AIDS Pathophysiology

The pathophysiology of AIDS is complex, as is the case with all syndromes. Ultimately, HIV causes AIDS by depleting CD4⁺ T helper lymphocytes. This weakens the immune system and allows opportunistic infections. T lymphocytes are essential to the immune response and without them, the body cannot fight infections or kill cancerous cells. The mechanism of CD4⁺ T cell depletion differs in the acute and chronic phases.

During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4⁺ T cell depletion, although apoptosis may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4⁺ T cell numbers.

Although the symptoms of immune deficiency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4⁺ T cell loss occurs during the first weeks of infection, especially in the intestinal mucosa, which harbors the majority of the lymphocytes found in the body. The reason for the preferential loss of mucosal CD4⁺ T cells is that a majority of mucosal CD4⁺ T cells express the CCR5 coreceptor, whereas a small fraction of CD4⁺ T cells in the bloodstream do so.

HIV seeks out and destroys CCR5 expressing CD4⁺ cells during acute infection. A vigorous immune response eventually controls the infection and initiates the clinically latent phase. However, CD4⁺ T cells in mucosal tissues remain depleted throughout the infection, although enough remain to initially ward off life-threatening infections.

Continuous HIV replication results in a state of generalized immune activation persisting throughout the chronic phase. Immune activation, which is reflected by the increased activation state of immune cells and release of proinflammatory cytokines, results from the activity of several HIV gene products and the immune response to ongoing HIV replication. Another cause is the breakdown of the immune surveillance system of the mucosal barrier caused by the depletion of mucosal CD4⁺ T cells during the acute phase of disease.

This results in the systemic exposure of the immune system to microbial components of the gut’s normal flora, which in a healthy person is kept in check by the mucosal immune system. The activation and proliferation of T cells that results from immune activation provides fresh targets for HIV infection. However, direct killing by HIV alone cannot account for the observed depletion of CD4⁺ T cells since only 0.01–0.10% of CD4⁺ T cells in the blood are infected.

A major cause of CD4⁺ T cell loss appears to result from their heightened susceptibility to apoptosis when the immune system remains activated. Although new T cells are continuously produced by the thymus to replace the ones lost, the regenerative capacity of the thymus is slowly destroyed by direct infection of its thymocytes by HIV. Eventually, the minimal number of CD4⁺ T cells necessary to maintain a sufficient immune response is lost, leading to AIDS

Cells affected

The virus, entering through which ever route, acts primarily on the following cells:

Lymphoreticular system:
- CD₄+ T-Helper cells
- Macrophages
- Monocytes
- B-lymphocytes
- Certain endothelial cells
- Central nervous system:
  - Microglia of the nervous system
  - Astrocytes
  - Oligodendrocytes
  - Neurones – indirectly by the action of cytokines and the gp-120

The effect

The virus has cytopathic effects but how it does it is still not quite clear. It can remain inactive in these cells for long periods, though. This effect is hypothesized to be due to the CD₄-gp120 interaction. An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.

Stage I: HIV infection is asymptomatic and not categorized as AIDS
Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.

CDC classification system

There are two main definitions for AIDS, both produced by the Centers for Disease Control and Prevention (CDC). The older definition is to referring to AIDS using the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus. In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4⁺ T cell count below 200 per µL of blood or 14% of all lymphocytes. The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4⁺ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

HIV test

Many people are unaware that they are infected with HIV. Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities.

Routinely used HIV tests for infection in neonates and infants (ie, patients younger than 2 years), born to HIV-positive mothers, have no value because of the presence of maternal antibody to HIV in the child's blood. HIV infection can only be diagnosed by PCR, testing for HIV pro-viral DNA in the children's lymphocytes.

AIDS Pathophysiology

Cells affected

The effect

CDC classification system

HIV test

Further Reading

Recent HIV/AIDS News