Role Of The Virus In Aids Pathogenesis

Acquired Immune Deficiency Syndrome (AIDS, SIDA in French and Spanish-speaking countries) was defined in the early 1980s, biologically by a profound defect of cellular immunity associated with a deep shortage of CD4+ T lymphocytes and clinically by the occurrence of opportunistic infections and cancers. In Western countries, the most frequent infections are those of the lungs by Pneumocystis carinii and of the brain by toxoplasmas, followed by visceral and retinal infections by cytomegalovirus (CMV). Tuberculosis is frequent in tropical areas (Africa, Asia, South America).

Among cancers, the most frequent are disseminated and aggressive Kaposi's sarcoma caused by human herpesvirus 8 (HHV-8) and B-lymphomas, often caused by Epstein-Barr virus (EBV).

The causal relationship between HIV and the immune depression has been assessed as follows:

1. On the basis of epidemiological studies, particularly in blood donors and recipients;

2. From the tropism and cytopathic effect of HIV and viral glycoproteins on CD4+ cells;

3. On the reproduction of the disease in macaques by virus derived from molecular clones of SIV (close to HIV-2).

The natural history of HIV-1 infection has been thoroughy studied by histological and molecular techniques. Three phases can be distinguished: primary infection, a clinical latency phase, the clinical phase (full blown AIDS).

In the primary infection, entry of the virus through mucosa involves its association with dendritic cells which then transport the virus to lymphatic tissues. The virus can rapidly multiply there in activated CD4+ lymphocytes and macrophages. Since the number of activated CD4 lymphocytes is small, it becomes a limiting factor which depends on intercur-ring microbial infections. Biologically, this phase is characterized by a peak of viral antigens (not always present) and a large number of viral RNA copies in blood, and a peak of interferons. Specific cytotoxic lymphocytes (CTL) then appear followed by the appearance of antibodies against viral glycoproteins and internal proteins. Clinically, when the level of viral replication is high, symptoms can be detected (fever, adenopathy, headaches). However, the infection can be sometimes completely inapparent.

This episode is followed by a phase of clinical latency, with no symptoms. However, in a majority of cases, there is a slow and progressive degradation of the immune system, leading finally to clinical AIDS which will last on average 10 years, in the absence of treatment. In a minority of individuals (5-10%) (long-term nonprogressors) this degradation does not take place or is very slow. In some others, on the contrary, immune depression can occur very rapidly within 1-2 years.

These variations reflect the complex interaction of HIV with the immune system of the host. In fact, the virus continuously replicates in lymphatic tissues (lymph nodes, spleen), with a rapid clearance from the blood. A relatively small number of infected cells is involved at the beginning and their destruction (either by the virus or by cytotoxic cells) cannot solely account for the large depletion of CD4+ cells. It is likely that indirect mechanisms of cell death are involved, bearing on cells which are not infected, but are in contact with noninfectious viral particles, or gp120 shed from cells or virions. Indeed, interaction of gp120 with the CD4 receptor or coreceptors could induce a wrong signaling leading to apoptotic cell death or anergy, when the T cell receptor is stimulated.

Evidence for the preapoptotic state of a large fractional circulating CD4 cells has been obtained. Defects in antigen-presenting cells, in bone marrow renewal of precursor cells, of faster thymic involution, of high oxidative stress, have also been involved to explain the specific CD4+ cell depletion. It is also clear that a state of chronic activation bearing not only on CD4 + cells, but also on CD8, NK and B cells exists all through this phase, associated with the production of inflammatory cytokines (interferons, interleukin (IL) 6, tumor necrosis factor).

In addition, a small pool of latently infected cells exists and is probably continuously renewed. This pool will escape any kind of treatment.

In the clinical phase, with the occurrence of more pathogenic variants (CXC4 tropic) and the decrease in cell-mediated immune response, the infection from local or regional becomes systemic and precipitates the fatal evolution.

Neurological signs are also frequent, particularly a subacute encephalopathy which can develop into a dementia syndrome and brain atrophy, and seems to be due to the virus itself. Some foci of brain macrophages infected with HIV can be detected in white matter, but neither neurons nor glial cells seem to be productibly infected in the same situation. Some astrocytes express large amounts of Nef protein. Therefore, indirect mechanisms for the action of HIV (cytokines, nitric oxide?) have also to be postulated in order to explain the neuronal effects.

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