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.


Apoptosis
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 individuals, both in the bloodstream and lymph nodes. Apoptosis is closely correlated 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.


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 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.


Anergy.
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 the development of 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 killing by the virus. However, these cells 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 impervious to most anti-HIV drugs.
Neurologic manifestations of HIV disease are seen in up to 50 percent of HIV-infected people, to varying degress of severity. People infected with HIV often experience cognitive symptoms, including impaired short-term memory, reduced concentration, and mental slowing; motor symptoms such as fine motor clumsiness or slowness, tremor, and leg weakness; and behavioral symptoms including apathy, social withdrawal, irritability, depression, and personality change. More serious neurologic manifestations in HIV disease typically occur in patients with high viral loads, generally when an individual 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.

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