Info

Host cell membrane

Step 2

Attachment

Binding occurs at CD4 and CCR5

Figure 29.5 Attachment and Entry of HIV into a Host Cell, Schematic Representation Step 1: Virion in close proximity to the cell membrane; blowup showing gp120 protein and sites of reaction with host cell receptors. Step 2: Initial contact of gp120 (SU) is with CD4. Attachment to a chemokine receptor such as CCR5 must occur before membrane fusion and entry of the viral genome can take place. Step 3: Membrane fusion probably is mediated by gp41 (TM).

Binding occurs at CD4 and CCR5

Step 3

Membrane fusion and entry of HIV

Step 3

Membrane fusion and entry of HIV

Viral genome

HIV envelope

Viral genome g* '

HIV envelope

Displacement of gp120; attachment of gp41

Host cell membrane

Host cell membrane

Displacement of gp120; attachment of gp41

initial contact of the virus with CD4. Penetration into the host cell probably involves gp41 (TM), probably with help from a host cell enzyme.

The co-receptor differs for different cell types. In early 1996, after a 10-year search, identification of a co-receptor for T lymphocytes was accomplished at the National Institutes of Health. Initially called fusin, it was later identified as CXCR-4, one of the cell's chemokine receptors. An HIV co-receptor of macrophages, CCR5, has been identified and is also a chemokine receptor, and other co-receptors are now known. These important findings have opened up several new avenues of research in the battle to control HIV disease.

Once HIV enters the host cell, its reverse transcriptase makes a DNA copy of the viral RNA genome. A complementary DNA strand is then added, and the ends of the resulting double-stranded DNA segment are joined non-covalently. The resulting circular DNA is then moved to the nucleus and is inserted into the host cell chromosome by the viral integrase (IN) enzyme. The viral segment thus becomes a provirus, a step necessary for efficient replication of HIV. No specific location is required for the insertion into the host chromosome. Following

29.1 Human Immunodeficiency Virus (HIV) Infection and AIDS 745

integration, spliced mRNA segments appear, mainly transcribed from the regulatory genes, tat, rev, and nef, and are translated into proteins that are probably involved in HIV gene expression. High levels of Tat are associated with replication of infectious virions. Nef protein, despite the name derivation from negative factor, may cause increased virion production and other effects increasing pathogenicity, depending on the viral strain and type of cell infected. In the case of Th lymphocytes, replication of mature virions results in lysis of the cells and release of infectious HIV. Macrophages, on the other hand, usually release infectious virus over long periods of time without death of the cells. The life cycle of HIV is shown schematically in figure 29.6, but in an infected person, at any one time, the vast majority of infected cells show neither lysis nor latency. Most of the HIV-infected cells show accumulations of various viral products that impair the normal functioning of the cells. ■ covalent bonds, p. 19

HIV is genetically highly variable. The variant viruses show differences in their preferred host cell, rates of replication, response to host immunity, and other characteristics. The variability is due to a high rate of "error" when reverse transcriptase copies the viral genome. Some regions of the genome are

Site of action of AZT and other reverse transcriptase inhibitors

Site of action of AZT and other reverse transcriptase inhibitors

Site of action of protease inhibitors

Site of action of antiretroviral drugs under development

Figure 29.6 The Steps in HIV Replication In step 4, the enzyme, integrase, mediates integration of the provirus into the host cell genome.This enzyme is potentially a target of new anti-HIV medications. In step 7, the accessory gene product Vpr and MA transport viral proteins to the cell membrane.

(5) With host cell activation, viral DNA is transcribed, yielding messenger RNAs-and viral genome RNA.'

Site of action of protease inhibitors

Site of action of antiretroviral drugs under development

Figure 29.6 The Steps in HIV Replication In step 4, the enzyme, integrase, mediates integration of the provirus into the host cell genome.This enzyme is potentially a target of new anti-HIV medications. In step 7, the accessory gene product Vpr and MA transport viral proteins to the cell membrane.

Chapter 29 HIV Disease and Complications of Immunodeficiency

PERSPECTIVE 29.1 Origin of AIDS-Causing Viruses

Where did the AIDS-causing viruses come from? Genetic evidence indicates that the HIV-1 virus mutated to its present form fairly recently, between 50 and 150 years ago. Although it first appeared in the United States in the 1970s, serological evidence indicates that it was present in Africa in rare individuals in the 1950s.

Viruses similar to HIV exist in a number of wild and domestic animals, including cats, dairy cattle, and monkeys. A virus closely related to HIV-1 has been found in animals belonging to a single West African subspecies of chimpanzees.The virus does not appear to harm the chimpanzees, suggesting that they have been living together for eons. Another virus, closely related to HIV-2, is present in a species of large monkey, the sooty mangabey. A likely theory is that the AIDS-causing viruses "jumped" to humans from these simian relatives, presumably through contact with their blood. Indeed, in Africa, chimps and mangabeys are often killed for food, exposing humans to their blood, and incidentally, driving some species nearly to extinction. Also, a number of humans were intentionally injected with chimpanzee and mangabey blood in the course of research on malaria carried out between 1922 and 1955.

Genetic comparisons of a large number of simian lentiviruses and AIDS-causing viruses from humans support the idea that the simian viruses can jump to humans. In the case of HIV-1, a jump to humans probably occurred only once, between 1910 and 1950 most likely around 1930. It is unlikely that HIV was transferred to humans by inadequately sterilized Salk polio vaccine grown in simian kidney cell cultures, but the possibility has not been completely ruled out.There is no credible evidence for another popular theory that the viruses resulted from botched biological warfare experiments by Russia or the United States.

It is possible that AIDS-causing viruses have existed for many years in people living in isolated African villages, perhaps even for centuries. According to this idea, population increases and migration to big, crowded cities to find work allowed the viruses to spread rapidly, becoming more virulent in the process.

The answer to the question about the origins of AIDS-causing viruses may never be known precisely, but the question is intriguing and may lead to better understanding of the emergence of new infectious diseases.

highly conserved, meaning they do not change much from one strain of virus to another. Other regions are highly variable. This is reflected for example in the glycoprotein composing gp120 (SU), which has conserved and variable regions (figure 29.7). The V3 variable region is important because it plays a role in the virulence of HIV. This antigenic variability of HIV enormously complicates the task of developing an effective vaccine against the virus. ■ reverse transcriptase, p. 356

Destruction of immune system Th cells by HIV can occur via multiple mechanisms:

■ Lysis following HIV replication. Lysis of activated helper CD4+ T lymphocytes during replication of

labeled V1 to V5, are "variable" and differ from strain to strain, frustrating attempts to develop a vaccine. Note the V3 loop, implicated in pathogenicity.

infectious virus is certainly one mechanism, but by itself it cannot account for the devastation that results from HIV disease.

■ Attack by HIV-specific cytotoxic CD8+ T lymphocytes. The earliest detectable immune response to HIV infection involves HIV-specific CD8+ T lymphocytes, which attack and lyse infected cells.

■ Natural killer cells. Natural killer cells probably also play a role in cell destruction.

■ Antibody-dependent cellular cytotoxicity. Humoral antibody may also play a role through antibody-dependent cytotoxicity.

■ Autoimmune process. Autoimmunity could be responsible, since HIV envelope proteins show some homology with MHC class II molecules.

■ Fusion of infected and uninfected cells. In cell fusion, a large number of uninfected cells fuse with an infected cell, whereupon the resulting syncytium is destroyed.

■ Apoptosis, also called programmed cell death, or death due to aging, is accelerated in HIV infections by a number of mechanisms, including induction by Tat, SU interaction with CD4, and certain cytokines.

Accumulation of viral products such as viral RNA and unin-tegrated viral DNA inside the cytoplasm of the infected cell can also result in its death. ■ natural killer cells, p. 411 ■ antibody-dependent cellular cytotoxicity, p. 400 ■ major histocompatibility complex, class II (MHC-II), p. 408 ■ apoptosis, p. 387

An acute retroviral syndrome (ARS) begins in 50% to 70% of HIV-infected subjects after an incubation period of 6 days to 6 weeks, with sore throat, fever, muscle and headaches, enlarged lymph nodes, and a rash. These symptoms generally last 1 to 4 weeks and disappear without treatment. Whether or not symptoms occur, the concentration of HIV in the blood rises to high levels as the newly infected cells release their progeny virus (figure 29.8). The marked viremia usually subsides as the supply of uninfected cells dwindles and anti-HIV MHC I CD8+ cytotoxic T cells appear. The CD4+ T-cell level falls initially, then slowly rises but does not reach the preinfection level. Following the acute episode, the HIV-infected individual generally enters an asymptomatic period ranging from months to many years. The levels of HIV virus as measured by circulating plasma and lymph node viral RNA are good predictors of the course of the illness, high levels pointing to a more rapid progression to AIDS. Regardless of the lack of symptoms, a silent struggle goes on between HIV and the immune system for the rest of the person's life. Infectious virus, a threat to others, continues to be present in the blood and body secretions.

In the typical case, as seen in approximately 80% of HIV-infected people, the immune system slowly loses ground to HIV even though the body can normally replace over a billion CD4+ cells per day. The peripheral blood CD4+ count (normally about 1,000 cells per microliter) steadily falls at a rate of roughly 50 cells/ml/year, symptoms ofAIDS usually appearing when CD4+ counts fall below 300 cells per microliter. Levels of infectious virus again rise dramatically. At this point in the illness, the pathology is dominated by malignant neoplasms or opportunistic infections. Half of the patients reach this stage of the illness within 9 to 10 years; the rest take longer. The typical course of HIV disease is summarized in figure 29.8.

Atypical progression to AIDS occurs in about 10% of persons with HIV disease who have high virus levels with the acute infection that do not fall dramatically within a few months. These subjects progress rapidly to AIDS within a few years. Another 5% to 10% of HIV-infected individuals show no fall in CD4+ cells. They maintain high levels of anti-HIV antibody and HIV-specific CD8+

29.1 Human Immunodeficiency Virus (HIV) Infection and AIDS 747

cytotoxic T cells. Estimates suggest that, with these cases and the more slowly progressing typical cases, 10% to 17% of HIV-infected persons will be free of AIDS 20 years after their infection.

Epidemiology

Indiscriminate sexual intercourse with multiple partners without the use of condoms is a major factor in the spread of HIV disease. In the United States, initially, promiscuous homosexual men were the hardest hit by the epidemic. An estimated 1.4% to 10% of American men are active homosexuals. An additional unknown number of men are bisexual, meaning they have sexual intercourse with both men and women. A survey done before the arrival of AIDS found that 33% to 40% of gay men had more than 500 lifetime sexual partners, and another 25% had 100 to 500. By 1978, 4.5% of one group of gay men in San Francisco were infected with HIV; by 1984, two-thirds were infected and almost one-third had developed AIDS. The pace of the epidemic among gay men has been slowing, but still there were more than 22,000 new AIDS cases reported among men who have sex with men in the year ending mid-1999, and these accounted for an estimated 45% of new HIV infections over the same period. These numbers, however, merely reflect how the virus was introduced into Western countries. Heterosexual spread of HIV is increasing and promises to become the dominant mode of transmission, as it is in many African countries. Sex with multiple partners; sex with a person who has had multiple partners; being the receptive partner, especially receptive anal sex; traumatic sex; and any irritation or inflammatory process as from another sexually transmitted disease—all increase the risk

ACUTE RETROVIRAL ASYMPTOMATIC INTERVAL AIDS

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