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Untreated HIV disease is characterized by a gradual deterioration of immune function. Most notably, the T cells that contain CD4 proteins (represented as CD4+ T cells) are disabled and killed during the typical course of infection. These cells, sometimes called "T-helper cells," play a central role in the immune response, signaling other cells in the immune system to perform their special functions.
A healthy, uninfected person usually has 800 to 1,200 CD4+ T cells per cubic millimeter (mm3) of blood. During untreated HIV infection, the number of these cells in a person's blood progressively declines. When the CD4+ T cell count falls below 200/mm3, a person becomes particularly vulnerable to the opportunistic infections and cancers that typify AIDS, the end stage of HIV disease. People with AIDS often suffer infections of the lungs, intestinal tract, brain, eyes, and other organs, as well as debilitating weight loss, diarrhea, neurologic conditions, and cancers such as Kaposi’s sarcoma and certain types of lymphomas.
Most scientists think that HIV causes AIDS by inducing the death of CD4+ T cells or interfering with their normal function, and by triggering other events that weaken a person's immune function. For example, the network of signaling molecules that normally regulates a person’s immune response is disrupted during HIV disease, impairing a person's ability to fight other infections. The HIV-mediated destruction of the lymph nodes and related immunologic organs also plays a major role in causing the immunosuppression seen in people with AIDS.
Early events in HIV infection
Once HIV enters the body, it infects a large number of CD4+ 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.
Two to four weeks after exposure to the virus, some people may suffer flu-like symptoms related to the acute infection. Their immune system fights back with killer T cells (CD8+ T cells) and B-cell-produced antibodies, which dramatically reduce HIV levels. A person's CD4+ T cell count may rebound somewhat and even approach its original level. A person may then remain free of HIV-related symptoms for years despite continuous replication of HIV in the lymphoid organs that had been seeded during the acute phase of infection.
One reason that HIV is unique is the fact that despite the body’s aggressive immune responses, which are sufficient to clear most viral infections, some HIV invariably escapes. This is due in large part to the high rate of mutations that occur during the process of HIV replication. Even when the virus does not avoid the immune system by mutating, the body’s best soldiers in the fight against HIV - certain subsets of killer T cells that recognize HIV - may be depleted or become dysfunctional.
In addition, early in the course of HIV infection, people may lose HIV-specific CD4+ T cell responses that normally slow the replication of viruses. Such responses include the secretion of interferons and other antiviral factors, and the orchestration of CD8+ T cells.
Finally, the virus may hide within the chromosomes of an infected cell and be shielded from surveillance by the immune system. Such cells can be considered as a latent reservoir of the virus. Because the antiviral agents currently in our therapeutic arsenal attack actively replicating virus, they are not effective against hidden, inactive viral DNA (so-called provirus). New strategies to purge this latent reservoir of HIV have become one of the major goals for current research efforts.
Course of HIV infection
Among people enrolled in large epidemiologic studies in Western countries, the median time from infection with HIV to the development of AIDS-related symptoms has been approximately 10 to 12 years in the absence of antiretroviral therapy. Researchers, however, have observed a wide variation in disease progression. Approximately 10 percent of HIV-infected people in these studies have progressed to AIDS within the first 2 to 3 years following infection, while up to 5 percent of individuals in the studies have stable CD4+ T cell counts and no symptoms even after 12 or more years.
Factors such as age or genetic differences among individuals, the level of virulence of an individual strain of virus, and co-infection with other microbes may influence the rate and severity of disease progression. Drugs that fight the infections associated with AIDS have improved and prolonged the lives of HIV-infected people by preventing or treating conditions such as Pneumocystis carinii pneumonia, cytomegalovirus disease, and diseases caused by a number of fungi.
HIV co-receptors and disease progression
Recent research has shown that most infecting strains of HIV use a co-receptor molecule called CCR5, in addition to the CD4 molecule, to enter certain of its target cells. HIV-infected people with a specific mutation in one of their two copies of the gene for this receptor may have a slower disease course than people with two normal copies of the gene. Rare individuals with two mutant copies of the CCR5 gene appear, in most cases, to be completely protected from HIV infection. Mutations in the gene for other HIV co-receptors also may influence the rate of disease progression.
Viral burden and disease progression
Numerous studies show that people with high levels of HIV in their bloodstream are more likely to develop new AIDS-related symptoms or die than those with lower levels of virus. For instance, in the Multicenter AIDS Cohort Study (MACS), investigators showed that the level of HIV in an untreated person’s plasma 6 months to a year after infection—the so-called viral "set point" is highly predictive of the rate of disease progression; that is, patients with high levels of virus are much more likely to get sicker faster than those with low levels of virus. The MACS and other studies have provided the rationale for providing aggressive antiretroviral therapy to HIV-infected people, as well as for routinely using newly available blood tests to measure viral load when initiating, monitoring, and modifying anti-HIV therapy.
Potent combinations of three or more anti-HIV drugs known as highly active antiretroviral therapy, or HAART, can reduce a person’s 'viral burden' (amount of virus in the circulating blood) to very low levels and in many cases delay the progression of HIV disease for prolonged periods. Before the introduction of HAART therapy, 85 percent of patients survived an average of 3 years following AIDS diagnosis. Today, 95 percent of patients who start therapy before they get AIDS survive on average 3 years following their first AIDS diagnosis. For those who start HAART after their first AIDS event, survival is still very high at 85 percent, averaging 3 years after AIDS diagnosis.
Antiretroviral regimens, however, have yet to completely and permanently suppress the virus in HIV-infected people. Recent studies have shown that, in addition to the latent HIV reservoir discussed above, HIV persists in a replication-competent form in resting CD4+ T cells even in people receiving aggressive antiretroviral therapy who have no readily detectable HIV in their blood. Investigators around the world are working to develop the next generation of anti-HIV drugs that can stop HIV, even in these biological scenarios.
A treatment goal, along with reduction of viral burden, is the reconstitution of the person's immune system, which may have become sufficiently damaged that it cannot replenish itself. Various strategies for assisting the immune system in this regard are being tested in clinical trials in tandem with HAART, such as the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) trial exploring the effects of the T cell growth factor, IL-2.
HIV is active in the lymph nodes
Although HIV-infected people often show an extended period of clinical latency with little evidence of disease, the virus is never truly completely latent. Researchers have shown that even early in disease, HIV actively replicates within the lymph nodes and related organs, where large amounts of virus become trapped in networks of specialized cells with long, tentacle-like extensions. These cells are called follicular dendritic cells (FDCs). FDCs are located in hot spots of immune activity in lymphoid tissue called germinal centers. They act like flypaper, trapping invading pathogens (including HIV) and holding them until B cells come along to start an immune response.
Over a period of years, even when little virus is readily detectable in the blood, significant amounts of virus accumulate in the lymphoid tissue, both within infected cells and bound to FDCs. In and around the germinal centers, numerous CD4+ T cells are probably activated by the increased production of cytokines such as TNF-alpha and IL-6 by immune system cells within the lymphoid tissue. Activation allows uninfected cells to be more easily infected and increases replication of HIV in already infected cells.
While greater quantities of certain cytokines such as TNF-alpha and IL-6 are secreted during HIV infection, other cytokines with key roles in the regulation of normal immune function may be secreted in decreased amounts. For example, CD4+ T cells may lose their capacity to produce IL-2, a cytokine that enhances the growth of other T cells and helps to stimulate other cells' response to invaders. Infected cells also have low levels of receptors for IL-2, which may reduce their ability to respond to signals from other cells.
Breakdown of lymph node architecture
Ultimately, with chronic cell activation and secretion of inflammatory cytokines, the fine and complex inner structure of the lymph node breaks down and is replaced by scar tissue. Without this structure, cells in the lymph node cannot communicate and the immune system cannot function properly. Investigators also have reported recently that this scarring reduces the ability of the immune system to replenish itself following antiretroviral therapy that reduces the viral burden.
Role of CD8+ T cells
CD8+ T cells are critically important in the immune response to HIV. These cells attack and kill infected cells that are producing virus. Thus, vaccine efforts are directed toward eliciting or enhancing these killer T cells, as well as eliciting antibodies that will neutralize the infectivity of HIV.
CD8+ T cells also appear to secrete soluble factors that suppress HIV replication. Several molecules, including RANTES, MIP-1alpha, MIP-1beta, and MDC appear to block HIV replication by occupying the co-receptors necessary for many strains of HIV to enter their target cells. There may be other immune system molecules - including the so-called CD8 antiviral factor (CAF), the defensins (type of antimicrobials), and others yet undiscovered - that can suppress HIV replication to some degree.
Rapid replication and mutation of HIV
HIV replicates rapidly; several billion new virus particles may be produced every day. In addition, the HIV reverse transcriptase enzyme makes many mistakes while making DNA copies from HIV RNA. As a consequence, many variants or strains of HIV develop in a person, some of which may escape destruction by antibodies or killer T cells. Additionally, different strains of HIV can recombine to produce a wide range of variants.
During the course of HIV disease, viral strains emerge in an infected person that differ widely in their ability to infect and kill different cell types, as well as in their rate of replication. Scientists are investigating why strains of HIV from people with advanced disease appear to be more virulent and infect more cell types than strains obtained earlier from the same person. Part of the explanation may be the expanded ability of the virus to use other co-receptors, such as CXCR4.
Theories of immunes system cell loss in HIV infection
Researchers around the world are studying how HIV destroys or disables CD4+ T cells, and many think that a number of mechanisms may occur simultaneously in an HIV-infected person. Data suggest that billions of CD4+ T cells may be destroyed every day, eventually overwhelming the immune system’s capacity to regenerate.
Direct cell killing
Infected CD4+ T cells may be killed directly when large amounts of virus are produced and bud out from the cell surface, disrupting the cell membrane, or when viral proteins and nucleic acids collect inside the cell, interfering with cellular machinery.
Infected CD4+ T cells may be killed when the regulation of cell function is distorted by HIV proteins, probably leading to cell suicide by a process known as programmed cell death or apoptosis. Recent reports indicate that apoptosis occurs to a greater extent in HIV-infected people, both in their bloodstream and lymph nodes. Apoptosis is closely associated with the aberrant cellular activation seen in HIV disease.
Uninfected cells also may undergo apoptosis. Investigators have shown in cell cultures that the HIV envelope alone or bound to antibodies sends an inappropriate signal to CD4+ T cells causing them to undergo apoptosis, even if not infected by HIV.
Uninfected cells may die in an innocent bystander scenario: HIV particles may bind to the cell surface, giving them the appearance of an infected cell and marking them for destruction by killer T cells after antibody attaches to the viral particle on the cell. This process is called antibody-dependent cellular cytotoxicity.
Killer T cells also may mistakenly destroy uninfected cells that have consumed HIV particles and that display HIV fragments on their surfaces. Alternatively, because HIV envelope proteins bear some resemblance to certain molecules that may appear on CD4+ T cells, the body’s immune responses may mistakenly damage such cells as well.
Researchers have shown in cell cultures that CD4+ T cells can be turned off by activation signals from HIV that leaves them unable to respond to further immune stimulation. This inactivated state is known as anergy.
Damage to precursor cells
Studies suggest that HIV also destroys precursor cells that mature to have special immune functions, as well as the microenvironment of the bone marrow and the thymus needed for developing such cells. These organs probably lose the ability to regenerate, further compounding the suppression of the immune system.
Central nervous system damage
Although monocytes and macrophages can be infected by HIV, they appear to be relatively resistant to being killed by the virus. These cells, however, travel throughout the body and carry HIV to various organs, including the brain, which may serve as a hiding place or 'reservoir' for the virus that may be relatively resistant to most anti-HIV drugs.
Neurologic manifestations of HIV disease are seen in up to 50 percent of HIV-infected people, to varying degrees of severity. People infected with HIV often experience
More serious neurologic manifestations in HIV disease typically occur in patients with high viral loads, generally when a person has advanced HIV disease or AIDS.
Neurologic manifestations of HIV disease are the subject of many research projects. Current evidence suggests that although nerve cells do not become infected with HIV, supportive cells within the brain, such as astrocytes and microglia (as well as monocyte/macrophages that have migrated to the brain) can be infected with the virus. Researchers postulate that infection of these cells can cause a disruption of normal neurologic functions by altering cytokine levels, by delivering aberrant signals, and by causing the release of toxic products in the brain. The use of anti-HIV drugs frequently reduces the severity of neurologic symptoms, but in many cases does not, for reasons that are unclear. The impact of long-term therapy and long-term HIV disease on neurologic function is also unknown and under intensive study.
Role of immune activation in HIV disease
During a normal immune response, many parts of the immune system are mobilized to fight an invader. CD4+ T cells, for instance, may quickly multiply and increase their cytokine secretion, thereby signaling other cells to perform their special functions. Scavenger cells called macrophages may double in size and develop numerous organelles, including lysosomes that contain digestive enzymes used to process ingested pathogens. Once the immune system clears the foreign antigen, it returns to a relative state of quiescence.
Paradoxically, although it ultimately causes immune deficiency, HIV disease for most of its course is characterized by immune system hyperactivation, which has negative consequences. As noted above, HIV replication and spread are much more efficient in activated CD4+ cells. Chronic immune system activation during HIV disease also may result in a massive stimulation of B cells, impairing the ability of these cells to make antibodies against other pathogens.
Chronic immune activation also can result in apoptosis, and an increased production of cytokines that not only may increase HIV replication but also have other deleterious effects. Increased levels of TNF-alpha, for example, may be at least partly responsible for the severe weight loss or wasting syndrome seen in many HIV-infected people.
The persistence of HIV and HIV replication plays an important role in the chronic state of immune activation seen in HIV-infected people. In addition, researchers have shown that infections with other organisms activate immune cells and increase production of the virus in HIV-infected people. Chronic immune activation due to persistent infections, or the cumulative effects of multiple episodes of immune activation and bursts of virus production, likely contribute to the progression of HIV disease.