How does HIV escape the formidable early immune responses that successfully clear most other viral infections? How do various immune system molecules -- some of which shut down HIV, and some of which boost it up -- interact to modulate the course of disease in HIV-infected individuals?
Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, will present new data that help answer these questions in the keynote address at the 3rd Conference on Retroviruses and Opportunistic Infections in Washington, D.C., on Jan. 28 at 6:00 p.m. Dr. Fauci's state-of-the-science lecture is titled "Host Factors in the Pathogenesis of HIV Disease."
One reason HIV is unique is that despite the body's immune responses following initial, or primary, infection, which usually reduce the virus to very low levels, some HIV invariably escapes," says Dr. Fauci. "Our laboratory has recently delineated several interesting mechanisms that help explain viral escape in primary HIV infection. We also have shown that the regulation of HIV expression by molecules secreted by immune system cells is even more complex than previously realized."
Among the new findings to be presented:
Following primary infection with HIV, up to 70 percent of HIV-infected individuals suffer an acute syndrome often characterized by flu-like symptoms. HIV replicates extensively during this period, and large quantities of HIV disseminate throughout the body, especially to the lymphoid organs. An immune response ensues, including the expansion of different subsets of T cells.
T cell expansion.
Dr. Fauci and his team in the NIAID Laboratory of Immunoregulation have analyzed the T cells that respond to primary HIV infection, classifying them according to a variable (V) region of their receptors. (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 (see Aug. 11, 1994 Nature), the NIAID investigators 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 (restricted expansion). Other patients have minor expansions of a wider array of T cells, with many different V beta families.
"We originally found three patterns: major expansion of a single subset, a second pattern in which there was a moderate expansion of one or two subsets, and a third pattern characterized by the diffuse expansion of several subsets or no expansion at all," explains Dr. Fauci.
The group's preliminary data suggested a correlation between these patterns and clinical course. Patients with a very restricted major V beta expansion did poorly, whereas those with no expansion or diffuse expansion did better.
"These early observations appear to be correct. We now have data on 27 patients, and they can be divided into the three groups we identified previously," says Dr. Fauci. "Patients with more dramatic but restricted V beta expansions clearly experience more rapid progression of HIV disease than other patients."
What happens to CTLs?
The NIAID researchers also have found that major, restricted expansion of T cells in primary HIV infection is transient, and that among these expanded cells are cytotoxic T lymphocytes (CTLs), also known as killer T cells, specific for HIV.
Studying patients with acute primary HIV infection, the researchers found that after a brief period of time the markedly expanded populations of CTLs, effective at killing HIV, disappear completely.
"Two reasons one might suggest as to why these initially expanded CTL clones disappear so quickly are that the virus has mutated or that there is no more virus around," says Dr. Fauci. "Neither of these situations appear to be the case. We found that the virus was present in abundant quantities and was still in its original form at the time of the study. What appears to be happening is the exhaustion or disappearance of the CTLs that had expanded greatly and that could down-regulate the virus."
He and his colleagues also have found that the CTLs that initially expand greatly appear to accumulate in the bloodstream, rather than in lymph nodes, where most HIV is sequestered.
"We have demonstrated that not only do these clones disappear rapidly, but even when they can be found, they're not really where they are supposed to be," says Dr. Fauci.
New data on suppressor molecules.
At the Washington meeting, Dr. Fauci will also present new data on how molecules secreted by cells of the immune system interact to regulate HIV replication.
"Our focus has been to investigate the positive and negative balance of forces between inductive cytokines and suppressive cytokines."
Previously, Dr. Fauci and his colleagues have demonstrated that cytokines such as tumor necrosis factor, interleukin-1-beta and interleukin-6 all can boost HIV replication in infected cells.
The group also has found that CD8+ T cells are able to block HIV expression in both the blood and lymph nodes, as first reported by Dr. Jay Levy of the University of California at San Francisco. The NIAID researchers recently have observed that the cytokine interleukin-2 is a potent inducer of this so-called "CD8 suppressor" phenomenon. In contrast, interleukin-12 does not significantly induce suppressing activity in CD8+ T cells (see Nov. 7, 1995 Proceedings of the National Academy of Science).
Building on the recent work of Dr. Robert Gallo, who used cells acutely infected with HIV in vitro, Dr. Fauci and his group have studied three immune-signalling molecules -- RANTES, MIP-1 alpha and MIP-1 beta -- that appear to be associated with the CD8 suppressor phenomenon. The NIAID group has further demonstrated that these molecules, called chemokines, suppress in vitro virus replication in cells from HIV-infected people. The researchers have shown that IL-2 induces CD8 suppressors by selectively inducing CD8+ T cells to secrete RANTES, MIP-1 alpha and MIP-1 beta. IL-12, on the other hand, does not induce these molecules. Blocking RANTES, MIP-1 alpha and MIP-1 beta eliminates the suppressor effect.
Other sources of HIV suppressors.
Finally, Dr. Fauci and his team have found that RANTES, MIP-1 alpha and MIP-1 beta are secreted not only by CD8+ cells, but also by CD8-depleted cells such as CD4+ T cells and monocytes.
"It is becoming clear that not all HIV suppression is due to CD8+ T cells," he says. "Suppression by chemokines can occur even in the absence of CD8+ cells."
To further complicate matters, the NIAID researchers have found that RANTES, MIP-1 alpha and MIP-1 beta may suppress HIV in one model system, but not in another. "As is always the case in immunology, the story ends up being much more complicated than you first expected," says Dr. Fauci. "Much more work needs to be done before these results can be translated to the patient."
Dr. Fauci's principal collaborators in these studies are Drs. Giuseppe Pantaleo, Drew Weissman and Audrey Kinter.
NIAID is a component of the National Institutes of Health. NIAID conducts and supports research aimed at preventing, diagnosing and treating illnesses such as AIDS and other sexually transmitted diseases, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Public Health Service, part of the Department of Health and Human Services.Further Reading:
Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995;270:1811-5, (Dec. 15, 1995).
Kinter AL, Bende SM, Hardy EC, Jackson R, Fauci, AS. Interleukin 2 induces CD8+ T cell-mediated suppression of human immunodeficiency virus replication in CD4+ T cells and this effect overrides its ability to stimulate virus expression. Proc Natl Acad Sci USA 1995;92:10985-9, (Nov. 21, 1995).
Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 1993; Mar;57(1):183-289, (March 1993).
Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, Borrow P, Saag MS, Shaw GM, Sekaly RP, Fauci AS. Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature 1994;370(6489):463-7, (Aug. 11, 1994).