IMMUNOLOGY - Roit I. - Mir 2000

Chapter 22. Secondary Immunodeficiency

AIDS

The CAUSATIVE AGENT OF AIDS is the HUMAN IMMUNODEFICIENCY VIRUS (HIV), which is transmitted sexually, via Blood transfusions or blood product administration, and from an infected mother to her child during the perinatal period. There are two main strains of the virus: HIV-1 and HIV-2, the latter being endemic to West Africa and apparently less pathogenic.

Over 80% of HIV-infected individuals live in developing countries, where 80% of transmissions occur sexually (70% through heterosexual and 10% through homosexual contact). According to World Health Organization (WHO) projections, by the year 2000 the total number of HIV-infected individuals worldwide will reach 30 million (99% of whom will reside in developing countries), and the annual death toll from AIDS will reach 2 million.

The Virus

HIV belongs to the Retroviruses containing single-stranded RNA; its particle diameter is 100-120 nm (Fig. 22.4). The main HIV genes are gag (which encodes the core protein), pol (the polymerase/Reverse Transcriptase Gene), and env (which encodes the viral envelope protein). In addition, several accessory genes regulate the synthesis of viral Proteins. The receptor for HIV is the CD4 antigen, which is present on CD4⁺ T Lymphocytes and Cells of the monocyte-macrophage Lineage. The viral glycoprotein gp120 binds to the CD4 molecule; chemokine coreceptors are involved in the subsequent processes of viral-Cell Fusion and internalization, mediated by the gp41 glycoprotein.

Class="center">

Fig. 22.4. Following virion uncoating, the single-stranded viral RNA (ssRNA) is transcribed by reverse transcriptase into double-stranded DNA (dsDNA). Mediated by the viral enzyme integrase, this DNA is integrated into the host cell genome as an HIV provirus. Cell activation leads to the METABOLISM/31.html">Transcription of DNA into viral mRNA and the subsequent synthesis of structural proteins that form the viral particle. Following assembly, Viral Particles are released by budding from The Cell surface; this is followed by further structural maturation—which involves the Cleavage of a large precursor core protein into smaller protein components by viral proteases—yielding mature virions.

Immune Function Disorders

THE SPECTRUM OF these disorders is exceptionally broad and includes impaired activation of immune system cells resulting from the direct action of HIV, as well as the depletion and dysfunction of the CD4⁺ T-cell subpopulation that develop over time and constitute the primary cause of immunodeficiency. The precise mechanism by which the virus kills target cells remains not fully understood. Various mechanisms have been proposed, notably the accumulation of RNA and unintegrated DNA in the Cytoplasm and intracellular binding of CD4 to gp120. Infected cells can fuse with uninfected cells via gp120-CD4 interactions, forming giant multinucleated cells and syncytia. By binding to The surface of uninfected CD4⁺ T cells, gp120 also renders them susceptible to antibody-dependent cellular cytotoxicity (ADCC); infected cells can be destroyed by gp120-specific cytotoxic T lymphocytes. HIV proteins can act as superantigens, triggering a pronounced expansion of the immunocompetent cell pool followed by its depletion. Furthermore, HIV can induce T-cell apoptosis and cause cell membrane damage and lysis during viral budding from the cell surface.

Immune function disorders induced by HIV involve the depletion of the CD4⁺ T-cell subpopulation and the suppression of their responses to Antigens, mitogens, alloantigens, and anti-CD3 Antibodies, accompanied by a parallel decrease in IL-2 production and other alterations in cytokine synthesis. As a consequence of these impairments, cytotoxic T cells lose their HIV-specific response capability alongside certain antigen-presenting cell Functions. Concurrently, there is an increase in the number of activated and unresponsive CD8⁺ T cells, elevated serum levels of β₂-microglobulin and neopterin, and polyclonal B-cell activation leading to The Emergence of B lymphocytes resistant to T-independent B-cell activators, as well as increased production of autoantibodies and immune complexes.

Model experiment results determining the response of plasma-borne virus and CD4⁺ T cells to antiretroviral therapy have demonstrated that the mean half-life of both the virus and infected cells in Circulation is less than 2 days. Every day, 10⁹-10¹⁰ viral particles are released from infected cells, and a similar number of new cells become infected and die.

Clinical Course of the Disease

Primary HIV infection may be accompanied by brief, infectious mononucleosis-like symptoms, including malaise, myalgia, lymphadenopathy, pharyngitis, and rash. This is marked by a temporary drop in peripheral CD4⁺ T-cell counts, an increase in CD8⁺ T lymphocytes, and elevated plasma HIV levels (Fig. 22.5). Using enzyme-linked immunosorbent assay (ELISA), antibodies to the core and envelope Proteins of the virus can be detected between 2 and 6 weeks post-infection. The chronic phase of the infection is clinically latent, although approximately 33% of patients present with lymphadenopathy. AIDS develops in half of infected individuals within 9-10 years.

Fig. 22.5. Typical course of HIV infection. (Illustration kindly provided by Dr. A.S. Fauci: from Pantaleo G., Graziosi C. 1993. N. Engl. J. Med. 328: 327-35, modified with permission.)

In the late Stages of the disease, non-specific constitutional symptoms appear—such as fever, night sweats, diarrhea, and weight loss—alongside minor manifestations primarily affecting the Skin and mucous membranes; for instance, patients may develop oral candidiasis (thrush), shingles, Herpes simplex virus infections in the anorectal region, and various cutaneous infections. These disorders frequently serve as precursors to severe opportunistic infections and malignancies, which clinically define AIDS. By this stage, the CD4⁺ T-cell count typically falls below 200/µL (Fig. 22.5).

The most common malignancy associated with AIDS is Kaposi's Sarcoma, a multicentric tumor of endothelial origin (Fig. 22.6). Spreading extensively, the tumor affects the skin, mucous membranes, Internal Organs (gut and Lungs), and Lymph Nodes. Tumor development is linked to human herpesvirus 8 (HHV8) infection. B-cell lymphomas affecting the Brain, gastrointestinal tract, and Bone Marrow have also been documented in AIDS patients.

Fig. 22.6. Pathological manifestations characteristic of AIDS. 1. Multiple lesions of Kaposi's sarcoma on the chest and abdomen. 2. Chest radiograph of a patient with Pneumocystis carinii Pneumonia, showing bilateral interstitial shadowing. 3. Small intestinal biopsy from a patient with Cryptosporidium-induced diarrhea. Cryptosporidium intermediate forms (small pink spots) are visible on the mucosal surface. 4. Cranial computed tomography scan of a patient with cerebral Toxoplasmosis, clinically presenting with seizures and left-sided hemiparesis. Contrast injection revealed a ring-enhancing lesion in the right hemisphere surrounded by edema (dark area).

Opportunistic infections develop primarily As a result of the reactivation of latent microbes already present in the body, and occasionally due to environmental exposure to microorganisms with which the individual is in constant contact. These infections are difficult to diagnose, and Treatment often merely suppresses their manifestations without achieving a complete cure. They are characterized by frequent relapses, necessitating continuous suppressive or maintenance therapy, which frequently involves drugs carrying significant adverse side effects.

The primary target systems in AIDS are the respiratory, gastrointestinal, and nervous systems. The most common opportunistic infection in AIDS is pneumonia, most frequently caused by Pneumocystis carinii (Fig. 22.6). However, pulmonary infections can also be caused by other Bacteria, including Mycobacterium tuberculosis, as well as Fungi. Dysphagia is typically caused by Candida (thrush), and esophageal ulcerations due to cytomegalovirus may also occur. In patients presenting with weight loss and diarrhea, pathogenic Protozoa (Cryptosporidium and microsporidia) are most frequently isolated (Fig. 22.6), alongside enteric bacteria such as Salmonella and Campylobacter.

Neurological complications of AIDS stem either from the direct action of HIV and opportunistic pathogens on The Nervous system or from The Development of lymphoma. AIDS dementia complex, initially diagnosed in 10-20% of patients with other AIDS manifestations, has become less frequent due to the Structure/175.html">Implementation of more effective antiretroviral therapies. Spinal Cord and peripheral nerve disorders also occur. Toxoplasmosis (a protozoal infection) causes brain cyst formation and neurological impairment (Fig. 22.6). The fungus Cryptococcus neoformans can cause meningitis. A range of other nervous system disorders arise from different infectious agents: cytomegalovirus causes retinitis, encephalomyelitis, and radiculopathy, while the polyomavirus (JC virus), which infects oligodendrocytes in the brain, causes a rapidly progressive and fatal demyelinating disease known as progressive multifocal leukoencephalopathy.

Antiviral Therapy

In 1987, zidovudine (AZT) was proposed for the treatment of HIV infection as the first nucleoside analogue reverse transcriptase inhibitor (NRTI). Since then, significant progress has been achieved in the development and application of other NRTIs, as well as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (see Fig. 22.4).

Zidovudine monotherapy in the late stages of the disease reduces short-term mortality after the initiation of treatment and delays disease progression. When administered during the early period of infection, this drug produces a weak and transient clinical effect and does not increase survival rates. Therefore, combinations of two or more therapeutic agents have been used aiming for an additive or synergistic effect, as well as to delay the emergence of drug resistance; such a delay can be achieved by lowering the mutation rate of the RT gene or by inducing reverse Mutations that may lead to the loss of resistance or render the virus less fit. Combining two NRTIs reduced The rate of AIDS progression and AIDS-related mortality by approximately 40% over a 1- to 3-year interval compared to monotherapy. The combined use of NRTIs and protease inhibitors has also proven clinically effective. The Use of other combinations comprising NRTIs, NNRTIs, and protease inhibitors yields a promising antiviral effect along with a sharp, short-term increase in CD4⁺ T-cell counts—an additional factor that improves the clinical course of the disease.

The optimal timing for initiating therapy remains unclear; however, most physicians believe that treatment should be started when repeat determinations show a drop in CD4⁺ cell count to 200–400/μL, as well as in all cases where patients develop symptoms of the disease. Serum viral RNA levels can also serve as a guideline. It should be noted that even monotherapy is an expensive treatment regimen, which creates difficulties for treating AIDS patients in developing countries. Since there is currently no cure for AIDS, nor a vaccine against this infection, the main weapon in the fight against AIDS is Prevention—namely, promoting a healthy lifestyle and controlling the spread of the infection.

Questions for Discussion

■ Why should antimitotic drugs possess immunosuppressive properties?

■ What effect do you think the combined use of cyclosporine and rapamycin should produce: non-additive, additive, or synergistic?

■ Imagine that you are a district HEAD in a developing country with limited budgetary resources. What measures to reduce the incidence of infectious diseases would you prioritize for funding?

■ What are the consequences of rapid mutation in RNA Viruses, such as HIV?

■ Suppose it were possible to transfect cells with an antisense nucleoside that incorporates into the mRNA of HIV regulatory proteins. Which cells would you choose as targets for transfection to achieve the maximum therapeutic effect for a given patient?

■ Which dietary elements, when prescribed in moderately excessive amounts, can enhance Immunity?

■ What are the most characteristic Changes in the immune system during protein-calorie malnutrition?

■ Imagine that you are treating severely ill patients and the elderly; what diet would improve their condition and reduce the severity of infection?

Introduction/47.html">Further Reading

Chandra R.K. (ed). 1992. Nutrition and Immunology. St John's NF, Canada ARTS Biomedical.

Chandra R.K. 1996 Nutrition, immunity and infection.

Proc. Natl. Acad. Sci USA 93: 14304-307.

Chandra R.K. 1997. Graying of the immune system,

Can nutrient supplements improve immunity in the elderly? JAMA 277: 1898-99.

Gershwin M.E., Beach R.S. Hurley L.S. 1984. Nutrition and Immunity. New York: Academic Press.