Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

C h a p t e r 1 6

Transfusions of whole blood or blood products before 1985 resulted in the transmission of HIV. Since 1985, all blood donations in the United States have been screened for HIV, dramatically reducing the trans- mission risk to an extremely small number. 2 Currently, all donated blood and plasma are screened for HIV- associated antigen and antibodies to HIV. Screening tests may be negative in the so-called window period , the 1 to 6 months following a new HIV infection and before seroconversion, the point at which HIV antibod- ies can be detected in the blood. Therefore, the U.S. Food and Drug Administration (FDA) requires blood collection centers to screen potential donors through interviews designed to identify behaviors known to present a risk for HIV infection. In addition, nucleic acid amplification testing (NAAT) of blood donors has reduced the risk of transfusion transmission of both HIV and hepatitis C virus to approximately 1 in 2 mil- lion blood units. 51 Occupational HIV infection among health care workers is uncommon. Universal blood and body fluid precautions should be used in encounters with all patients in the health care setting because HIV status is not always known. Occupational risk of infection for health care workers most often is associated with per- cutaneous inoculation (e.g., needle stick) of blood from a patient with HIV infection. Transmission is associated with the size of the needle, amount of blood present, depth of the injury, type of fluid contamination, stage of illness of the patient, and viral load of the patient. The average risk for HIV infection from percutaneous exposure to HIV-infected blood is about 0.3%, and about 0.09% after mucous membrane exposure. 52,53 The HIV-infected person is infectious even when no symptoms are present. The point at which an infected person converts from being negative for the presence of HIV antibodies in the blood to being positive is called seroconversion. Seroconversion typically occurs within 1 to 3 months after exposure to HIV, but rarely can take as long as 6 months. Recent data suggest that 50% of transmissions occur during primary HIV infection and early HIV infection. 54 The time after infection and before seroconversion is known as the window period. During the window period, a person’s HIV antibody test result will be negative but he or she can still transmit the virus. The primary etiologic agent of AIDS is HIV, an envel- oped ribonucleic acid (RNA) retrovirus that carries its genetic material in RNA rather than DNA. Two geneti- cally different but antigenically related forms of HIV— HIV-1 and HIV-2—have been isolated in people with AIDS. 1–3 Human immunodeficiency virus-1 is the type most commonly associated with AIDS in the United States, Europe, and central Africa, whereas HIV-2 causes a similar disease principally in western Africa. Human immunodeficiency virus-2 spreads more slowly and causes disease more slowly than HIV-1. Specific tests are now available for HIV-2, and blood collected Molecular and Biologic Features of HIV Infection

for transfusion is routinely screened for HIV-2. The remaining discussion focuses on HIV-1, but the infor- mation is generally applicable to HIV-2 as well. HIV infects a limited number of cell types in the body, including CD4 + T lymphocytes, macrophages, and den- dritic cells (see Chapter 15). The CD4 + T cells are nec- essary for recognition of foreign antigens, activating antibody-producing B lymphocytes, and orchestrating cell-mediated immunity, in which cytotoxic CD8 + T cells and NK cells directly destroy virus-infected cells, tuber- cle bacilli, and foreign antigens. The phagocytic func- tion of monocytes and macrophages is also influenced by CD4 + T cells. The HIV is spherical and contains an electron-dense core surrounded by a lipid envelope 1–3 (Fig. 16-8A). The core contains an outer shell, or capsid, made up primar- ily of a protein called p24; two copies of the genomic RNA; and three viral enzymes (protease, reverse tran- scriptase, and integrase). The viral core is surrounded by a matrix protein called p17 , which lies beneath the viral envelope, a structure studded with two viral gly- coproteins, gp120 and gp41, which are critical for the infection of cells. Replication of HIV occurs in eight steps 2,3 (see Fig. 16-8B). Each of these steps provides insights into the development of methods used for preventing or treat- ing the infection. The first step involves the binding of the virus to the CD4 + T cell. Once HIV has entered the bloodstream, it attaches to the surface of a CD4 + T cell by binding to the CD4 molecule, which acts as a high- affinity receptor for the virus. This process is known as attachment. However, attaching to the CD4 molecule is not sufficient for infection; the virus must also bind with other surface molecules (chemokine coreceptors, such as CCR5 and CXCR4) that bind the gp120 and gp41 envelope glycoproteins. The chemokine corecep- tors are critical components of the HIV infection pro- cess: the virus can only infect cells expressing CD4 + and the coreceptors. People with defective coreceptors are more resistant to development of HIV infection, despite repeated exposure. 55 Research aimed at developing core- ceptor-targeted viral entry inhibitors raises new hope for bridging the gap toward a cure of HIV infection. The second step of the replication process allows for internalization of the virus. After attachment, the viral envelope peptides fuse to the CD4 + T-cell membrane. Fusion results in an uncoating of the virus, allowing the contents of the viral core (the two single strands of viral RNA and the reverse transcriptase, integrase, and pro- tease enzymes) to enter the host cell. The third step con- sists of DNA synthesis. In order for HIV to reproduce, it must change its RNA into DNA. It does this using the reverse transcriptase enzyme. Reverse transcriptase makes a copy of the viral RNA, and then in reverse makes a complementary DNA (cDNA) strand. The result is a double-stranded DNA that carries instruc- tions for viral replication. The fourth step is called integration. In dividing cells, the cDNA enters the nucleus and, with the help of the enzyme integrase, is inserted into the cell’s original DNA. The integrated virus is called a provirus . In quiescent