Retrovirus HIV1 Is the Causative Agent of AIDS

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Within a few years after recognition of AIDS as an infectious disease, the causative agent was discovered and characterized by efforts in the laboratories of Luc Montagnier in Paris and Robert Gallo in Bethesda (Figure 19-8). This immunodeficiency syndrome was novel at the time in that the type of virus causing it was a retrovirus. Retroviruses carry their genetic information in the form of RNA. When the virus enters a cell, the RNA is reverse transcribed to DNA by a virally encoded enzyme, reverse transcriptase (RT). As the name implies, RT reverses the normal transcription process and makes a DNA copy of the viral RNA genome. This copy, which is called a provirus, is integrated into the cell genome and is replicated along with the cell DNA. When the provirus is expressed to form new virions, the cell lyses. Alternatively, the provirus may remain latent in the cell until some regulatory signal starts the expression process.

Only one other human retrovirus, human T-cell lym-photropic virus I, or HTLV-I, had been described before HIV-1. This retrovirus is endemic in the southern part of Japan and in the Caribbean. Although most individuals infected with HTLV-I display no clinical signs of disease, a small percentage develop serious illness, either adult T-cell leukemia, which is aggressive and usually fatal, or a disabling progressive neurologic disorder called HTLV-I-associated myelopathy (called tropical spastic paraparesis in early reports). Although comparisons of their genomic sequences revealed that HIV-1 is not a close relative of HTLV-I, similarities in overall characteristics led to use of the name HTLV-III for the AIDS virus in early reports. There is also a related human virus called HIV-2, which is less pathogenic in humans than HIV-1. HIV-2 is similar to viruses isolated from monkeys; it infects certain nonhuman primates that are not infected by HIV-1.

Viruses related to HIV-1 have been found in nonhuman primates. These viruses, variants of simian immunodeficiency virus, or SIV, cause immunodeficiency disease in certain infected monkeys. Normally, SIV strains cause no disease in their normal host but produce immunodeficiency similar to AIDS when injected into another species. For example, the virus from African green monkeys (SIVagm) is present in a high percentage of normal healthy African green monkeys in the wild. However, when SIVagm is injected into macaques, it causes a severe, often lethal, immunodeficiency.

A number of other animal retroviruses more or less similar to HIV-1 have been reported. These include the feline and bovine immunodeficiency viruses and the mouse leukemia virus. Study of these animal viruses has yielded information concerning the general nature of retrovirus action, but specific information about HIV-1 cannot be gained by infecting ani-

VISUALIZING CONCEPTS

VISUALIZING CONCEPTS

gpl20

gp41

p32 integrase ssRNA

gpl20

gp41

p32 integrase ssRNA

Lyc Virus Simple

MHC proteins

Reverse transcriptase (p64)

protease (JC^

MHC proteins p17

Reverse transcriptase (p64)

Hiv Virions

FIGURE 19-8

Structure of HIV. (a) Cross-sectional schematic diagram of HIV virion. Each virion expresses 72 glycoprotein projections composed of gp120 and gp41. The gp41 molecule is a transmembrane molecule that crosses the lipid bilayer of the viral envelope. Gp120 is associated with gp41 and serves as the viral receptor for CD4 on host cells. The viral envelope derives from the host cell and contains some host-cell membrane proteins, including class I and class II MHC molecules. Within the envelope is the viral core, or nucleocapsid, which includes a layer of a protein called p17 and an inner layer of a protein called p24. The HIV

genome consists of two copies of single-stranded RNA, which are associated with two molecules of reverse transcriptase (p64) and nucleoid proteins p10, a protease, and p32, an integrase. (b) Electron micrograph of HIV virions magnified 200,000 times. The glycoprotein projections are faintly visible as "knobs" extending from the periphery of each virion. [Part (a) adapted from B. M. Peterlin and P. A. Luciw, 1988, AIDS 2:S29; part (b) from a micrograph by Hans Geldenblom of the Robert Koch Institute (Berlin), in R. C. Gallo and L. Montagnier, 1988, Sci. Am. 259(6):41.]

mals because HIV-1 does not replicate in them. Only the chimpanzee supports infection with HIV-1 at a level sufficient to be useful in vaccine trials, but infected chimpanzees only rarely develop AIDS, which limits the value of this model in the study of viral pathogenesis. In addition, the number of chimpanzees available for such studies is low and both the expense and the ethical issues involved in experiments with chimpanzees preclude widespread use of this infection model. The SCID mouse (see above) reconstituted with human lym-phoid tissue for infection with HIV-1 has been useful for certain studies of HIV-1 infection, especially in the development of drugs to combat viral replication.

Reasons for the limited host range of HIV-1 include not only the cell-surface receptors required for entry of the virus into the host cell but dependence of the virus on host-cell factors for early events in its replication process, such as transcription and splicing of viral messages. For example, mouse cells transfected with genes that mediate expression of the human receptors for HIV-1 will not support HIV-1 replication because they lack other host factors. By contrast, cells from hamsters or rabbits transfected to express the human receptors support levels of virus replication similar to those seen in human cells. Despite some progress in understanding the factors needed for HIV-1 infection, no clear candidate for an animal model of HIV-1 infection exists. This lack of a suitable infection model hampers efforts to develop both drugs and vaccines to combat AIDS.

Recent publicity focused on activists claiming that there is no connection between HIV and AIDS and that antiretrovi-ral drugs are useless to combat the disease. The so-called AIDS denialists believe that precautions against infection are not necessary, and that testing for HIV infection has no value because treatment is worthless or harmful. Some even deny the existence of an epidemic or that AIDS is an actual disease. While science requires that all ideas should be tested, denial of medical care to infected individuals based on this fringe group's notions is not an option. All relevant studies support a near perfect correlation between HIV infection and disease; drugs that lower the amount of virus in a patient (viral load) prevent opportunistic infections.

CLINICAL FOCUS

Prevention of Infant HIV Infection by Anti-Retroviral Treatment

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