Hiv

HIV infections are not latent infections. The virus is extremely active in the lymph nodes from the earliest stages of the disease process, but the clinical manifestations or susceptibility to opportunistic pathogens only occurs in the later stages of the disease.

Lymph Nodes and HIV. From a mechanisitic viewpoint, HIV infection is a disease of the immune system. Early in the disease process, viruses are localized in the lymph node follicular dendritic cells where they initiate a normal immune response. However, continued viral replication in the node destroys the follicular dendritic cells, reducing the antigen presentation and production of IL-12 (Miedema, 1995).

The production of IL-12 is necessary for a multitude of immunological functions (Fig. 1). Production of IL-12 by phagocytic cells is necessary for development and differentiation of Thl cells, enhancing the NK cell response and the production of IFN-y (Trinchieri, 1995a).

In AIDS patients, the normal levels of IL-12 are reduced by 90-95%. The lack of IL-12 results in a skewed lymphocyte subset population in the blood. The development of Thl cells is downregulated and the Th2 lymphocyte population, the permissive site ofHIV replication, becomes the predominant Th population in the blood and spleen (Dalgleish, 1995).

Figure 1. The effect ofHIV on follicular dendritic and CD8 cells. Differentiation patterns of CD4 and CD8 cells. The differentiation of CD4 Thl and CD8 Tc2 cells is under the control of IL-12. HIV destruction of the dendritic cells in the lymph node shifts the pattern of cytokines in favor of the development of CD4 Th2 and CD8 Tc2 cells. The CD4 Th2 cells subsequently become infected with HIV. Solid arrows denote normal cytokine pattern. Dashed arrows indicate HIV-induced cytokine pattern. Modified from Immunology Today, Mossman and Sad, 1996, 17:138-45.

Figure 1. The effect ofHIV on follicular dendritic and CD8 cells. Differentiation patterns of CD4 and CD8 cells. The differentiation of CD4 Thl and CD8 Tc2 cells is under the control of IL-12. HIV destruction of the dendritic cells in the lymph node shifts the pattern of cytokines in favor of the development of CD4 Th2 and CD8 Tc2 cells. The CD4 Th2 cells subsequently become infected with HIV. Solid arrows denote normal cytokine pattern. Dashed arrows indicate HIV-induced cytokine pattern. Modified from Immunology Today, Mossman and Sad, 1996, 17:138-45.

HIV and CD4 Helper Cells. The mechanism by which HIV infects the cells has only recently been defined. Interaction of the virus with two receptors is necessary for cell binding and infection. The CD4 interaction is necessary for cell binding, but HIV binding to a chemokine receptor designated CCRS is necessary for infection of the cell. Persons in high-risk groups resistant to HIV have a mutation in the gene coding for CCRS. This mutation appears to confer resistance to the disease (Cohen, 1997).

During rapid viral reproduction, the Th2 cells in the immune system are undergoing HIV-induced apoptosis. Reactions between the HIV envelope glycoprotein gpl20 and the Th2 cells induce lymphocyte apoptosis. High viral loads in the blood can induce apoptosis in 1 X 109 Th2 cells per day. The body attempts to maintain homeostasis by constantly repopulating the blood with Th2 cells. As the capacity to repopulate Th2 cells from stem cells appears to be finite, the system ultimately becomes exhausted and production of Th2 cells ceases (Miedema, 1995).

HIV and CD8 Cytotoxic T Cells. Cytotoxic T cells are involved in protection from HIV. Early during the disease, two types of CD8 cells are involved in the response. One CD28+ population is the classical MHC-restricted cytotoxic T cells capable of lysing infected cells. A second population consists of noncy-totoxic CD8, CD28- cells that secrete the soluble protein CD8 T-cell antiviral factor (CAF). CAF has no homology or identity with known cytokines, interferons, growth factors, or chemokines. It appears to inhibit viral replication, preventing viral mutations leading to drug-resistant or highly pathogenic strains. CAF is active against HIV-1, HIV-2, and SIV strains including cytopathic and noncytopathic strains. In addition, CAF blocks the function of classical CD8 T killer cells (Levy et al., 1996). From a clinical perspective, there is a strong correlation between the presence of noncytotoxic CD8+, CD28-T cells and the symptomatic status of HIV patients.

These noncytotoxic CD8 T cells may be part of a natural or innate defense mechanism against massive and overwhelming viral infections (Levy et al., 1996) that must be eradicated without damage to the host. During HIV infections, approximately 250 million lymphocytes, macrophages, and other cell types are infected with the virus. Cytotoxic T-cell killing of infected lymphocytes and macrophages would further damage the immune system and compromise the host. Lysis of other infected tissue cells would cause massive tissue injury and release large amounts of virus into the blood. It is unlikely that the host would survive such an insult.

Later in the disease process, the CD8 cell population ceases to effectively function in defense of the host. In part, this may be reflect the shift from Thl to Th2 cells described above. Cytokines from Thl cells (e.g., IL-2) enhance the antiviral activity of CD8 cells. Conversely, IL-4 and IL-10 from Th2 cells de crease the antiviral CD8 response. The fate of CD8 cells exposed to high levels of IL-4 and IL-10 is unclear.

Loss of CD8 cell function may be associated with anergy induced by a loss of the CD28 marker and apoptosis. Downregulation of the CD28 is triggered by IL-4. Failure of CD28 to ligate with the CD80 on APCs or CD86 on memory cells leads to anergy, a loss of T-cell activation, and reduced proliferation in the CD8 population. In addition, apoptosis of CD8+, CD28-, and CD28+ cells is initiated by the induction of the Fas ligand causing endonuclease-mediated DNA fragmentation commonly observed in apoptosis.

Cytotoxic CD8 cells are important in HIV infections. Long-term survivors of AIDS have an intact cytotoxic T-cell function. CD8 cells are involved in the initial clearance of the virus and continual destruction of virus-infected cells. In children and adults, a loss of CD8 function correlates with increased viremia, spread of the virus within the host, and the onset of clinical symptoms.

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