Immunopathogenesis of HIV infection: concepts and questions.

"Disease can never be conquered, can never be quelled by emotion's wailful screaming or faith's cymballic prayer. It can only be conquered by the energy of humanity and the cunning in the mind of man."

--Sean O'Casey, Irish dramatist, 1949

HIV infection causes a primary immune deficiency, leaving the host vulnerable to an array of opportunistic pathogens and malignancies. Understanding the damage HIV does to the immune system has implications for both clinical care and laboratory research. Unfortunately, healthcare providers have not always acted promptly or appropriately on the clinical implications of HIV infection (N Engl J Med, 3,t:2:19, p. 1416, 2000) and answers to important questions of basic science have eluded bench researchers. This article recapitulates current concepts in the immunopathogenesis of HI V disease, emphasizing the clinical implications of those concepts and reviewing research questions for which answers remain ,elusive.

Persistent infection and its consequences. H IV establishes a chronic infection. The virus's ability to do this--despite an initially robust immune response--is central to its immunopathogenesis. In the case of most viral infections, the host clears the antigen and develops immunity against future infection. For reasons not yet fully understood, HIV evades immune-mediated elimination. The persistent infection that :results is characterized by:

* a dramatic decrease in cell number,

* a sharp decrease in cell function,

* a profound increase in cell activation,

* anatomic disruption of the immunologic environment, and

* abnormal cytokine expression.

Decrease in cell number. According to Anthony Fauci, MD, and Cliff Lane, MD, "The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper or inducer T cells. This subset oft cells is defined ... by the presence on its surface of the CD4 molecule."(1) Since CD4 T cells are essential for coordinated, effective immune function, the progressive loss of these cells underlies the immune deficiency that characterizes HIV infection. However, the exact mechanisms by which HIV causes the loss of CD4 T cells are still unknown, and other cell lines--such as CD8 T cells, which are presumably resistant to HIV infection--are also diminished over the course of infection. Any or all of the following mechanisms may contribute to CD4 T cell loss, including: virus-mediated cell killing, immune-mediated cell killing, chronic activation leading to the premature death of uninfected cells, generation of auto-antibodies and impaired CD4 T cell production. Cells of the monocyte/macrophage lineage represent the other major target of HIV infection, but these cells are relatively unaffected by HIV's cytopathic effects.

Clinicians have sought to arrest or reverse the decline in CD4 T cell count using antiretroviral drugs. For individuals with counts below 200 cells/[mm.sup.3], investigators have demonstrated that highly active antiretroviral therapy (HAART) prolongs survival time and decreases the incidence of opportunistic infections and malignancies. Investigators have not yet validated clinically the use of HAART in other HIV-infected patient populations, particularly those with asymptomatic disease and CD4 T cell counts above 500 cells/[mm.sup.3].

Decrease in cell function. Although CD4 T cells and monocytes/macrophages are both the targets and producers of HIV, other cellular components of the immune system are also damaged by the infection. Moreover, while the decline in CD4 T cell number typically occurs over several years, impaired CD4 T cell function is seen from the earliest days of infection. For example, CD4 T cells show a diminished capacity for responding to recall antigens; cytokine production by these cells is defective and helper function is diminished. B cells produce inappropriate and excessive antibodies. Natural killer cells (which protect against cancer) perform poorly, and certain antigen presenting cells may also be functionally defective. Finally, the immune system is unable--at least in the absence of antiretroviral therapy--to restore lost cells. This inability to replace cell loss probably results from the damage HIV does to the bone marrow and thymus, which respectively serve as the sites of CD4 T cell production and maturation.

Investigators have attempted to remedy the decrease in both cell number and function with experimental agents, such as interleukin-2 (Proleukin). Although research has shown that interleukin-2 increases CD4 T cell number, whether those cells are functional and clinically beneficial is not yet known, Two Phase III studies are now underway to determine the clinical effect, if any, of interleukin-2. If the trials end positively, interleukin-2 will become the first therapy directed specifically at increasing cell number and improving immune function.

Increase in cellular activation. As a consequence of HIV infection, the immune system loses CD4 T cells and experiences functional deficits. Paradoxically, it is also in a state of hyperactivation, which results from the chronic nature of HIV infection and unrelenting cycles of viral replication. Chronic activation damages the immune system further and propagates the infection. Despite its importance, chronic activation is arguably the component of HIV pathogenesis to which investigators have paid the least attention.

In the setting of HIV infection, stimulation of the immune system increases virus production and programmed cell death, both of which in turn accelerate cell loss and diminished cellular responses to antigen, further impairing the immune system's functional competence. These observations are not without clinical consequence. For example, Fauci and colleagues have shown that individuals infected with both HIV and tuberculosis--and thus experiencing heightened immune activation--progress to AIDS and death much sooner than individuals infected with HIV alone.

Vaccinations, such as those against pneumococcal pneumonia and influenza, as well as prophylaxis against Pneumocystis pneumonia and Mycobacterium avium complex, are intended to prevent specific clinical diseases. However, by preventing fulminant infections, vaccination precludes episodes of immune activation and may therefore also be important to delaying HIV disease progression.

Cofactors. Although infection by HIV itself is almost certainly all that is required to produce an eventual depletion of CD4 T cells, other pathogens may play a role in accelerating the course of clinical disease. By inducing cellular activation and hence increased virus production, any infectious pathogen may serve as a cofactor to HIV disease progression. Prevention of exposure and infection by all potential pathogens is impractical. However, the United States Public Health Service has issued guidelines for the prevention of opportunistic infections in persons infected with HIV, including recommendations on avoiding environmental and occupational exposures. These guidelines are available by calling 800.448.0440 or by downloading the document from hivatis.org.

Anatomic disruption of the immunologic environment. Not only does HIV impair the physiology, or function, of the immune system, it also damages the system's anatomy, or form. Lymph nodes are the major sites for normal immune system activity; unfortunately, in the setting of HIV infection, the nodes are also the major sites for establishment and spread of the virus. Indeed, although the clinical course of HIV disease and the success or failure of its treatment may vary greatly from one individual to another, viral infection of the lymph nodes is universal among those infected.

HIV infection results in the eventual collapse of the architecture of the lymph nodes. The nodes are no longer able to trap the virus or other infectious pathogens and the immune system's ability to contain foreign organisms is lost. As HIV spills into peripheral circulation, plasma viral load rises.

Abnormal cytokine expression. Investigation has shown that cytokines, the chemical messengers that regulate the immune system, influence HIV replication. Some cytokines can increase HIV replication, while others inhibit viral production. An infected person's "viral setpoint" is probably influenced by an equilibrium between virus-inducing and virus-inhibiting cytokines. In the setting of HIV infection, cytokine patterns are skewed in favor of so-called TH-2 type responses and away from the TH-1 type responses of CD4 T cells. However, the clinical significance, if any, of these changes has not been demonstrated.

Effect of antiretroviral therapy on pathogenesis. On a population basis, HAART has produced striking decreases in the incidence of AIDS-related opportunistic illnesses and death. However, the population benefits of' antiviral therapy have not always translated into benefit for the individual patient. For example, although post-HAART incidence of toxoplasmosis has fallen sharply, post-HAART survival time following a diagnosis of toxoplasmosis has also fallen, from 582 days in the no therapy/monotherapy era to 323 days in the post-HAART era.

Still, there can be no doubt that the clinical prognosis for HIV infection is markedly better today than it was during the early days of the epidemic. For many patients, HAART results in restored immunity, repaired lymph node architecture and increased peripheral CD4 T cell count.(2) At the same time, antiviral therapy has raised new questions about the pathogenesis of HIV infection. For example, investigation has shown that some patients remain clinically and immunologically stable on protease inhibitor containing regimens despite viral rebound. This observation suggests that HIV can be hobbled in ways other than direct suppression of viral replication. On the other hand, some patients continue to experience immunologic decline even after maximal suppression of plasma viral load, which suggests that high-level viral replication is not essential to disease progression. Finally, the identification under HAART of a persistent pool of HIV-infected CD4 T cells indicates that HIV cannot be cytopathic for every cell it infects.

Summary. HIV infection is characterized by deficits in both the number and function of CD4 T cells, deficits in the function of other cell lines, a marked increase in cellular activation, physical disruption of the immune environment and abnormal expression of cytokines. The mechanisms for these abnormalities are not fully understood; however, these abnormalities have clinical implications, and some are already the target of therapeutic intervention. HAART has altered the natural history of HIV while simultaneously raising new questions about pathogenesis.

(1) Fauci and Lane, Harrison's Principles of Internal Medicine, p. 1802, 1998.

(2) The source of this increase (i.e., new production or redistribution from nodes to periphery) is controversial.