Su

TM

Figure 29.3 Human Immunodeficiency Virus, Type 1 (HIV-1) (a) Diagrammatic representation of the virus showing important antigens. (b) Map of the HIV-1 genome showing its nine genes and flanking long terminal repeats (LTRs).The LTRs contain regulatory sequences recognized by the host cell. (c) HIV-1 gene products.The accessory gene products are translated into proteins of final size, while gag and pol products must be cleaved by viral protease, and env products by host cell protease.The small arrows indicate the sites of cleavage.

rev tat messenger RNA (figure 29.3c). The resulting protein is split into functional segments by viral protease. This enzyme releases itself from the large protein and enzymatically splits the remaining protein into functional enzymes and structural units. The final yield is three enzymes: protease, reverse transcriptase, and integrase, and a number of other proteins, including p24 (CA) capsid and p17 (MA) matrix. The virus, however, has a greater need for structural proteins MA, CA, and NC than for the enzymes PR, RT, and IN, and so gag is usually expressed by itself, only rarely joining pol through a frameshift. Reverse transcriptase and protease are the targets of the medicines currently available for treating AIDS. The former enzyme is essential for early viral replication, and the latter is required for production of infectious virions at the time they bud from the host cell. The env gene is translated from a spliced messenger RNA, yielding a precursor protein that is processed by host cell enzymes to give the gp120 (SU) surface glycoprotein and the gp41 (TM) transmembrane glycoprotein. ■ RNA splicing, p. 180

There are six additional genes, known as accessory genes, all translated from spliced messenger RNAs. These genes, tat, rev, nef, vif, vpr, and vpu, code for the proteins Tat, Rev, Nef, Vif, Vpr, and Vpu. These gene products and their known or assumed functions are listed in table 29.2.

The functions of these HIV accessory genes are exceedingly complex, as they interact in different ways with host cell substances and vary with the type of cell infected. Developing knowledge of their gene products promises to reveal new ways to attack AIDS.

29.1 Human Immunodeficiency Virus (HIV) Infection and AIDS 743

Table 29.2 HIV Accessory Gene Products

Gene Product

Function

Tat (transactivating protein)

Regulates transcription of genes that code HIV proteins

Rev (regulator of viral expression)

Binds to unspliced RNA transcripts and targets them for passage out of the host cell nucleus

Nef (negative factor)

Regulates HIV replication

Vif (viral infectivity factor)

Aids viral infectivity; role in virion assembly

Vpr (viral protein R)

Aids virus replication

Vpu (viral protein U)

Aids virus budding and release from host cell

Pathogenesis

HIV virions enter the body; there, they attach to and infect certain types of cells. Which cells are affected and their response to infection vary with the particular viral strain and the type of host cell. Some of the cell types and the consequences of infection are shown in figure 29.4. Infection of intestinal epithelium is partly

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Infection of intestinal epithelium and lymphoid tissue probably contributes to chronic diarrhea and weight loss.

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Infection of intestinal epithelium and lymphoid tissue probably contributes to chronic diarrhea and weight loss.

Infection of several types of brain cells probably contributes to lethargy and HIV dementia.

CD4+Th1 inflammatory cells are the principal target of HIV. These cells are normally responsible for macrophage activation and cell-mediated immunity through CD8 cytotoxic cell activation.

CD4+ macrophages, dendritic and other antigen-presenting cells harbor HIV but are not usually killed by it. The cells are a continuing source of the virus and can carry it into the brain.

Infection of several types of brain cells probably contributes to lethargy and HIV dementia.

CD4+Th1 inflammatory cells are the principal target of HIV. These cells are normally responsible for macrophage activation and cell-mediated immunity through CD8 cytotoxic cell activation.

CD4+ Th2 helper cells normally control antibody production by B cells.

CD4+ macrophages, dendritic and other antigen-presenting cells harbor HIV but are not usually killed by it. The cells are a continuing source of the virus and can carry it into the brain.

Figure 29.4 Some of HIV's Cellular Targets

CD4+ Th2 helper cells normally control antibody production by B cells.

744 Chapter 29 HIV Disease and Complications of Immunodeficiency responsible for the chronic diarrhea and weight loss, and infection of brain cells for HIV dementia. Infected macrophages and other antigen-presenting cells are a continuing source of infectious virus and show impairment of chemotaxis, phagocytosis, and antigen presentation. They and the Th (T-helper) lymphocytes are exceedingly important targets of HIV because of their central role in the body's specific immune response. The cytokines of Th lymphocytes regulate cytotoxic action of Tc cells, immunoglobulin production by B cells, and chemotaxis of antigen-presenting cells such as macrophages.

HIV must attach to and enter the body's cells to establish infection. Like most other cells susceptible to HIV, Th lym phocytes and macrophages are CD4 + , meaning they possess the CD4 surface antigen. HIV attaches to CD4 by its surface gp120 (SU) antigen. The presence of the CD4 antigen, however, is by itself not sufficient to cause entry of HIV. In addition, there must be a host cell co-receptor specific for HIV in order for viral entry to occur (figure 29.5). The nature of HIV attachment and entry into the host cell has been a mystery subject to intense study because antibodies and other substances designed to block SU and CD4 have not been very successful in preventing infection. Findings so far indicate that SU is flexible, irregular in shape, and divided into two parts connected by peptide strands. The main binding sites for CD4 and the co-receptor are only exposed after

Step 1

,gp41

Step 1

,gp41

gp120

Fusion site

Step 2

Attachment

Fusion site

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