Pathogenesis of HIV Infection
HIV belongs to a subgroup of retroviruses known as lentiviruses – or "slow" viruses. The course of infection with these viruses is characterized by a long interval between initial infection and the onset of serious symptoms.
The pathogenesis of HIV infection is a function of the virus life cycle, the host cellular environment, and quantity of viruses in the infected individual. 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.
The probability of infection is a function of both the number of infective HIV virions in the body fluid which contacts the host as well as the number of cells available at the site of contact that have appropriate CD4 receptors. Many types of cells express CD4 receptors and are susceptible to HIV infection, including: cells of the mononuclear phagocyte lineage (principally blood monocytes and tissue macrophages), T and B lymphocytes, natural killer (NK) cells, dendritic cells (Langerhans cells and follicular dendritic cells in lymph nodes), hematopoetic stem cells, endothelial cells, microglial cells in the brain and gastrointestinal epithelial cells.
Cellular Response
Cells with CD 4 receptors at the site of HIV entry become infected and viral replication begins within them. The infected cells can then release virions by surface budding or infected cells can undergo lysis to release new virions, which can then infect additional cells. Some HIV virions are carried from the site of infection to the regional lymph nodes where other immune system cells become infected. Large amounts of virus can become trapped here in networks of specialized cells with long, tentacle-like extensions. These cells are called follicular dendritic cells (FDCs) and are susceptible to infection but will survive for a long time.
CD4+ T cells, the primary targets of HIV, may become infected as they encounter HIV trapped on FDCs. Active replication of HIV occurs at all stages of the infection. Over a period of years, even when little virus is detectable in the blood, significant amounts of virus accumulate both within infected cells and bound to FDCs. HIV trapped on FDCs remains infectious, even when coated with antibodies. Thus, FDCs are a significant reservoir of infectious HIV and may explain in part how the momentum of HIV infection is maintained.
Although CD4+ T cells appear to be HIV's main target, as previosly mentioned, other immune system cells with CD4 molecules on their surfaces are infected as well. Long-lived cells called monocytes and macrophages, can harbor large quantities of the virus without being killed. Even CD4+ T cells serve as important reservoirs of HIV: a small proportion of these cells maintain HIV in a stable, inactive form. Normal immune processes may activate these cells, resulting in the production of new HIV virions.
In and around germinal centers, increased production of a variety of cytokines such as tumor necrosis factor (TNF) and IL-6 can activate CD4+ T lymphocytes and make them more susceptible to HIV infection. Activation allows uninfected cells to be more easily infected and increases replication of HIV in already infected cells. While greater quantities of certain cytokines are secreted during HIV infection, others 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 interleukin 2 (IL-2), a cytokine that enhances the growth of other T cells and helps to stimulate other cells' response to invaders. Once infected, CD4+ T cells may leave the germinal center and infect other CD4+ T cells that congregate in the region of the lymph node surrounding the germinal center. There are several theories of how HIV may destroy or disable CD4+ T cells in an HIV infected individual. Recent data suggest that billions of CD4+ T cells may be destroyed every day, eventually overwhelming the immune system's regenerative capacity.
Direct cell killing. Infected CD4+ T cells may be killed directly when large amounts of virus are produced and bud off from the cell surface, disrupting the cell membrane, or when viral proteins and nucleic acids collect inside the cell, interfering with cellular machinery.
Syncytia formation. Infected cells also may fuse with nearby uninfected cells through CD4-mediated fusion, forming balloon-like giant cells called syncytia. This mechanism of cell-to-cell spread of HIV has been associated with the death of uninfected cells. The presence of syncytia-inducing variants of HIV has been correlated with rapid disease progression in HIV-infected individuals.
Apoptosis. Infected CD4+ T cells may be killed when cellular regulation is distorted by HIV proteins, probably leading to their suicide by a process known as programmed cell death or apoptosis. 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 CD8+ T cells causing them to undergo apoptosis even though not infected by HIV.
Innocent bystanders. 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.
Central Nervous System Damage
Although monocytes and macrophages can be infected by HIV, they appear to be relatively resistant to killing. However, these cells travel throughout the body and carry HIV to various organs, especially the lungs and brain. People infected with HIV often experience neurologic abnormalities. Investigators have hypothesized that an accumulation of HIV in brain and nerve cells, or the inappropriate release of cytokines or toxic byproducts by these cells, may be to blame.
Course of Infection
Primary HIV infection is followed by a burst of viremia in which virus is easily detected in peripheral blood in mononuclear cells and plasma. The number of CD4+ T cells in the bloodstream decreases by 20 to 40 percent. Two to four weeks after exposure to the virus, up to 70 percent of HIV-infected persons suffer flu-like symptoms related to the acute infection. The burst is followed by replication at a lower level when, the patient's immune system fights back to dramatically reduce HIV levels with killer T cells (CD8+ T cells), which attack and kill infected cells that are producing virus, and B-cell-produced antibodies. A patient's CD4+ T cell count may rebound to 80 to 90 percent of its original level. A person then may remain free of HIV-related symptoms, often for years, despite a smoldering low-level replication of HIV in the lymphoid organs and latent, ongoing immune system destruction. During the latency period, enough of the immune system remains sufficiently intact to provide immune surveillance and to prevent most infections. Since the HIV provirus becomes part of the infected host's cellular DNA, the host cells may be infectious even if there are detectable HIV antibodies or if no virus can be measured in the patient's serum. In addition, HIV can mutate very easily; the HIV reverse transcriptase enzyme makes many mistakes while making DNA copies from HIV RNA. As a consequence, many variants of HIV develop in an individual (known as antigenic variation), some of which may escape immune attack by antibodies or killer T cells. Due to antigenic variation, antibodies formed against HIV are not protective and an infective state can persist despite the presence of even high antibody titers. Chronic immune system activation during HIV disease may also result in a massive stimulation of a person's B cells, impairing the ability of these cells to make antibodies against other pathogens.
The final phase of HIV infection occurs when a significant number of CD4 lymphocytes have been destroyed and when production of new ones cannot match destruction. Patients exhibit fatigue, long-lasting fever (>1 month) and weight loss. The failure of the immune system leads to appearance of clinical AIDS.
Typical course of HIV infection
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| During primary infection, HIV disseminates widely through the body, usually accompanied by an abrupt decrease in CD4+ T cells. An immune response to HIV ensues, with a detectable decrease in viral load. Clinical latency follows but CD4+ T cells slowly continue to decrease until they fall to a critical level below which there is a substantial risk of opportunistic infections. Adapted from NIAID website publication (3). |
Progression to AIDS
The HIV-infected person may live up to an average of 8 or 10 years after initial infection and before development of the clinical symptoms of AIDS. Progression to AIDS does not appear to be modified by gender race, or pregnancy and does not seem to be modified by risk factor. Most AIDS-defining conditions are marked by a CD4+ T count of less than 200 cells per cubic millimeter of blood and the appearance of 1 or more of the typical opportunistic infections or cancers, including Kaposi's sarcoma, Pneumocystis carinii pneumonia, and Mycobacterium avium complex. Opportunistic infections are caused by microbes that usually do not cause illness in healthy people; infections are often severe and sometimes fatal because the immune system is so ravaged by HIV that the body cannot them. There is a loss of lymph node architecture as the immune system fails. In about 50% of patients syncytia-forming (SI) variants of HIV appear. Not only do SI variants have a greater affinity for CD4+ T cells, increasing their decline, but when they infect macrophages, they have also been shown to trigger a suicide response in CD8+ T cells. Upon the rapid disappearance of these important immune cells the virus and infectious microbes take over.
HIV disease is not uniformly expressed in all individuals. A small proportion of infected individuals develop AIDS and die within months following primary infection, while approximately 5% of HIV infected individuals exhibit no signs of disease even after 12 or more years. The latter are called "long term non-progressors" and are the subject of intense scientific scrutiny. Scientists hope that understanding the body's natural method of controlling this infection may lead to ideas for protective HIV vaccines and use of vaccines to prevent disease progression.
Questions on this portion of the web page? Email: Liz_Lavigne@brown.edu
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