Contact: Greg Folkers
National Institute of Allergy and Infectious Diseases
Certain patterns of immune responses to the human immunodeficiency virus (HIV) during the first weeks of infection are highly predictive of an individual's subsequent rate of disease progression, according to investigators at the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues.
"Our data strongly suggest that the immunologic factors at work during this early period of infection, as much or more than virologic factors, are the critical determinants of the ultimate outcome of HIV disease," says Anthony S. Fauci, M.D., NIAID director and chief of the NIAID Laboratory of Immunoregulation. "The growing understanding of the initial interaction between HIV and the immune system, and of the immune responses to HIV during primary infection, both favorable and unfavorable, is important to the development of effective HIV vaccines."
Drs. Fauci, Giuseppe Pantaleo, formerly of NIAID's Laboratory of Immunoregulation and now with the Centre Hospitalier Vadois in Lausanne, Switzerland, and their coworkers report their findings in the January 1997 Proceedings of the National Academy of Sciences.
Once it enters the body, HIV infects a large number of CD4+ T cells and replicates rapidly. During this acute, or primary phase of infection, the blood contains many viral particles that spread throughout the body, seeding various organs, particularly the lymphoid organs such as the lymph nodes, spleen, tonsils and adenoids. Two to four weeks after initial infection with the virus, up to 70 percent of HIV-infected persons suffer flu-like symptoms. The patient's immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies.
"One important way in which a person's immune system responds to primary HIV infection is by mobilizing different subsets of certain white blood cells -- CD8+ T cells -- that can destroy cells that have been infected with HIV," says Dr. Fauci. "We found a clear correlation between the patterns of CD8+ T cell expansion during primary infection and how well a patient did clinically during the subsequent year or 18 months. Regardless of the amount of HIV in the blood during primary infection, patients who mobilized a broad repertoire of CD8+ T cells had slower progression of disease than individuals who showed a pronounced expansion of only a single subset of CD8+ T cells."
Scientists currently do not know the reasons for the qualitative differences in the immune responses of different individuals during primary HIV infection, Dr. Fauci notes, but they probably include factors intrinsic to the HIV-infected person, such as the genes that encode specific markers called human leukocyte antigens (HLAs) on immune system cells.
The current report is the latest from an ongoing series of experiments begun several years ago in the Laboratory of Immunoregulation. In their research, Dr. Fauci and his team have carefully analyzed CD8+ T cells taken from patients during primary HIV infection, classifying the cells according to the variable (V) regions of their receptors. All T cells have receptors with alpha and beta chains, and on the beta chain is a region known as V-beta that varies among T cells. Humans have 24 different V-beta families.
Previously, the NIAID team demonstrated that during primary infection, some HIV-infected patients have a marked expansion of a limited variety of T cells, representing very few V-beta families. Other patients mobilize a wider array of T cells, with many different V-beta families.
In the current study, the investigators studied 21 individuals with documented primary HIV infection at clinics in the United States, Canada, Switzerland and Italy. Blood samples from these patients were analyzed in NIAID's Laboratory of Immunoregulation.
Four of these 21 patients had major expansions of a single V-beta subset during primary infection. Approximately one year later, each of these four individuals had developed AIDS, as indicated by CD4+ T cell counts below 200 cells per cubic millimeter (mm3) of blood. The mean CD4+ T cell count among these patients was 101 cells/mm3; a healthy person without HIV infection usually has a CD4+ T cell count of 600-1500 cells/mm3.
Four other patients had moderate expansions of one or two V-beta subsets. At approximately one year, this group of patients had a mean CD4+ T cell count of 456/mm3.
Thirteen patients had expansions of multiple V-beta families or no expansion at all. The mean CD4+ T cell count in this group of patients was 651/mm3 after approximately one year.
Previous studies have shown that levels of HIV in a person's bloodstream six to 12 months following primary infection are highly predictive of that person's clinical course, with more virus generally correlating with more rapid disease progression. The current findings add a new level of complexity to the understanding of the relationship between "viral load" and a person's clinical outcome.
"In the current analysis, we studied an earlier stage of disease -- the primary infection -- and found that the initial level of HIV in the blood does not predict clinical outcome. At this early stage of disease, the qualitative nature of a person's immune response, rather than plasma viremia, proved to be the best prognostic indicator," notes Dr. Pantaleo.
"Individuals with an effective primary immune response -- those with a broad expansion of CD8+ T cell subsets -- appear to be the same people who will have low levels of virus six or 12 months later, levels which in turn are predictive of relatively slow disease progression. In contrast, individuals with an ineffective primary immune response (i.e., expansion of only a single subset of CD8+ Tcells) may have less success in controlling the virus over time, and therefore, have high levels of virus six to 12 months later," says Dr. Fauci.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the Public Health Service, U.S. Department of Health and Human Services.
Pantaleo G, et al. The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia. Proc Natl Acad Sci USA 1997;94:254-258.