Confronting AIDS Directions for Public Health, Health Care, and Research (1986) / Chapter Skim
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6. Future Research Needs
6. Future Research Needs
Pages 177-260
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From page 177... ...
Such insights, however impressive, are only the beginning of what promises to be a long and difficult path toward effective therapeutic interventions to minimize or eliminate the debilitating effects of HIV infection and toward limiting the spread of the virus by means of safe and effective vaccines. This chapter summarizes some of the opportunities and obstacles that will be encountered along that path.
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From page 178... ...
The pol gene specifies the viral enzyme known as reverse transcriptase, which is responsible for synthesizing a DNA copy of the retroviral RNA genome early after infection. The gag and pot proteins are first synthesized as a large precursor, which is then cleaved by a virus-encoded protease to give the final proteins.
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From page 179... ...
. Retroviral Replication Retroviral infection (see Figure 6-2)
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From page 180... ...
After binding takes place, the retrovirus enters the cell and uncoats in the host cell's cytoplasm. The retroviral genetic information contained in its single-stranded RNA genome is then transferred to a full-length linear duplex DNA intermediate by the synthetic activities of the reverse transcriptase enzyme, which accompanied it in the virion particle.
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From page 181... ...
The production of large quantities of all of the virus's genes in a biologically active form will provide necessary substrates for structural and functional analyses. In addition to the study of such recombinant DNA products, it will be important to directly study the native proteins as they exist in the virion and in infected cells.
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From page 182... ...
The retroviral core is composed of collections of the gag proteins in association with the genomic RNA molecules, the reverse transcriptase, and other enzymes. Although there are generally accepted models for the structure of the interior of retrovirus virions, the models are conceptual in character and lack experimental validation (Weiss et al., 1982, 19851.
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From page 183... ...
The structural definition of the molecular components involved in this specific recognition process will be of central importance in the development of vaccines or other prophylactic measures to prevent HIV infection. The HIV envelope protein, through its specific interaction with the CD4 molecule, plays an important role in the cytopathic effect of viral infection on T lymphocytes (Lifson et al., 1986, in press; Sodroski et al., 1986a)
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From page 184... ...
Once the retroviral particle has uncoated in the cytoplasm, the critical and characteristic process of reverse transcription of the viral RNA genome into a double-stranded DNA copy ensues. The enzyme that catalyzes this process, reverse transcriptase, provides a specific and potentially very effective target for antiviral therapy.
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From page 185... ...
The significance and origin of unintegrated HIV DNA are unclear, but they may have significant implications for understanding the cytopathic effects of the virus and for the potential of therapeutic agents to limit infection. Improved understanding of the requirements for and mechanisms of HIV integration, increasing availability of enzymatically active viral proteins involved in the process, and the development of cell-free systems for their assay will help in drug design and screening.
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From page 186... ...
The gag gene is translated through the synthesis of a protein precursor, Pr55, which is subsequently proteolytically processed into ply, p24, p9, and p7. The pol gene, which encodes the HIV reverse transcriptase, integrate, and probably protease, is thought to be initially translated into a polyprotein precursor, Prl50, which is then processed into p64/53, p22, and p34, respectively.
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From page 187... ...
Glycosylation could conceivably be an important determinant of the structure of the envelope, it could mask functionally important antigenic sites from human immune responses, or it could do both. The mature form of the viral envelope is achieved by the proteolytic cleavage of the gpl60 precursor to gpl20 and gp41.
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From page 188... ...
studies of HIV, reverse transcriptase, protease, integrate, glycoproteins, and regulatory proteins. · Strategies dedicated to prevention of the clinical manifestations of HIV infection and AIDS must also be predicated on a greatly improved understanding of the normal functioning of the human immune system (see section on "Natural History of HIV Infection," below)
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From page 189... ...
Significant harm to the public's perception of the AIDS threat and to the credibility of the scientific community will also accrue if laboratory, clinical, or epidemiologic results are presented with exaggerated significance. NATURAL HISTORY OF HIV INFECTION Transmission of HIV For an HIV infection to become established, infectious virus must be delivered to a susceptible host.
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From page 190... ...
While epidemiologic studies clearly show that receptive anal intercourse is associated with an increased risk of HIV infection, interpretation of this observation is difficult in light of the high prevalence of viral infection in the sexual partners of persons engaging in this practice. Recent reports of seroconversion in women who were artificially inseminated by an asymptomatic virus carrier argue against a requirement for "traumatic" sexual intercourse in the transmission of HIV (Stewart et al., 19851.
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From page 191... ...
The Immune System Response to HIV Infection As described in Chapter 2, the earliest and most easily detectable marker for viral infection is the presence of antibodies reactive with HIV in the serum of an infected individual. However, a very small subset of infected individuals have been reported to remain seronegative for prolonged periods of time (Salahuddin et al., 19841.
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From page 192... ...
Whether the currently used assays for HIV neutralization bear any correlation with disease progression remains to be established, but this is an important area for further evaluation. In addition to the antibody response generated by the humoral components of the host immune system, a protective response to a viral infection can also be mediated through the cellular immune system.
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From page 193... ...
Many questions remain to be answered, including the specific types of cellular immune responses that might afford some protection from HIV infection, potential means of enhancing their antiviral efficacy, and the reasons for their apparent failure in the course of a natural infection (Weissman, 19861. The Immunologic Consequences of HIV Infection Once an HIV infection becomes established, compromise of the immune system can be detected in most, if not all, infected persons.
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From page 194... ...
. The central nervous system also provides a common target for viral infection and pathology, although the identity of the infected target cells within the brain is controversial (see section on "Neurologic Complications" in Appendix A)
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From page 195... ...
The relative inability of sera from persons infected with HIV to prevent virus-induced T-lymphocyte cell fusion may allow both the continued spread of viral infection and the cytopathic consequences of viral expression. Also, the ability of one HIV-expressing cell to recruit other uninfected CD4-expressing T lymphocytes into syncytia may greatly amplify the extent of T-lymphocyte depletion, given only a few virus-expressing cells.
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From page 196... ...
Because the interaction between the HIV envelope protein and the CD4 molecule plays an important role in both viral infectivity and pathogenicity, development of ways to interfere with it may afford valuable strategies for disease prevention. As discussed in Chapter 2, the opportunistic infections and unusual malignancies that characterize AIDS are the most obvious manifestations of a severe underlying state of immunodeficiency.
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From page 197... ...
However, an intrinsic defect has been observed in the ability of residual CD4 T cells derived from AIDS patients to recognize and respond to soluble antigens, irrespective of numerical correction (Lane et al., 19851. A measurable defect in reactivity to soluble antigens can also be identified in HIVinfected persons who possess near-normal levels of CD4 T cells.
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From page 198... ...
As discussed in Chapter 2, the appearance of Kaposi's sarcoma in HIV-infected persons does not correlate with the degree of observed immunodeficiency, and it is unclear whether it derives from an absence of normal direct or indirect regulatory influences exerted on the Kaposi's target cell by a specific subpopulation of CD4 T cells or from the failure of immune surveillance against incipient tumors. Since the manifestations of Kaposi's sarcoma may not predict the extent of underlying immunosuppression, it may be a poor determinant of which patient population to use in the evaluation of the efficacy of antiviral drugs (see section on "Antiviral Agents," below)
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From page 199... ...
Much, perhaps most, of the available knowledge about the disease derives from epidemiologic research for two reasons: there are presently no entirely suitable animal models in which to study the disease, and certain sorts of experimentation with human beings are precluded by the ethics of research. Much has been learned from epidemiologic research during the first five years of the AIDS epidemic, but future research needs remain great.
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From page 200... ...
Recommendations on Natural History of HIV Infection · There is a need to determine what proportion of HIV-infected persons will become sick and to define many other features of the disease's natural history. · Additional information is needed on the natural history of HIV in
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From page 201... ...
, and coupled with studies of HIV molecular virology. Careful attention should also be given to the definition and assessment of important predictive parameters of the human immune response.
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From page 202... ...
Such data would also be critical for assessing the possibility that HIV transmission will be perpetuated among heterosexuals, as are many other sexually transmitted diseases. The ideal subjects for this type of study are the male sexual partners of women who acquired HIV infections through transfusion.
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From page 203... ...
Improved or new techniques would greatly facilitate studies of the natural history and epidemiology of HIV infection and AIDS. The areas of greatest need are as follows: · Improved tests for antibodies to HIV, particularly tests having greater specificity.
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From page 204... ...
Animal models of immunosuppressive retroviral infections will be crucial in addressing and resolving these biological questions. Similarly, studies of methods to control HIV infection whether by blocking transmission, by chemotherapy of the infected, or by immunization of the uninfected will ultimately have to be done in human populations.
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From page 205... ...
This model is therefore of little use in studying the later stages of disease pathogenesis, but it will be indispensable in the development of HIV vaccines. Chimpanzees are the only animals now known in which HIV vaccines can be tested before clinical application.
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From page 206... ...
. In general, SIV induces a disease in monkeys remarkably similar to human AIDS, making it suitable for studies of pathogenesis, drug trials, and vaccine development.
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From page 207... ...
Conclusions and Recommendations The committee is particularly concerned about the nurturing and preservation of primate animal model resources, which will be essential for drug and vaccine development and for basic investigation of disease pathogenesis and natural history. There are approximately 1,400 chimpanzees in the United States today available for all biomedical research.
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From page 208... ...
· Animal models that reproduce or mimic the consequences of HIV infection will play a crucial role in improving our understanding of disease pathogenesis and the development and testing of antiviral drugs and vaccines. Available animal models of HIV infection and the immunocompromised state must be vigorously supported, and efforts must be made to develop and validate new animal models.
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From page 209... ...
In these times of recombinant DNA manipulations of retroviruses, of tissue culture cells, and of transgenic mouse strains, it is possible that a completely analogous animal model of HIV-induced human diseases might be developed. Therefore, development of possible animal models should be considered that would include both natural models and the deliberate modification of existing species to render them susceptible to AIDS by HIV infection.
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From page 210... ...
Recent in vitro analyses suggest that the cytopathic effects that HIV exerts on CD4 T lymphocytes result from the active expression of viral gene products. The exact mechanisms of CD4 T cell depletion in vivo are not known, but they have been postulated to include a direct cytopathic effect of the viral envelope protein (Lifson et al., in press; Sodroski et al., 1986a)
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From page 211... ...
Cells of the macrophage/monocyte lineage are known to be susceptible to viral infection in vitro and may also serve as in vivo hosts for viral replication (Gartner et al., 1986~. Given their relative longevity, wideranging migration, and apparent relative resistance to the cytopathic effects of viral infection, protracted systemic antiviral therapy may be required for cure or even stabilization.
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From page 212... ...
Certain parameters of these criteria can be measured in vitro, and innovative assay systems have been established to permit the screening of potential candidate drugs. The HIV reverse transcriptase plays an essential role in the viral life-cycle and is presently a primary target of antiviral agents.
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From page 213... ...
Current Antiviral Agents Under Clinical Study The major candidate drugs undergoing preclinical and clinical evaluation for efficacy against HIV infection have been identified empirically in studies of other viruses. Although the mechanisms of action of many of them are unknown, some are thought to exert their antiviral effects through inhibition of reverse transcriptase.
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From page 214... ...
Clinical evaluation of suramin in AIDS patients resulted in a transient inability to recover virus from treated individuals, but it produced little or no evidence of clinical improvement or immunologic recovery (Broder et al., 1985; Levine et al., 1985; Rouvroy et al., 1985; Stein et al., 1986~. Suramin therapy was complicated by fever, rash, renal and liver function abnormalities, and serious adrenal compromise.
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From page 215... ...
, which has been previously referred to as "compound S" and BW A509U, is a thymidine analog modified so that it acts as a chain terminator during DNA synthesis. Although not an inhibitor of reverse transcriptase per se, it can effectively prevent the synthesis of proviral DNA by HIV reverse transcriptase by frequently interrupting the growing viral template.
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From page 216... ...
and has been shown to limit retroviral replication in vivo in mice infected with murine leukemia viruses (Shannon, 1977; Sidwell et al., 1975~. It has also been reported to partially inhibit HIV replication as measured by a decreased level of viral reverse transcriptase activity produced following infection of lymphocytes with HIV (McCormick et al., 1984~.
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From page 217... ...
Recent studies have documented an in vitro inhibition in HIV reverse transcriptase activity at levels pharmacologically acceptable in vivo (Sandstrom et al., 1985; Sarin et al., 19851. Administration of foscarnet is occasionally complicated by acute renal failure.
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From page 218... ...
In early clinical studies of alpha interferon in AIDS patients, no enhancement of immunologic function was detected, but a percentage of persons with Kaposi's sarcoma (especially those with early disease restricted to the skin) achieved a complete remission (Gelmann et al., 1985; Groopman et al., 1984; Krown et al., 19831.
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From page 219... ...
When drugs may offer slight, yet clinically important, benefit or harm, it is especially important to establish that the benefits outweigh the risks in a placebo-controlled randomized trial. This is the quickest, most efficient, and least-biased way to ensure the most efficacious treatment possible for present and future AIDS patients.
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From page 220... ...
· A conference should be convened as soon as possible to bring together researchers from industry, academia, and the Public Health Service to consider the key issues necessary for the development of antiviral drugs. Such a meeting could consider the unique capabilities of NIH including its drug screening program, its treatment evaluation units, and its provision of special animal models to facilitate industry's development efforts.
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From page 221... ...
Biologically, the characteristic genomic diversity and persistence of infection by HIV may present serious obstacles to the generation of broadly effective immunity. Vaccine development is also constrained by the presently limited basic understanding of the immune response to HIV infection, its apparent impotence in clearing the viral load, and the ways it might be bolstered through protective immunization.
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From page 222... ...
, recent preparations induce protection from laboratory or experimental challenges (Lewis et al., 1981; Olsen et al., 1980; Osterhaus et al., 19851. Effective vaccines have been formulated consisting of prepared aggregates of the viral envelope glycoproteins shed from infected cells and combined with immunostimulatory adjuvants.
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From page 223... ...
Thus, neutralizing antibodies alone may not be sufficient to protect against retroviral infections transmitted through cellular intermediates. A similar situation may prevail in humans infected with HTLV-I, where high titers of neutralizing antibodies are detectable using sera from infected persons in in vitro assays, but the infection persists in vivo (Ho et al., 1985b; Robert-Guroffet al., 1985; Weiss et al., 19851.
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From page 224... ...
Although new antigenic viral variants arise in the course of infection by visna viruses, the original viral strain is not replaced by them, suggesting that antigenic variation is not necessary for the maintenance of a persistent infection. Rather, the low titers and low affinity of virus-neutralizing antibodies seen following visna virus infection appear unable to prevent viral infection and spread (Kennedy-Stoskopf and Narayan, 19861.
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From page 225... ...
The developmental effort for an HIV vaccine is handicapped by the lack of a meaningful in vitro measure of immunologic protection from infection. The extent of antigenic variation generated during lentivirus replication presents a major concern for development of an HIV vaccine.
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From page 226... ...
Since the cellular arm of the immune response is thought to be most relevant to the elimination of virally infected cells, its recruitment may be the most effective target for vaccination strategies (Weissman, 19861. The cellular immune response is known to be involved in the immune clearance of a number of types of viruses.
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From page 227... ...
This approach seems unlikely at present, given the lack of a clear definition of the extent or significance of viral heterogeneity. As noted above, the most likely approach to an HIV vaccine is through the discovery of meaningful, broadly protective immunizing antigens and epitopes and their expression by recombinant DNA technology.
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From page 228... ...
With subunit vaccines, probably derived from recombinant DNA technology, the immune response would be distinguishable from natural infection. Some have argued that it might be possible for this reason to compress the usual evaluation schedule to use those at risk of infection in early safety and immunogenicity trials.
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From page 229... ...
Unless problems of vaccine liability are dealt with swiftly and effectively, no manufacturer may be willing to produce HIV vaccine for use in the American market. The liability issue is critical, but the degree of its impact will depend on the proposed approaches and target populations for vaccine development.
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From page 230... ...
For instance, states could enact malpractice and product liability reform laws that would encourage programs of HIV vaccine development. The enactment of a reasonable financial limitation or "cap" on court and jury awards in personal injury and product liability cases arising out of the clinical testing of an HIV vaccine or out of the use of a licensed vaccine on the market may provide one reasonable approach.
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From page 231... ...
And it can guide the establishment of improved health care and social services that further the ability to treat AIDS patients effectively, humanely, and at reasonable cost. To date, there has been little social science research specifically focusing on HIV infection and AIDS, but there have been studies of the factors influencing behavior change, risk perception, attitudes toward civil liberties, tolerance and discrimination, communication, and the organization of health care that are relevant to the AIDS epidemic.
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From page 232... ...
emphasize the importance of peer leaders and social support networks in effecting behavior change. Studies of drug treatment and rehabilitation programs confirm these findings.
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From page 233... ...
Increased knowledge of sexual behaviors and the factors that affect those behaviors will be necessary to design improved approaches to inducing behavior change. Areas for study include the development of sexual orientation, the selection of sexual partners and practices, and choices about methods for safeguarding health or preventing pregnancy in various groups.
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From page 234... ...
It will also be very important to study the social dynamics, rituals, and practices of various risk populations. The point of such studies would be to analyze and develop effective means to reach people at risk, delineate the obstacles to behavior change (for example, rituals concerning the sharing of needles and syringes among IV drug users)
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From page 235... ...
AIDS appears to be a new problem, one of uncertain origin and rapid but silent spread. It thus presents enormous challenges regarding the adjustment of public perceptions to the accumulating medical and scientific understanding of AIDS and HIV transmission.
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From page 236... ...
The sick are often blamed for their ill health, the poor for their economic plight (Navarro, 1977; Donzelot, 19791. For instance, there has been a striking contrast between media accounts of AIDS patients in pediatric and transfusionassociated cases, who are often portrayed as "innocent victims," as opposed to the depiction of implicit responsibility in cases among homosexual men and IV drug users.
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From page 237... ...
Goals of such a project would be to identify areas where institutional fragmentation or professional specialization are counterproductive, to understand the effects of the present system of financing medical care and social services, and to develop better and more cost-effective means of coordination. Similarly, there is a need to document and evaluate the various types of services that are presently available to persons infected with HIV in different communities, ranging from hospitals to terminal care facilities and home services.
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From page 238... ...
Social science research should be directed toward the following goals: · Establishing the demography of heterosexual, homosexual, and IV drug use behaviors and the characteristics of the groups that practice different patterns of behavior; · Identifying credible information sources for various groups and opinion leaders; · Conducting experiments and demonstration projects on approaches to behavior change to understand what does or does not work; · Tracking discriminatory practices and their dynamics (Why is discrimination a problem in some areas and situations and not in others? ; · Evaluating treatment, social service programs, and hospital management practices to understand what works and is cost-effective; · Studying the special problems of caring for addicted individuals and preventing transmission among IV drug users; 0 Linking experimental educational programs with epidemiologic evaluation of their effectiveness in reducing the rate of seroconversion across the spectrum of populations at risk; · Making comparative studies of international responses to the epidemic; · Studying the public's understanding of and attitudes toward AIDS and related issues in order to better design interventions to promote accurate awareness; · Studying and analyzing the ethical and legal aspects of the AIDS .
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From page 239... ...
A variety of novel and innovative partnerships have been formed between industrial firms, private research institutes, and the academic research community. In addition, a number of relatively small research-intensive companies have arisen in recent years and have invested significant energies and funds in the new biotechnologies.
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From page 240... ...
Other states are also considering the support of AIDS research, either as it relates to specific issues within their jurisdictions or as it relates to broader basic or applied research questions. Industry It is not possible to estimate the contribution by industry to AIDS research and development, but the amount must be only a small portion
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From page 241... ...
Among the areas under investigation are possible antiviral drugs for individuals already infected with HIV, drugs for treating opportunistic infections, and new kinds of diagnostic tests. The creation, testing, and distribution of new drugs and vaccines require numerous and diverse types of expertise.
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From page 242... ...
In FY 1986, $22.7 million (19 percent) of NIH AIDS funds went for support of new or continuing research grants (including some cooperative agreements)
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From page 243... ...
An additional problem with NIH's funding for AIDS research in recent years is that it has been derived largely through reprogramming of funds from other health areas (Krause, 1986; Stoto et al., 19861. These funds were diverted from ongoing NIH activities, in the form of personnel positions and research support, to satisfy expectations of progress on AIDS in the absence of a commensurate provision of adequate funding.
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From page 244... ...
Nor did it attempt to address in detail a variety of specific questions, such as the relative claims of research on vaccines versus drug development or research versus educational efforts (in each case both efforts are justifiable)
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From page 245... ...
It is clear that the problem will worsen considerably over the next 5 to 10 years, and without much question it will persist into the next century. The presently uncertain rate of spread of HIV infection further into the heterosexual population will determine the ultimate magnitude of the epidemic.
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From page 246... ...
246 CONFRONTING AIDS world in handling disease problems. This country has the largest biomedical research community in the world, has been the main source of progress in biomedical research for the world since the l950s, and is looked to as a major intellectual and financial resource for dealing with international health crises.
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From page 247... ...
· Social Science and Behavioral Research Funding for the various types of social science and behavioral research needed, especially that for mounting effective public education programs, is seriously deficient. · Vaccine and Drug Development Efforts to develop both vaccines and drugs will have to expand as new leads develop and new candidates are identified.
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From page 248... ...
This will involve characterizing the structure and function of each of the viral components and greatly expanded in viva research efforts. · Epidemiologic Studies Greatly expanded epidemiologic research will be needed to monitor the spread of the infection in various groups and to better understand its natural history.
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From page 249... ...
Necessary studies include, but are not limited to, increased epidemiologic surveillance and study, increased examination of multiple routes to vaccine or drug development, increased investigation of the nature of the virus and its effects on the immune system, increased study of the immune system itself, increased investigation of animal models, increased study of modes of human behavior modification, investigation of human sexuality, and analysis of ethical and legal options in responding to the AIDS epidemic. Many of these are expensive areas of research; $1 billion may prove to be insufficient.
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From page 250... ...
1986. Animal models for AIDS and their use for vaccine and drug development.
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From page 251... ...
1986b. Persistent infection of chimpanzees with human T-lymphocyte retrovirus in brains and other tissues from AIDS patients.
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From page 252... ...
1986b. Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization.
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From page 253... ...
1985. Persistent infection with human T-lymphotropic virus type III/lymphadenopathy-associated virus in apparently healthy homosexual men.
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From page 254... ...
1986. Animal models for AIDS and their use for vaccine and drug development.
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From page 255... ...
: Antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.
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From page 256... ...
1985. Induction of protective immune response in cats by vaccination with feline leukemia virus iscom.
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From page 257... ...
1985. Isolation of infectious human T-cell leukemia/lymphotropic virus type III (HTLV-III)
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From page 258... ...
1979. Phosphonoformate inhibits reverse transcriptase.
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From page 259... ...
1986. Current status of attempts to transmit acquired immunodeficiency syndrome (AIDS)
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