Host-Directed and Immune-Based Therapies for Human Immunodeficiency Virus Infection

  1. Michael M. Lederman, MD
  1. From the AIDS Clinical Trials Unit, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio. Requests for Reprints: Michael M. Lederman, MD, Department of Medicine/Division of Infectious Diseases, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106. Acknowledgments: The author thanks Drs. Jerrold Ellner, Jonathan Kagan, Norman Letvin, and Robert Schooley for their thoughtful comments. Grant Support: By the National Institutes of Health (AI 25879).
     
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    Abstract

    This essay reviews the rationale underlying host-directed or immune-based therapeutic strategies for human immunodeficiency virus (HIV) infection and its complications. These approaches have seen only limited trial in the past 10 years, but as more is learned about the immunopathogenesis of HIV disease and as the limitations of virus-directed therapies become more apparent, the need to pursue other therapeutic avenues has become increasingly important. Moreover, properly designed trials of host-directed and immune-based therapies can provide key insights into the pathogenesis of HIV disease that may be otherwise unattainable through in vitro studies.

    The first decade since the discovery of the acquired immunodeficiency syndrome (AIDS) has seen progress in therapy for HIV infection and its complications. Better prevention and treatment of opportunistic infections have contributed substantially to improved survival and quality of life for persons with HIV disease. In the laboratory, much progress has been made in understanding the life cycle of HIV, and numerous antiviral drugs that act against HIV in vitro have been identified. However, the activity of these agents has been low and their clinical value has been modest and of limited duration. Although in vivo antiviral activity and clinical and immunologic responses can be shown in patients treated with antiretroviral drugs [1-4], the emergence during therapy of drug-resistant isolates is common, and such resistance both limits the effectiveness of therapy [5-7] and is predictive of poor outcome [8]. Thus, the benefits of available antiretroviral drugs are limited by relatively weak antiviral activity and by the rapid emergence of resistance.

    The rapid emergence of drug-resistant isolates during therapy is a great disappointment but not a surprise. The HIV-1 reverse transcriptase, which must transcribe the viral genome twice for each viral replication cycle, is inaccurate. Lacking a proofreading function, this enzyme has a calculated error rate of 1 per 1700 bases [9]. Thus, for each replication cycle, several mutations are to be expected in the 10 000-base HIV-1 genome. The substantial genomic variation seen among quasi-species isolated from individual patients with HIV disease [10] is a likely consequence of this genetic instability. It is therefore not surprising that introduction of a selection pressure (in this instance, an antiviral drug) will favor the rapid emergence of resistant viruses just as error-prone DNA polymerases accelerate the emergence of antibiotic resistance in bacteria [11]. It is important to note that escape mutations may be seen not only in response to antiviral drugs but also after application of immune-based therapies that target specific viral peptides (Koenig S. Personal communication) and that they are predictable responses to genetic therapies targeting viral nucleotide sequences.

    It is possible that an agent will be identified that targets a critical viral protein or nucleic acid sequence and has the unique characteristic of rendering all resistant viruses lethally defective. I know of no precedent for such an antimicrobial strategy and, thus, the development of such a drug is unlikely. Similarly, it is conceivable (though not yet supported by available data) that combinations of agents that target a single viral protein will limit the viability of potential escape mutants by imposing too many constraints on the resistant conformations, thus rendering mutants resistant to all drugs nonfunctional (a concept called “convergent combination chemotherapy”) [12]. This hypothesis has not yet been validated in vitro or in vivo; moreover, the usefulness of such a strategy is limited by the relatively modest activity of the agents currently available. Although resistance to all agents may result in a nonviable isolate, viruses sensitive to one or more drugs may survive, propagate, and cause disease, because viral load in plasma or cells is not brought to zero even among patients with presumed sensitive isolates newly treated with zidovudine [13].

    Lastly, combined antiviral strategies targeting different viral elements may provide synergistic in vitro and in vivo activity against HIV as they have against bacterial pathogens such as Mycobacterium tuberculosis. Even in the setting of mycobacterial disease, however, the emergence of multidrug-resistant isolates has ultimately limited the usefulness of these combinations for many patients [14]. The development of multidrug-resistant tuberculosis is often related to inadequate therapy or poor compliance with prescribed medications [15]. The increasing coprevalence of multidrug-resistant tuberculosis and HIV disease among the poor and the homeless indicates that HIV disease is now seen in populations in which poor compliance with drug therapy occurs frequently. This may limit the potential usefulness of combination therapies in HIV even if powerful combinations were to become available.

    Although more research is clearly needed to identify good targets for antiviral drugs and to develop more effective agents, the usefulness of any strategy that targets a virus-encoded element may be limited by the mutability of HIV, which promotes the rapid emergence of resistance during therapy. For these reasons and others, more effort also should be directed at host mechanisms that play a role in the pathogenesis of HIV infection and AIDS.

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    Host Elements and Viral Propagation

    Like all viruses, HIV is dependent on numerous host elements for replication. Almost every phase of the viral replication cycle—binding, fusion, reverse transcription, nuclear transport, transcription, cytoplasmic transport, translation, post-translational processing, assembly, budding, and cell-cell transfer—requires interaction with host elements. Attachment of HIV to the cell depends on a high-affinity binding of the gp120 envelope glycoprotein to the host CD4 surface antigen [16]. Fusion and syncytium formation may require interaction with host LFA-1 molecules [17]. Reverse transcription uses the host transfer RNAlys,3 for priming [18]. Preliminary evidence suggests that nuclear transport of the newly reverse-transcribed viral double-stranded DNA is an energy-dependent mechanism that is enhanced in activated cells [19].

    Synthesis and processing of viral RNA are absolutely dependent on host elements. Transcriptional activation of integrated HIV has been carefully studied and various host nuclear factors, such as NFAT-1, NF- κ B, SP1, and AP-1, have recognition sequences on the HIV-1 promoter, the long terminal repeat (LTR) [20]. Of these, NF- κ B is probably the most important in the inducible activation of HIV expression [21]. The HIV-1 Tat protein is a novel trans-acting transcriptional enhancer that binds to a stem-loop structure on the 5′ end of all newly synthesized HIV-1 messenger RNAs where critical interaction with host proteins is required for elongation of HIV-1 transcripts [22]. Longer messenger RNAs encoding HIV-1 sequences must bind the viral Rev protein for transport to the cytoplasm [23]; Rev activity probably requires interaction with host elements for this function [24].

    Viral protein synthesis occurs on host ribosomes. Proteolytic cleavage of the gag-pol preprotein is effected by viral protease, whereas cleavage of the envelope gp160 precursor to the gp120 and gp41 proteins is mediated by a host protease [25]. Post-transcriptional modification of viral proteins, such as glycosylation and fatty acylation [26], are mediated by host enzymes; assembly of the core polyprotein requires interaction with host cyclophilins [27]. Broadly distributed host elements may be poor targets for antiviral strategies, but elements with more restricted expressions or activities may prove to be useful targets.

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    Rationale for Targeting Host Elements in HIV Disease

    Strategies that target host cellular factors are advantageous because, in principle, they are far less susceptible to escape mutation in response to selection pressure than are strategies that target HIV directly. First, because the targets of these strategies are encoded by host genes and the fidelity of host DNA polymerases supports a far slower mutation rate, the evolutionary response to selection pressure would not occur as quickly as it would if viral elements were targeted. Second, somatic mutations may occur, but they will probably affect only a subpopulation of cells. An escape mutation in a precursor cell that renders its progeny more susceptible to lytic infection with HIV will result in a survival disadvantage to that cell. This favors the survival of cells expressing “wild type” host factor. Thus, from an evolutionary perspective, targeting host cell factors may provide a longer-lasting antiviral effect.

    An obvious drawback to strategies aimed at cellular elements is the predictable toxicity that may ensue when host cellular factors are targeted. Because HIV predominantly infects cells involved in immune responses, the toxicities that may arise as a consequence of host-directed therapies are likely to be immunosuppressive. Nonetheless, host defenses are surprisingly redundant and, as studies with gene “knockout” mice have shown, host defenses and susceptibility to infection are only minimally affected after deletion of such critical sequences as those encoding interleukin-2 [28]. Whether immunotoxicities will be as well tolerated in patients with the preexisting immune dysfunction of AIDS remains to be seen.

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    Immune Mechanisms and the Pathogenesis of HIV Disease

    Increasing evidence now suggests that immune mechanisms may play important roles in the pathogenesis of HIV disease [29]. Despite profound cell-mediated immune deficiency, growing evidence indicates that the lymphocytes of persons infected with HIV are activated [30-32]. There are numerous laboratory models in which lymphocytes, antibody, viral proteins, complement, and combinations of these elements can result in lymphocyte destruction [33-38]. Proinflammatory cytokines such as tumor necrosis factor-α may activate HIV expression [39, 40] and may play roles in the febrile wasting syndromes of AIDS [41] and the pathogenesis of neoplasia in AIDS [42, 43]. More recently, evidence has accumulated to show that cells in persons with AIDS may be lost through apoptosis, an intrinsic mechanism of cell death that is actively mediated by host cell factors [44, 45]. Targeting these host cell mechanisms may, therefore, interfere with the pathogenesis of HIV disease by blocking these pathways.

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    Trials of Host-Directed Therapies for HIV Disease

    Several of these approaches have been tested to date with only modest success. Soluble CD4 can decrease viral load in vitro by competing with cellular CD4 molecules for free virus [46] and perhaps by stripping gp120 from the viral membrane [47]. Intravenous administration of soluble recombinant CD4 to persons with HIV infection has been shown to decrease the titer of infective virus in plasma [48]; antiviral activity required high doses of drug and the duration of activity as detected by changes in plasma viral titer was brief. It is important to note that clinical isolates of HIV are far less susceptible to the neutralizing activity of soluble CD4 than are laboratory-passed strains [49]. This observation underscores the importance of the preclinical testing of promising approaches on fresh clinical isolates of HIV-1 as well as on well-characterized laboratory strains. Nonetheless, this preliminary report suggests a “proof of concept.”

    A benzodiazepine-class agent, Ro-24-7429, inhibits Tat-mediated transactivation of the HIV-1 LTR, although the drug binds neither Tat nor the Tat-responsive TAR element. This agent is presumed to interact with the host element or elements required for Tat-mediated transcriptional activation, an assumption that is supported by the observation that Ro-24-7429 can affect proliferation and survival of normal lymphocytes in vitro (Patki A, Lederman M. Unpublished data). In a large phase I/II clinical trial, administration of three doses of Ro-24-7429 to patients with HIV infection did not affect viral load or CD4 counts [50]. These data are discouraging, but the hypothesis that interference with Tat-dependent host transcriptional factors can block HIV replication in vivo has not been sufficiently tested; Ro-24-7429 is highly protein-bound and plasma drug levels may not have achieved sufficient intracellular penetration to inhibit Tat activity in patients' lymphocytes.

    Intralymphocytic concentrations of glutathione are diminished in persons with HIV infection [51, 52]. Although the significance of this observation is not clear, repletion of glutathione in vitro with agents such as N-acetylcysteine or L-2-oxothiazolidine-4-carboxylate (Procysteine, Free Radical Sciences, Cambridge, Massachusetts) can block HIV replication through inhibition of NF- κ B activation [53-55]. These agents are well tolerated, and Procysteine has been shown to be bioavailable after oral administration [56]. Phase II clinical trials of these compounds are currently examining their effects on clinical and laboratory markers of HIV disease progression.

    Trials of pentoxifylline, a tumor necrosis factor (TNF) inhibitor, have shown that the drug causes some inhibition of TNF expression and either has no demonstrable effect on [57, 58] or modestly inhibits HIV-1 propagation [59]. The role of TNF inhibition as therapy for HIV-1 disease is therefore unknown at present. If such a role exists, it is likely to be in settings where TNF expression is predictably elevated (such as tuberculosis complicating HIV infection [60]), in combination with other transcriptional inhibitors of HIV-1 expression [61], or through the use of agents more active than pentoxifylline in vivo.

    High doses of cyclosporine may inhibit HIV expression through inhibition of transcriptional activation [62] or inhibition of cyclophilin-dependent core protein polymerization [27]. An early trial of cyclosporine was halted because of a clinical deterioration among the patients with AIDS who received the drug [63]. The immunosuppressive effects of cyclosporine may be better tolerated in early HIV infection; more importantly, cyclosporine derivatives with less immunosuppressive activity [64] may inhibit HIV replication with fewer opportunistic complications.

    Preliminary indications suggest that the administration of certain host cytokines also may prove useful in HIV disease. Administration of α- and β-interferons may decrease HIV-1 antigen levels in serum and also the amount of virus detectable in peripheral blood cells, but the modest activities of these agents are limited by their systemic toxicities [65, 66]. Interleukin-2 administration has increased the numbers of circulating CD4 cells in persons infected with HIV [67, 68], although the origin and immunologic activities of these cells are unknown. In vitro, interleukin-12 can partially correct the impaired type 1 cytokine response seen in lymphocytes of patients with HIV infection [69]. The clinical benefit of these approaches awaits the results of further study.

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    Immune Reconstitution in HIV Disease

    Approaches to immune reconstitution that involve the transfer of lymphoid or precursor cell populations are now in infancy, but with better methods for cell harvest and expansion, the benefit of these strategies can be tested. As techniques for gene transfer improve, genetic strategies that target HIV or host elements may be applied to treatment or immune reconstitution in patients with AIDS. Several strategies involving targeted ribozymes that cleave HIV RNA [70], introduction of transdominant mutations in critical HIV genes such as tat or rev [71, 72], and introduction of decoy Tat- or Rev-binding RNAs [73, 74] have been shown to inhibit HIV propagation in vitro. With advances in techniques of gene transfer, immune reconstitution with autologous cells rendered at least partially resistant to HIV infection may be an achievable and more broadly available goal even for patients with advanced immune deficiencies. As noted above, genetic strategies that target viral elements also are susceptible to viral escape mutation.

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    Summary

    Presently, the usefulness of host-directed and immune-based strategies is unproved and broad implementation of these approaches must await the results of carefully designed clinical trials. Such trials will also provide the opportunity to test critical hypotheses of AIDS pathogenesis that may not be testable in vitro. For example, if apoptosis plays an important role in the mechanism of cell loss in AIDS, then agents that inhibit apoptosis might be expected to preserve lymphoid cell numbers in HIV disease. If cytokine activation enhances viral propagation in vivo, inhibitors of these cytokines may be expected to decrease viral burden.

    Certainly, research on antiviral drugs that target HIV directly must continue. Nonetheless, in a setting where the pathogenesis of immune deficiency is uncertain and where targeted antiviral strategies have been only modestly successful, more emphasis also must be placed on pathogenesis-directed clinical trials of host-directed or immune-based therapies. These trials may both evaluate the usefulness of these relatively untested approaches and also may help to delineate more clearly the pathogenesis of immune deficiencies in HIV disease. The potential scientific and therapeutic advances to be gained from trials of host-directed and immune-based therapies require a firm commitment to these approaches. The second decade of research on AIDS will undoubtedly fill in more pieces of the puzzle; trials of host-directed and immune-based therapies can and should play a significant role in this effort.

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    Appendix 1: Glossary

    Acylation: Addition of a fatty acid group

    Allogeneic: Derived or obtained from another person who is not an identical twin

    AP-1: A family of proteins that regulate transcription by forming homodimers and heterodimers that bind to sequence-specific sites on cellular and HIV-1 promoter regions

    Apoptosis: A pathway of cellular self-destruction

    CD4: A cell surface protein that binds class II MHC (major histocompatibility complex) antigens on antigen-presenting cells and that serves as the binding site for HIV

    Cyclophilins: A family of cellular proteins that are thought to direct folding and intracellular trafficking of proteins; they are targets for the immunosuppressive drug cyclosporine

    DNA polymerase: Enzyme that synthesizes DNA. DNA-dependent DNA polymerases use DNA templates to direct DNA synthesis; RNA-dependent DNA polymerases (reverse transcriptases) use RNA templates to direct DNA synthesis

    Glycosylation: Addition of sugar molecules

    Envelope glycoprotein: Surface glycoprotein of HIV-1 composed of membrane-spanning component (gp41) and external CD4-binding glycoprotein (gp120)

    LFA-1: A surface protein of T lymphocytes that binds to the ICAM-1 protein on the surface of antigen-presenting cells. May play a role in syncytium formation in HIV infection

    LTR: The long terminal repeat region of the HIV genome that contains nucleotide sequences important in the regulation of transcription. The upstream LTR serves as the HIV-1 promoter

    NFAT-1: Nuclear factor of activated T cells. A host protein that activates transcription of certain host genes, such as the interleukin-2 gene, that are activated during the process of T-lymphocyte activation

    NF- κ B: Nuclear factor κ B, a host protein that helps activate transcription of numerous important host genes in activated lymphoid and monocytoid cells

    Post-translational processing: Modification of newly synthesized proteins by addition of other molecules such as sugars (glycosylation) and fatty acids (acylation)

    Promoter: The region of DNA containing sequences important in the regulation of gene transcription

    Rev: An HIV protein needed for the transport of longer HIV messenger RNA molecules from nucleus to cytoplasm

    Reverse transcription: A form of DNA synthesis that uses an RNA template catalyzed by a reverse transcriptase

    Ribosome: Host cytoplasmic complex in which messenger RNA is “translated” and protein is synthesized

    Ribozyme: An RNA molecule capable of catalytic cleavage of RNA

    SP1: Ubiquitous cellular transcription factor for which binding sites are found on various cellular promoters and on the HIV-1 promoter

    TAR: Trans-activation response element on newly transcribed viral RNA that binds Tat protein and brings it into proximity with the transcriptional complex to enhance transcription

    Tat: Transactivator of transcription. An HIV regulatory protein that enhances transcription from the HIV promoter through binding to TAR and interaction with host elements

    Transdominant: Trait of a mutant gene or its product that confers its phenotype in the presence of the wild type gene or product

    Transcription: Synthesis of RNA or DNA

    tRNAlys,3: A transfer RNA used to add lysine in the synthesis of protein; also used as a primer to initiate reverse transcription of HIV-1

    Translation: Process of protein synthesis in ribosomes where peptides are linked in a growing chain according to nucleotide sequences encoded in messenger RNA

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    1. Ann Intern Med February 1, 1995 vol. 122 no. 3 218-222
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