The clinical course of HIV infection is characterized by several phases, culminating in immune deficiency (Fig. 1A).

Fig1. Clinical course of human immunodeficiency virus (HIV) disease. A, Blood-borne virus (plasma viremia) is detected early after infection and may be accompanied by systemic symptoms typical of acute HIV syndrome. The virus spreads to lymphoid organs, but plasma viremia falls to very low levels (detectable only by sensitive reverse transcriptase–polymerase chain reaction assays) and stays this way for many years. CD4+ T cell counts steadily decline during this clinical latency period because of active viral replication and T cell destruction in lymphoid tissues. As the level of CD4+ T cells falls, there is increasing risk of infection and other clinical components of acquired immunodeficiency syndrome. B, Magnitude and kinetics of immune responses, shown in arbitrary relative units. CTLs, Cytotoxic T lymphocytes. (Reproduced with permission from Pantaleo G, Graziosi C, Fauci AS: The immunopathogenesis of human immunodeficiency virus infection, New England Journal of Medicine 328:327–335, 1993.)

• Acute HIV syndrome. Early after HIV infection, patients may experience a mild acute illness with fever and malaise, correlating with the initial viremia. This illness subsides within a few days, and the disease enters a period of clinical latency.

 • Latency. During latency, there may be few clinical problems, but there usually is a progressive loss of CD4+ T cells in lymphoid tissues and destruction of the architecture of these tissues. Eventually, the blood CD4+ T cell count begins to decline, and when the count falls below 200 cells/mm3 (normal level about 1500 cells/mm3), patients become susceptible to infections and are diagnosed as having AIDS. • Clinical AIDS. AIDS ultimately causes increased susceptibility to infections and some cancers, as a consequence of immune deficiency. Patients not given antiretroviral drugs often are infected by intracellular microbes, such as viruses, the fungal pathogen Pneumocystis jiroveci, and nontuberculous mycobacteria, all of which normally are com bated by T cell–mediated immunity. Many of these microbes are present in the environment, but they do not infect healthy persons with intact immune systems. Because these infections are seen in immunodeficient persons, in whom the microbes have an opportunity to establish infection, these types of infections are said to be opportunistic. Reactivation of latent viruses, such as cytomegalovirus and Epstein-Barr virus (EBV), may also occur because patients with AIDS show defective cytotoxic T lymphocyte (CTL) responses to viruses. Even though HIV does not infect CD8+ T cells, the CTL responses are defective probably because CD4+ helper T cells (the main targets of HIV) are required for full CD8+ CTL responses against many viruses. Latent viruses, which are normally kept in check by CTL responses, become reactivated in AIDS patients and cause severe disease. AIDS patients are at increased risk for infections by extracellular bacteria, probably because of impaired helper T cell dependent antibody responses to bacterial antigens. Patients also become susceptible to cancers caused by oncogenic viruses. The two most common types of cancers are B cell lymphomas, caused by EBV, and a tumor of small blood vessels called Kaposi sarcoma, caused by a herpesvirus. Patients with advanced AIDS often have a wasting syndrome with significant loss of body mass, caused by altered metabolism and reduced caloric intake. The dementia that develops in some patients with AIDS is likely caused by infection of macrophages (microglial cells) in the brain.

The clinical course of HIV infection has been dramatically changed by effective antiretroviral drug therapy. With appropriate treatment, patients exhibit much slower progression of the disease, fewer opportunistic infections, and greatly reduced incidence of cancers and dementia.

T he immune response to HIV is ineffective in controlling spread of the virus and its pathologic effects. Infected patients produce antibodies and CTLs against viral antigens, and the responses help limit the early, acute HIV syndrome (see Fig. 1B). But these immune responses usually do not prevent progression of the disease. Antibodies against envelope glycoproteins, such as gp120, may be ineffective because the virus rapidly mutates the region of gp120 that is the target of most antibodies. CTLs often are ineffective in killing infected cells because the virus inhibits the expression of class I MHC molecules by the infected cells. Immune responses to HIV may paradoxically promote spread of the infection. Antibody-coated viral particles may bind to Fc receptors on macrophages and follicular dendritic cells in lymphoid organs, thus increasing virus entry into these cells and creating additional reservoirs of infection. If CTLs are able to kill infected cells, the dead cells may be cleared by macrophages, which can migrate to other tissues and spread the infection. By infecting and thus interfering with the function of immune cells, the virus is able to prevent its own eradication.

A small fraction of patients control HIV infection without therapy; these individuals are often referred to as elite controllers or long-term nonprogressors. T here has been great interest in defining the genes that may protect these individuals, because elucidation of these genes may suggest therapeutic approaches. The presence of certain HLA alleles, such as HLA-B57 and HLA-B27, seems to be protective, perhaps because these HLA molecules are particularly efficient at presenting HIV peptides to CD8+ T cells. In addition, a 32 base pair deletion in the CCR5 gene is a known polymorphism, especially in Northern Europeans. Rare individuals with a homozygous form of this polymorphism lack functional CCR5, rendering these individuals completely resistant to HIV infection. 

مواضيع ذات صلة

Pathogenesis of AIDS

Congenital Immunodeficiencies : Defects in Lymphocyte Activation and Function

Congenital Immunodeficiencies: Defects in Lymphocyte Maturation

Congenital Immunodeficiencies: Defects in Innate Immunity

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Disorders of Neutrophils

Cell Surface Receptors

Sepsis

Acute Inflammation

Diseases Caused by T Lymphocytes

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases