BIO-31: Ch.19 part 2, in-class quiz #17

Grafts

• Autografts utilize the patient's own tissue.
• Isografts utilize tissue from an identical twin.
• Allografts use tissue from another person.
• Xenotransplantation uses nonhuman tissue.
• Hyperacute rejection must be overcome in xenotransplantation, and is a response to nonhuman antigens.
• Graft-versus-host (GVH) disease results from transplanted bone marrow containing immunocompetent cells.

Immunosuppression

• Immunosuppression prevents cell-mediated immune responses to transplanted tissue.
• Cyclosporine and tacrolimus suppress IL-2, disrupting cytotoxic T cells.
• Sirolimus inhibits cellular and humoral immunity.
• Mycophenolate inhibits the proliferation of T cells and B cells.
• Basiliximab is a chimeric monoclonal antibody that blocks IL-2.

The Immune System and Cancer

• Cancer cells are removed by immune surveillance.
• Cancer cells have tumor-associated antigens that mark them as nonself.
• CTLs (activated TC cells) and macrophages lyse cancer cells.
• Limitations include no antigenic epitope for the immune system to target, rapid tumor cell reproduction, and tumors becoming vascularized and invisible to the immune system.

Immunotherapy for Cancer

• Endotoxins from bacteria (Coley's toxins) stimulate TNF, which interferes with the blood supply to cancers.
• Vaccines are used for prophylaxis, such as feline leukemia, cervical cancer (Gardasil), and liver cancer (hepatitis B).
• Monoclonal antibodies, like Herceptin for breast cancer, are used.
• Immunotoxin combines a Mab with a toxic agent; it targets and kills a tumor without damage to healthy cells.

Immunodeficiencies

• Immunodeficiencies are characterized by the absence of a sufficient immune response.
• Congenital immunodeficiencies are due to defective or missing genes.
• Acquired immunodeficiencies develop during an individual's life and can be due to drugs, cancers, and infections.

Table 19.4 Immunodeficiencies

• Acquired Immunodeficiency Syndrome (AIDS) is caused by HIV infection and allows cancer, bacterial, viral, fungal, and protozoan diseases via the destruction of CD4+ T cells.
• Selective IgA immunodeficiency affects about 1 in 700 and causes frequent mucosal infections, with a specific cause that is uncertain.
• Common variable hypogammaglobulinemia affects about 1 in 70,000 and is the second most common immune deficiency. Symptoms include frequent viral and bacterial infections, and the condition is inherited.
• Reticular dysgenesis is a rare and usually fatal genetic condition that is a combined immunodeficiency that has deficiencies in B and T cells and neutrophils. It can be treated with a bone marrow transplant.
• Severe combined immunodeficiency affects about 1 in 100,000, allows severe infections, is inherited, and is treated with bone marrow and fetal thymus transplants. Gene therapy treatment is promising.
• Thymic aplasia (DiGeorge syndrome) is caused by a defective thymus causing deficiency of T cells and causing absence of cell-mediated immunity. It is usually fatal in infancy from Pneumocystis pneumonia or viral or fungal infections, due to the failure of the thymus to develop in the embryo.
• Wiskott-Aldrich syndrome has few platelets in the blood and abnormal T cells, causing frequent infections by viruses, fungi, and protozoa, as well as eczema and defective blood clotting. This condition is usually fatal in childhood, and is inherited on the X chromosome.
• X-linked infantile (Bruton’s) agammaglobulinemia has decreased immunoglobulins in B cells and leading to frequent extracellular bacterial infections. It is the first immunodeficiency disorder recognized (1952), affecting about 1 in 200,000, and is inherited on the X chromosome.

Acquired Immunodeficiency Syndrome (AIDS)

• In 1981, a cluster of cases of Pneumocystis pneumonia, Kaposi's sarcoma, and loss of immune function were discovered in young homosexual men in the United States.
• In 1983, the virus causing the loss of immune function was discovered and named HIV.
• HIV selectively infects T helper cells.

The Origin of AIDS

• SIV crossed over into the human population in west and central Africa from chimpanzees around 1908, probably from bushmeat.
• AIDS spread throughout Africa as a result of urbanization and increased sexual promiscuity.
• The oldest known case is a patient who died in 1959 in the Congo.
• The first known case in the Western world is a Norwegian sailor who died in 1976.

The Structure of HIV

• HIV is from the genus Lentivirus and is a retrovirus.
• It contains two identical strands of RNA, reverse transcriptase enzyme, and a phospholipid envelope.
• It has gp120 glycoprotein spikes.

The Infectiveness and Pathogenicity of HIV

• HIV is spread by dendritic cells and carried to the lymphoid organs, where it contacts activated T cells.
• gp120 combines with the CD4+ receptor and either CCR5 or CXCR4 coreceptors.
• CD4 molecules are carried on T helper cells, macrophages, and dendritic cells.
• The virus then fuses and enters the cell.
• Inside the cell, viral RNA is transcribed into DNA using reverse transcriptase.
• This DNA is integrated into the host's chromosomal DNA, leading to either active infection with new viruses budding from the host cell or latent infection with DNA is hidden in the chromosome as a provirus.
• Some cells become memory T cells and serve as the reservoir for HIV.
• The virus undergoes rapid antigenic changes and a high rate of mutation.

Subtypes of HIV

• HIV-1 is related to viruses that infect chimpanzees and gorillas, accounts for 99% of cases, and Group M (majority) accounts for 90% of cases.
• HIV-2 is related to viruses that infect monkeys and sooty mangabeys, is not often encountered outside of Africa, and is less pathogenic than HIV-1.

The Stages of HIV Infection

• Phase 1 is asymptomatic or involves lymphadenopathy.
• Phase 2 involves the steady decline of CD4+ T cells, with only a few infected cells releasing the virus and few serious disease symptoms. Symptoms can include persistent infections, fever, and oral leukoplakia.
• Phase 3 is when AIDS develops. The CD4+ count is below 200 cells/µl and indicator conditions develop.

Resistance to HIV Infection

• There is an initial strong and effective immune response.
• CTLs suppress viral numbers
• Once HIV establishes a pool of latently infected CD4+ T cells, it is impossible to clear the infection.
• This is a challenge for vaccine development

Impact of Age on Survival with HIV Infection

• Older adults and young children do not have a fully developed immune system, making them more susceptible.
• Some individuals have been exposed, but not infected with HIV.
• This is linked to the CCR5 mutation.
• Long-term survivors have a low viral load and effective CTLs.

Table 19.5 - Some Diseases Commonly Associated with AIDS

• Protozoan diseases include Cryptosporidium hominis (persistent diarrhea), Toxoplasma gondii (encephalitis), and Isospora belli (gastroenteritis).
• Viral diseases include Cytomegalovirus (fever, encephalitis, blindness), Herpes simplex virus(Vesicles of skin and mucous membranes), and Varicella-zoster virus (shingles).
• Bacterial diseases include Mycobacterium tuberculosis (Tuberculosis) and M. avium-intracellulare, that may infect many organs and cause gastroenteritis and other highly variable symptoms.
• Fungal diseases include Pneumocystis jirovecii (life-threatening pneumonia), Histoplasma capsulatum (disseminated infection), Cryptococcus neoformans (disseminated, but especially meningitis), Candida albicans (overgrowth on oral and vaginal mucous membranes in phase 2 stage of HIV infection), and C. albicans (overgrowth in esophagus and lungs in phase 3 stage of HIV infection).
• Cancers/precancerous conditions include Kaposi’s sarcoma (cancer of skin and blood vessels caused by human herpesvirus 8), Hairy leukoplakia (whitish patches on mucous membranes and commonly considered precancerous), and Cervical dysplasia (abnormal cervical growth).

Diagnostic Methods

• Seroconversion is the period of time between infection and the appearance of antibodies and takes up to 3 months.
• HIV antibodies can be detected by ELISA.
• Viruses are detected by Western blotting or APTIMA (RNA testing).
• Plasma viral load (PVL) is determined by PCR or nucleic acid hybridization.

HIV Transmission

• HIV survives 6 hours outside a cell and over 1.5 days inside a cell.
• Routes of transmission include intimate sexual contact, breast milk, transplacental infection, contaminated needles, organ transplants, and blood transfusion.
• Anal-receptive intercourse is the most dangerous form of sexual contact.

AIDS Worldwide

• 35 million people are infected worldwide, with 70% in sub-Saharan Africa.
• The incidence could exceed 1 million cases per year.
• Heterosexual transmission accounts for 85% of cases.
• Women comprise 42% of cases.
• One-third of cases in eastern Europe and central and southeast Asia are from injected drugs.

Preventing and Treating AIDS

• Strategies include the use of condoms, discouraging sexual promiscuity, use of sterile needles, and the availability of medications.
• AIDS is now considered a treatable chronic disease in the developed world

Fusion/Cell Entry Inhibitors

• Target the gp41 region of the viral envelope, preventing fusion of the virus with the cell, and including Enfuvirtide and maraviroc.

Reverse Transcriptase Inhibitors

• Nucleoside reverse transcriptase inhibitors (NRTIs) like Tenofovir and emtricitabrine.
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) like Efavirenz.
• Highly active antiretroviral therapy (HAART) involves using combinations of drugs to minimize survival of resistant strains.
• Integrase inhibitors inhibit HIV integrase, like Raltegravir.

Protease Inhibitors

• Inhibit proteases that cleave viral precursor proteins like, Atazanavir, indinavir, and saquinavir.

Other Treatments

• Maturation inhibitors
• Tetherins (tether viruses to the cells, preventing their release and spread)

Challenges of Developing HIV Vaccines

• No model of natural immunity to mimic
• Lack of a research animal
• Lack of understanding of the mechanisms of retroviruses
• High mutation rate, leading to resistant strains
• An ideal vaccine would induce immunity before reservoirs of latent virus are established, stimulate production of CTLs, and be affordable.