July 15, 2004
Dr. Fauci will deliver his special lecture, entitled "Pathogenic Mechanisms of HIV Disease: The Role of Viral Replication and Immune Activation," on July 15 at 12:30 p.m. Bangkok time (1:30 a.m. Eastern Time). He will present new data that underscore the paradoxical nature of HIV infection -- the very immune cells that are activated to destroy the virus provide a permissive environment for virus propagation and persistence.
Early on in the AIDS epidemic, scientists recognized that HIV destroys the immune system through multiple pathways. But they did not understand just how the virus causes such mass destruction and have been foiled in attempts to completely eradicate the virus.
Through one method of attack, the virus directly infects T lymphocytes that bear the CD4 surface protein -- the so-called CD4+ T cells that orchestrate the immune response. But it has become clear that HIV also wreaks havoc using indirect approaches. The virus triggers certain cells of the immune system to become hyperactive, thereby boosting HIV replication and leading to a vicious cycle of enhanced immune activation and viral production, ultimately resulting in the dysfunction or death of multiple types of immune cells.
"Cells that are in a state of activation very efficiently support the replication of virus," he says. "This insidious mechanism compounds the propagation of HIV and ultimately the depletion of the cells that are supposed to protect against infection."
A major focus of Dr. Fauci's lab has been to identify and characterize latent reservoirs of HIV in resting CD4+ T cells. Highly active antiretroviral therapy (HAART) has been effective in drastically reducing levels of HIV in infected patients and slowing the progression of the disease. However, hope of eliminating the virus was quashed with the sobering discovery that small numbers of latently infected resting CD4+ T cells persist even after long-term therapy with HAART. When therapy is discontinued, viral replication and CD4+ T-cell proliferation and destruction resume.
At the Bangkok meeting, Dr. Fauci will present data demonstrating that HIV-induced aberrant immune activation has a profound impact on the resting CD4+ T-cell viral reservoir. Previously, it has been suggested that the viral reservoir does not produce any HIV regardless of levels of plasma viremia in infected patients. Dr. Fauci will discuss data demonstrating that resting CD4+ T cells isolated from viremic patients (who have actively replicating virus) are subtly different from resting CD4+ T cells isolated from aviremic patients (who are being treated with antiretroviral drugs and do not have actively replicating virus) in terms of spontaneously releasing virus in vitro.
Although resting CD4+ T cells from viremic and aviremic patients look the same under the microscope and appear to lack any differences in cell surface marker proteins, resting CD4+ T cells from viremic patients spontaneously produce HIV virions, but cells from aviremic patients do not. Using DNA microarray analysis, LIR investigators found that the two types of cells express different sets of genes. In particular, cells from viremic patients have an increased expression of genes that makes the cells permissive to viral replication.
"There is a fundamental difference in the resting CD4+ T-cell reservoir in viremic versus aviremic patients," says Dr. Fauci. "Cells from viremic patients are continually poised to express virus."
Active viral replication affects the physiologic state of resting CD4+ T cells in HIV-infected viremic patients, he explains. This, in turn, allows the release of HIV into plasma without exogenous activation stimuli, further contributing to the vicious cycle of HIV replication and immune cell hyperactivation and depletion.
The question of how virus can be produced by infected T cells without their concomitant activation remained puzzling, because it had been thought that virus primarily replicates in actively dividing, and not quiescent, or resting cells. To address this issue, Dr. Fauci and his team also looked at the effects of the HIV envelope protein on normal lymphocytes. They found that the envelope proteins induce the expression of cellular genes, including certain cytokine genes, associated with enhancement of HIV replication. This subtle induction of gene expression occurs in the absence of the expression of the classical markers of cellular activation. One of these genes, called NFAT, codes for a transcription factor that regulates the transcription of cytokine genes needed for immune cell activation as well as genes needed for replication of HIV.
Dr. Fauci will discuss data demonstrating that the induction of NFAT by HIV envelope proteins requires coordinate signaling through the CD4 receptor and the appropriate co-receptor. He will also discuss how envelope proteins that bind to the CCR5 co-receptor induce a different set of genes than those that bind to the CXCR4 co-receptor.
Thus, binding of the HIV envelope to the surface of T cells may trigger the replication and release of virus from infected quiescent cells as well as induce the expression of cytokines that contribute to aberrant immune cell activation.
Dr. Fauci and his team also have looked at how HIV replication affects B cells, the immune cells that produce antibodies. More than 20 years ago, Dr. Fauci and his colleagues reported that AIDS patients have abnormalities in B cells, including an overproduction of antibodies. Now, LIR scientists have identified a subset of B cells with abnormal characteristics, isolated from viremic patients. These cells lack the CD21 cell surface marker and have a reduced proliferative capacity, enhanced antibody secretion and visible changes in morphology.
These abnormal B cells also express a different set of genes compared to B cells from uninfected and aviremic infected individuals. In particular, there is an increased expression of genes involved in apoptosis -- or programmed cell death -- and a greater tendency of these cells to die. Many of the genes upregulated in this subset of B cells are induced by interferon or associated with terminal differentiation of B cells.
"Although B cells are not infected with HIV, the virus apparently induces indirect effects on a subset of cells resulting in aberrant activation and, ultimately, cell death," says Dr. Fauci. "This contributes to the widespread immune cell depletion and dysfunction, characteristic of HIV infection."
Other members of the Fauci lab have examined the effects of HIV on a third class of immune cells, natural killer (NK) cells. NK cells, which make up part of the innate, or non-specific immune system, recognize and kill invading or foreign cells, as well as cells that are virally infected or oncogenically transformed. NK cells are able to distinguish "self" from "non-self" and respond accordingly through a delicate balance of inhibitory and activating receptors expressed on the cell surface. Inhibitory receptors prevent NK cells from attacking other cells considered "self" while activating receptors enhance the ability of NK cells to bind to virally infected and other "nonself" cells for destruction. Such abnormal target cells do not express the appropriate MHC class I molecules that are recognized by the inhibitory receptors on NK cells. Under normal circumstances, in situations where MHC class I is expressed on cells, the inhibitory receptors dominate over the activating receptors in the control of NK cell function. In viremic patients, Dr. Fauci's team identified a population of NK cells with lower-than-normal expression of activating receptors and a normal or increased expression of inhibitory receptors. The cells also produced less perforin and granzymes, proteins involved in cell killing, and they secreted less TNF-alpha and interferon-gamma, important cytokines in host defense.
"Like the abnormal B cells, this subset of aberrantly activated NK cells are more susceptible to cell death and unable to eliminate virally infected cells during HIV infection," Dr. Fauci notes.
In summary, HIV pathogenesis paradoxically involves both direct and indirect effects of HIV that constitute a relentless cycle of aberrant immune activation. HIV can directly infect and lead to the death of CD4+ T cells. But it can also indirectly activate CD4+ T cells when envelope proteins bind to the cell surface and trigger activation, and when bursts of cytokines compound the state of activation. Cellular activation induces the expression of genes that directly trigger viral replication. The genes induced by HIV envelope binding to a cell can also increase the release of cytokines that contribute to the aberrant activation of other immune cells producing a permission microenvironment that further feeds the process of virus replication. Thus, the complex process of aberrant immune activation associated with HIV infection and replication is the major driving force of the pathogenesis of HIV disease.
Dr. Fauci's principal LIR collaborators on the studies presented in Bangkok include: Tae-Wook Chun, Ph.D.; Audrey Kinter, Ph.D.; Susan Moir, Ph.D.; Angela Malaspina, Ph.D.; Mark Dybul, M.D.; Domenico Mavilio, M.D.; Shyam Kottilil, M.D., Ph.D.; James Arthos, Ph.D.; and Claudia Cicala, Ph.D.
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