Confronting AIDS Update 1988 (1988) / Chapter Skim
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6. The Biology of HIV and Biomedical Research Needs
6. The Biology of HIV and Biomedical Research Needs
Pages 123-158
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From page 123... ...
Less progress has been made in understanding the behavior of HIV in viva and the interaction of the virus with its human host. This chapter describes new knowledge gained from AIDS research efforts, ways in which that knowledge may be used against HIV infection, the difficulties of developing drugs and vaccines to combat the epidemic, and the variety of resources needed for the task.
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From page 124... ...
Shortly after the isolation of HIV-1, a related lentivirus, simian immunodeficiency virus, or SIV, was identified in a variety of monkey species (Daniel et al., 1985; Kanki et al., 1985~. HIV-2, in fact, is more closely related in its genetic structure to this simian virus than to HIV-1 (Chakrabarti et al., 1987; Franchini et al., 1987; Guyader et al., 1987; Hirsch et al., 19871.
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From page 125... ...
As discussed in Confronting AIDS, a fuller understanding of the origin and immunologic significance of variations in the nucleotide sequences of HIV is central to efforts to engender protective immunity through vaccination. Work in this area has brought improved definition of conserved and variable domains in the envelope glycoproteins, but little is known as yet about the biological processes that may give rise to and possibly select for sequence divergence (Coffin, 1986; IOM/NAS, 1986~.
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From page 126... ...
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From page 127... ...
The transcription of retroviral RNA uses the host cell's synthetic machinery, but it is regulated by genetic elements resident in the viral long terminal repeats, or LTRs. The complex behavior of HIV is thought to include mechanisms that facilitate both the amplification and attenuation of viral expression (production)
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From page 128... ...
It appears that HIV may encode a specific, novel gene to regulate the pattern of spliced RNAs produced in infected cells and, consequently, the amount of virus particles produced (Feinberg et al., 19861. HIV envelope glycoproteins play an essential role in the replication of HIV and may be responsible for many of the cytopathic consequences of viral infection (Lifson et al., 1986a; Sodroski et al., 1986a; Somasundaran and Robinson, 1987; McCune et al., 1988~.
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From page 129... ...
In the absence of art/trs expression, the smaller, multiply spliced mRNA species that encode the viral regulation proteins predominate, at the expense of the full-length and singly spliced ens transcripts that provide viral genomes and specify translation of the HIV-1 virion structural components (Feinberg et al., 1986; Sadaie et al., 19881. The art/trs function may specifically affect the splicing of viral RNA and thus permit important differential regulation of HIV expression; additional art/trs effects on the translation of specific viral mRNAs have also been
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From page 130... ...
have postulated that the art/trs protein acts through specific, incompletely defined sequences contained in HIV-1 RNA transcripts. Like the tat-III protein, the art/trs protein is localized in the nucleus of HIV-1-infected cells, consistent with its postulated role in the splicing of viral RNA.
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From page 131... ...
It is hoped that small fragments of CD4 may soon be identified that will prevent HIV infection but that will not interfere with the critical immunologic functions of the CD4 molecule in viva. Experimental clinical trials of the soluble CD4 preparation in HIV-positive persons are expected to begin shortly; however, this approach may be limited by the inability of such preparations to cross the blood-brain barrier and thus reach the important reservoir of infection within the central nervous system (Ho et al., 1985; Shaw et al., 1985; Gartner et al., 1986b; Koenig et al., 19861.
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From page 132... ...
, is an even more potent inhibitor of HIV replication in vitro and is now the subject of clinical trials (Yarchoan and Broder, 1987~. Another area of potential inhibition involves the processes that control the transcription and translation of HIV RNA.
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From page 133... ...
In addition to the CD4 helper-inducer cell population that is progressively depleted in the clinical development of AIDS, researchers now recognize that cells of the macrophage-monocyte lineage are important targets in the establishment, dissemination, and persistence of the infection (Gartner et al., 1986a; Ho et al., 1986; Koenig et al., 19861. Because macrophages permit HIV replication, are capable of wide-ranging migration, and are relatively resistant to the cytopathic consequences of viral infection, they probably play a major role in the pathogenesis of HIV-induced disease.
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From page 134... ...
The number and types of infected cells in HIV-positive persons remain incompletely defined. The persistence of HIV infection in viva, which is often imprecisely called a latent infection (because there is no evidence as yet that the HIV genome is integrated and not expressed)
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From page 135... ...
As often happens in scientific investigation, serendipitous developments that initially are unrelated to HIV may unexpectedly contribute to progress in AIDS research. For example, many of the techniques that have been used to study HIV were developed during research in other fields.
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From page 136... ...
The search for therapeutic agents for HIV-infected persons must also encompass the screening of existing compounds. Scientists and industry leaders who are experienced in drug development predict that screening existing compounds rather than designing or attempting to discover new drugs to treat HIV infection and AIDS may prove more successful, at least in the immediate future (IOM, 1987~.
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From page 137... ...
After the completion of phase III trials, the drug sponsor files a new drug application (NDA)
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From page 138... ...
In addition, FDA has proposed new procedures to facilitate patients' access to promising new drugs as early as possible in the drug development process (Young, 1987~. Drug sponsors may now apply for a special treatment status for their investigational new drug when the following conditions are met: · the drug will treat an immediately life-threatening or otherwise .
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From page 139... ...
For example, the pharmaceutical industry has expressed concern that the use of the treatment IND mechanism may make it more difficult to enroll sufficient numbers of patients in clinical trials: people who know that the drug under investigation could be offered to them as treatment in the near future may be reluctant to participate in tests (Cooper, 1988~. There is also concern about potential issues of legal liability on the part of drug manufacturers and individual physicians: for instance, when patients who are receiving investigational new drugs under the treatment IND mechanism develop adverse reactions or when patients fail to receive an investigational drug because their physicians are unaware of its availability.
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From page 140... ...
, has opportunities for such communication and encouragement, in part because of the role of ACTUs in the clinical evaluation of new drugs. The ACTUs, a component of the newly organized AIDS Clinical Trials Cooperative Group, are located at 35 sites around the country.
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From page 141... ...
With this general strategy in mind, researchers have looked to the HIV envelope glycoprotein gpl20 and its precursor gpl60 as promising vaccine candidates. For one thing, these envelope glycoproteins induce antibody production during the course of natural HIV infection; in addition, humans generate cytotoxic T-cell responses directed toward gpl20 (Shearer, 19871.
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From page 142... ...
Total HIV antibody levels drop in AIDS patients in very late stages of the disease, a drop that may be the result of antigen excess. Thus, it appears that HIV infection proceeds in the presence of neutralizing antibodies and cytotoxic T cells that are capable of killing HIV-infected cells in vitro.
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From page 143... ...
Fourth, as in the case of measles, HIV-infected cells may avoid immune detection by not displaying their HIV-encoded antigens. Fifth, some of the body's immune responses to HIV mask viral antigens so that protective mechanisms cannot be stimulated.
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From page 144... ...
Furthermore, testing vaccines composed of viral envelope antigens for safety in humans will provide information, in general, about both humoral and cell-mediated human immune responses to HIV antigens.
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From page 145... ...
, or in another suitable animal model, or (2) the vaccine candidate rests on fundamental new knowledge of the relevant human response that cannot be adequately modeled in animals.
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From page 146... ...
Future animal experiments should use cloned viruses and standardized neutralization tests. ROUNDTABLE ON DRUGS AND VACCINES The institute of Medicine Conference on Promoting Drug Development Against AIDS and HIV Infection (August 31-September 1, 1987)
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From page 147... ...
lentiviruses such as maedi-visna virus, caprine arthritis-encephalitis virus, and equine infectious anemia virus, all of which induce disease in hoofed animals; (3) HIV-related viruses of Old World primates (i.e., simian immunodeficiency virus, or SIV)
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From page 148... ...
Sufficient lead time and funding must also be provided for the production of macaques in large numbers (Desrosiers and Letvin, 19871. The use of chimpanzees and other primates for AIDS research and, in particular, efforts to increase the available numbers of animals through breeding demand national-level coordination.
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From page 149... ...
A completely analogous animal model of HIV-induced human disease, especially in a small, plentiful, and wellunderstood animal such as the mouse, would greatly enhance vaccine and drug development. If efforts to develop a small animal model are carried out under carefully regulated, safe laboratory conditions, the committee strongly supports further work in this area.
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From page 150... ...
This information should be forwarded to Congress for evaluation and subsequent action. Reagent Distribution Center To support AIDS research and provide the scientific community with the necessary biological materials for this work, NIAID has established the AIDS Research and Reference Reagent Program asking investigators to contribute appropriate materials that are needed for AIDS research.
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From page 151... ...
1986. Synthesis of the complete trans-activation gene product of human T-lymphotropic virus type III in Escherichia coli: Demonstration of immunogenicity in viva and expression in vitro.
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From page 152... ...
1987. Human immunodeficiency virus type 2 infection associated with AIDS in West Africa.
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From page 153... ...
1987. Sequence of simian immunodeficiency virus and its relationship to the human immunodeficiency viruses.
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From page 154... ...
1988. Mutational analysis of the trans-activation-responsive region of the human immunodeficiency virus type I long terminal repeat.
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1987. Human Tlymphotropic virus type 4 and the human immunodeficiency virus in West Africa.
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From page 156... ...
1988. Human immunodeficiency virus infection of CD4-bearing cells occurs by a pH-independent mechanism.
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From page 157... ...
Immunology of human immunodeficiency virus infection and the acquired immunodeficiency syndrome.
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From page 158... ...
1988. Soluble CD4 molecules neutralize human immunodeficiency virus type 1.
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