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