorial and multiphasic process of HIV disease.
Role of cytokines
Looking at cytokines in the milieu of the lymph node from an HIV-infected individual, Dr. Fauci and his colleagues found substantial changes in cytokine expression including over-expression of certain cytokines that probably reflects a state of heightened cellular activation. These cytokines include interleukin-6 (IL-6), tumor necrosis factor alpha and IL-1-beta, which they had shown earlier to be important in the induction of HIV expression."This over-expression of cytokines very likely plays a major role in the propagation and perpetuation of persistent HIV replication," explains Dr. Fauci.
The investigators also looked at the profiles of cytokines in individuals as they progressed from early to late disease. They found under-expression of IL-2 and IL-4 and over-expression of other cytokines throughout the course of disease. However, as reported in the July 8, 1994 issue of Science, the researchers could not find a predominance of a particular pattern of cytokine expression, designated as T-helper 1 (Th-1) versus T-helper 2 (Th-2), when comparing patients who had early HIV disease with those who had advanced disease. In addition, a shift from the Th-1 to Th-2 cytokine pattern was not noted in individual patients as they progressed from early to advanced disease.
Th-1 cells are immune system cells that produce interferon gamma and IL-2, as well as several other cytokines. These cells also appear to be crucial to cell-mediated immune responses, in which immune cells kill invading organisms directly. Th-2 cells trigger a second arm of the immune system called the humoral response, which uses antibodies to fight infection. Th-2 cells secrete IL-4, IL-5, IL-10 and other cytokines.
Dr. Fauci and his colleagues studied lymph node tissue from individuals who had been infected with HIV for approximately 10 years, remained healthy and had CD4+ T cell counts well within the normal range. The lymph node architecture in these individuals is remarkably well preserved, according to Dr. Fauci. Viral burden is low, although the virus that is present generally is infectious and can replicate. Levels of viremia vary in non-progressors, but generally are low compared to progressors.
"These findings indicate," Dr. Fauci states, "that the host's response to HIV vis-a-vis virus trapping, tissue reaction to virus, and perhaps the initiation of immunopathogenic processes in the lymphoid tissue probably plays an important role together with the competency of the virus in the evolution of the state of long-term non-progression."
"The presence of low level, but persistently replicating, HIV in some individuals was also reflected by a robust immune response to the virus," says Dr. Fauci. "Specifically, high levels of neutralizing antibodies and adequate levels of cytotoxic T cells were detected in long-term non-progressors as compared to progressors."
Events associated with primary infection
Many individuals experience an acute illness associated with primary infection with HIV. In studying the T-cell-mediated immune response to primary HIV infection, Dr. Fauci and his colleagues found considerable expansion in a restricted set of variable-domain beta-chain (V-beta) families of T cell receptors. They demonstrated that this V-beta expansion was almost exclusively within the activated CD8+ T cells. Certain patients were followed for up to two years.
"Of note," says Dr. Fauci, "is the fact that those individuals who had a major expansion of a restricted number of V-beta subsets among their CD8+ T cells tended to do more poorly with more rapid decline of their CD4+ T cells compared to patients who did not manifest this phenomenon. Portions of this study will be reported in Nature Aug. 11, 1994.
NIAID, a component of the National Institutes of Health (NIH), supports investigators and scientific studies at universities, medical schools, hospitals and research institutions in the United States and abroad aimed at preventing, diagnosing and treating such illnesses as AIDS, tuberculosis and asthma as well as allergies. NIH is an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.
Prepared by: Office of Communications National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, MD 20892
Public Health Service U.S. Department of Health and Human Services June 1994