TiPS - March 1991IVo!. 121 olizing Enzymes: Cenetia.

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ReguI4kut

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Toxicology (Ingkman-Sundberg, M., Custafsson. J. A. and @genius, S., ads), Karolinska Institute, Stockholm Yue, Q. Y. et al. (199) Lancef ii, 870 Mortimer, 0. et al. (1990) Clin Phammcool. Ther. 47, 27-35 Yue. Q. Y., Svensson, J-O., Alm, C., Spqvist, F. and Sawe, J. (1989) Br. 1. C/in. Ph4t7~4col. Z&629-637 Yue, Q. Y., Svenuon, J-O., Aim, C., Sjvist. F. and Sawe, J. (1989) Br. /. C/in. Phmacol. 28,639-645 Woolhouse, N. M., Eichelbaum, M.,

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Oates, N. S., Idie. 1. R. dnd Smith, ?. L. (1985) Clin. Pharmocol.Ther. 37,512-521 Tyndale. R. F., Inaba, T. and Katow, W. (1989) Dncg Metab. Dispos.17, 334-340 Whittaker, M. (1986) Ckrr!inesterase, Karger Choneim, M. M. et 41. (1981) Clrrl. Phnmmcol.Ther. 29,74%756 Kumana, C. R., Lauder, I. J., Chan, M., Ko, W. and Lin, H. J. (1987) Eur. /. Clir. Pharmncot.32,211-215 Rosenblat, R. and Tang, S. W. (1987) Cna. J. Psychinlr.32,270-274 Bertilrwn, L. rt al. (1989) Clb~.Pbamln-

Immunotherapy of human immunodeficiency virus infection John W. Hadden HIV infection results in the destruction of the thymus-dependent cellular immune syskm and death due to opporfunisrir infection and malignancy. fmmunosuppressitle influences (other sexually or Wood-transmitted Cruses, HIV-dcriued peptides, semen, poor nutrition, drugs, efc.) favor the progression of the disease. Although immunorestorative agsrfi may be expected to delay progression of the disease, John Hadden argues that no agent has yet proven usefur in reuersing the immunodcficiency in full-blown AIDS. However, two thymomimetic drugs, isoprinosine and diethyldithiocarbama!e, inhibit fhe development of infections in patients with pre-AIDS in large multicenter trials, and preliminary data from trials with two thymomimefic peptides, thymopentin and ImReg-1, in pre-AIDS patients are encouraging.

HIV infection and AIDS are complicated and expensive in terms of human suffering, amount of care and financial cost. Like the treatment of cancer, palliation is necessary but difficult. Between prevention and cl;re lies a complex area of management that has spawned three important therapeutic efforts: vaccine development as a strategy of management as well as prevention; antiviral therapy to p-vent the p*agression of infection; and immunorestorative therapy as a strategy to reduce the rate of progression of the disease and to prevent opportunistic infections. Vaccine development for both prophylactic and therapeutic purposes is receiving major attention, /.

W. Hadden L Director of lhr iIiltMW-

pJtrmwolc?qy Dhiow. Utduersity 01 Sottth

Florida Mediral Cortege.Tatrrpr, FL 33612. USA.

and will not be reviewed here’“. The virus has been fully described and the surface glycoprotein gp16O/gpl20 has been detailed with respect to its conserved sequences. Knowledge of viral surface epitopes necessary for binding to the CD4 receptor of helper T lymphocytes and those expressed on HIV-infected cells should provide the basis for potent synthetic vaccine formation using synthetic adjuvants such as the muramyl peptides and synthetic, detoxified lipid A. Antiviral therapy has developed in a remarkable way. Zidovudine (AZT, azidothymidine) is now licensed and widely used in the palliation of the condition of AIDS initial testing with patients; lower, less toxic doses indicates that it may be useful prophylactically in not=vmptomatic HIVpositive patients’. Many other antiviral drugs are under develop

col.Thrr.45, 348-355 32 Lin, K. M. et al. (1988) Psvrhouhenncology%,365-369

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33 Schaefer, 0. (1986) in EIhrtir Drffermres in Rearfio!ts 10 Drugs nnd Xenobiolirs (Kalow. W., Goedde, H. W. and Agarwal. D. P., eds). PP. 77-83, Liss 34 Bmsen, K. and Cram, L. F. (1989) EIW. /. Clin. Phnnnacol.36,537~547 35 Suddendorf, R. F. (1%9) Pubf. Health Rep. 104.615-620 36 Kassam,J. P ,Tang. B. K.. Kadar. D. and Kalow. W. (1989) Drag Melab. Dispos. 17,567-572

ment (e.g. 2’,3’-dideoxyinosine and 2’,3’-dideoxycytidine or under study (2’,3’-dideoxythymidine, etc.; see Ref. 5). The notion that companion viruses (e.g. EBV, CMV, herpes virus-6, HTLV-1) are critical in the acceleration of the development of AIDS in genera! and Kaposi’s sarcoma in particular has spawned a number of antiviral approaches in which zidovudine treatment is combined with acyclovir, ribaviran or AS-101’. Although these approaches offer hope that longterm nontoxic antiviral therapy may be possible, zidovudineresistant viruses are increasingly being detected. More sensitive detection techniques indicate that the number of T cells infected in HIV-positive patients is higher than previously thought (i.e. 0.1~1.0% versus 0.01% of T lymphocytes’). This emphasizes the fact that a single transcript of the virus dooms the infected T cell even though other induction events are required to yield viral replication. Since transcription has already taken place, the ultimate fate of the virus is not affected by a reverse transcriptase inhibitor like zidovudine; other antiviral therapies, even those acting at subsequent steps of viral replication, will therefore prove ineffective in eradicating the virus. The only means known to eradicate a virus is through the immune response, and this is the focus of this review: immunorestorative therapy in HIV disease. Although their relatij-e importance and detailed mechanisms are not known, neutralizing antibody, antibody-dependent ceflular cytotoxicity, cytotoxic T cells and natural killing mechanisms are thought to be the four key factors in defense against HIV and

TiPS - March 1991 [Vol. 121

AIDS: markem and drugs The human immunodeficiency virus (HIV)is the cause of the AIDS epidemic. This blued-borne virus is transmitted through contact with blood or semen of infected individuals. On entry to the body, it binos to the CD4 molecule on the surfaceof the major subset of thymus-derived lymphocytes cakd T belpcr lyrnphocytes. It enters and becomes latent within the T lymphocytes.immunity to the virus develops involving antibody and cytotoxic CM+ lymphocytes. Antibody-

coated viruses may enter other c4s like macmphages and glial cells, by binding to their surface immunoglobulin receptors(F&s). Thus despite the presence of the immune response, the virus replicatesto infect other CD4+ and Fc+ cells. Following a long latent period, on average ten years, the progressive loss of CD4+ T lymphocytes results in an inversion of the normal 2: 1

its companion viruses as well as the other opportunistic pathogens that invade as a result of the immunodeficiency. The immunotherapy of AIDS Immunotherapy in AIDS at the end stage of HIV infection was

predicted to be an unsuccessful strategy*, and a number of subsequent reviews of the collected studies’*“’ document the fulfilment of this prediction. Immunotherapy in the absence of con-

current antiviral therapy in AIDS has not been effective in reversing the immunodeficiency. Two preparations of interferon-n (IFN-a; Schering and Hoffman-LaRoche) have been licensed by the Food and Drug Administration (FDA) for treatment of Kaposi’s sarcoma. IFN-a is effective alone (20-40% major response rates) and in conjunction with zidovudine (>60% response rate”), but it does not reverse immunodeficiency. Also, uniike the anticancer chemotherapy generally employed in AlDS-independent Kaposi’s sarcoma, it is not immunosuppressive and has not been proven to reduce the incidence of infections. Various types of transplantation techniques have been attempted: ?? Bone marrow transplantation is a widely used treatment for severe combined immunodeficiency (SCID) and certain forms of leukemia. While it is expensive and is associated with high morbidity, in these diseases it can be curative. By contrast, its use in AIDS has been generally unsuc-

cessful .

A recent reporP

using bone marrow transplantation plus zido??

ratio of helper (CM+) to supprewor/cytotoxic (CDe’) lymphocytes. This is associated with dtnical hnmunodeficiency, with the developmart of suswptibillty to infections and malignancies such aa Rapooi’s nreoma. During the final phase of the fllneaa (AIDB),the virus andviralantigenslikepllappearintherkubt&md Sgum mar+ of fympboid inktion like &mrao&Wm and neqfuin increase, indiathtg a poor

Prognosis Antiviral agents like zidovud@ (azidothymidlne; AZT) inhibit vfraf repfication but do not em&ate it. Zidovudine effectively slows the pmgma&m of the

final phases cf AIDS and also slows the pmgmasion from pm-AIDS to full-blown AIDS. Toxicity and cost limit its use. &ny ahematives and complementary forms of therapy are under study.

vudine claims success in eradicating virus, but conclusions are premature since the patient died and long-term follow up was impossible. ?? Transplantation of thymic tissue and adoptive transfer of heterologous lymphocytes has been unsuccessful in AIDS”. a Ex vivo expansion of autologous lymphocytes with interleukin 2 (IL-2) and zidovudine is under study and theoretically may offer some palliation, if economically feasible. e Adeptive transfer of virus-inactivated serum from individuals with high titer neutraiizing antibody against HIV is another approach being tested6; preliminary results indicated reduced p24 antigenemia, increased CD4+ T lymphocytes, and apparent improvement in the clinical status of a number of the patients. Intravenous immunoglobulin therapy is generally considered to be useful and nontoxic in the treatment of pediatric AIDS patients for the management of bacterial infections. A multicenter phase !I! tria! with zidovudinc in 250 patients is underway to confirm this widely accepted but unproven notion’. A number of anecdotal reports indicate that such therapy may improve the course of AIDS and Art?+related complex (ARC) in adult patients and a multicenter trial has been initiated to test this using intravenous immunoglobulin therapy alone and in combination with zidovudinet3.

Ir.iti;i! studies with recombinant IL-2 in AIDS were negative’+“; however, with persistent i-v. in-

fusion of high doses, lymphocytosis without enhanced viral recovery was observed. Toxicity is associated with a ‘flu-like’ syndrome, fluid accumulation, and increased bacterial infectiorts. A number of combined IL-2 and zidovudine phase I protocols are in progress. Schwartz et al.” treated several AIDS patients with this combination: preliminary data indicated that the combination is compatible, that the toxicity levels are acceptable and that the ability of IL-2 to inorraK CD4+ T-cell counts and cehlat cytotoxicity, and to enhance &in test reactivity was not parented by zidovudine. No increase in vial antigenemia or viral recovery was observed. The authors condude that further study is warranted. A number of trials of combined immunotherapy and antiviral therapy are in progress in AIDS patients. However, the ensuing discussion should make it clear why relatively little can be expected. Immunorestoration &I ARC and

asymptontaticHIVi&ction IFN-ar modulates various immune responses. Thus it enhances killer .cell activity by lymphocytes, mac@tages and naiural killer ceBa while depressing lymphocyte proliferation and S;?cretO responses. Two recent reports’7 Jb indicate that IFN-IX treatment of pre-AIDS patients reduces HIV virus recovery, p24 antigenemia, and opportunistic infection despite toxic side-&e&s. Several combined protocoIs (IFNr?*vith diethyldithiocarbamak, see below, IL-2 or ridsvudine) are underway.

‘JWS- Marc!r 1991 IVoL 12! Am&en is a polynucleotide derivative of poly(IC) with spaced uridines to provide RNase cleavage sites. It has anti-HIV activity in vitro. It also induces interferon and acts as an immunomodulator in oivo, which is characteristic of other interferon inducers including natural killer cell activation. However, despite this activity and despite the lack of toxic sideeffects observed with poIy(lC), a multicenter, double-blind phase II study was terminated early due to lack of activityb. ImReg-1 (see Fig. 1) is a dialysed leukocyte extract from normal donors in which the oligopeptides Tyr-Gly-Cly and Tyr-Gly are thought to be the nonspecific active components. ImReg-1 modulates lymphokine production in vitro and enhances dermai skin test responses in uivo when given intracutaneously with tetanus toxoid antigen. In a multicenter trial” totaRing 141 ARC patients, 93 were treated with SmReg-1 bi-weekly and showed a significantly reduced tendency to progress to a clinically relevant endpoint (4.3% versus 25%) or to AIDS (3% versus 17%). Marginally significant changes in CD4+ counts and symptom scores were also observed. No toxicity was observed. A larger confirmatory trial is planned. Methyldithiocarbamate (OTC) jlmuthiol) is an orally active thymomimetic drug that is more active and less toxic than its predecessor levamisole’s, Multicenter controLled studies1950 in 143 symptomatic pm-AIDS patients indicate that OTC decreases symptoms and AIDS conversion (13% to 4.5%) and tends to increase CD4* lymphocytes. Kaplan et aLa reported that decreased lymphadenopathy occurred in most patients with CD4 counts greater than ZOO,in a small randomized controlled trial. These findings have been extended in a large multicenter study of AIDS and ARC patients heated orally with 400mgm-2 OTC weekly, where 389 patients showed a significant (-50%) reduction in opportunistic infections in both AIDS and ARC subjects=. Although the number of T cells expressing CD4 increased in he MT-treated group (255 to 30 mm-‘), they did not decline, as had been exwcted, in the control

group (unchange\; at 270 mm-‘); the changes were, therefore, not significant. No significant toxicity was observed. A 1600-patient trial is in progress in Europe to determine the effect of DTC on asymp tomatic HIV-positive patients. Isoprinosine, an inosine-containing complex, is a thymomimetic drug that induces T-cell differentiation and promotes Tcell function in oitrs and in aivo’s. lnitial controlled trial!?’ demonstrated significant increases in CD4 counts and natural killer cell activity and significant decreases in symptoms. Fewer cases of ARC converted to AIDS in patients with progressive generalized lymphadenonathv and mean CD4 counts greate; th& 500 mme3. Several multicenter doubleblind triafs have been completed. In the USA a trial of 696 HIVpositive symptomatic patients with CD4 counts less than 400 mmv3 did not reveal significant immunological or clinical results (see Ref. 6). By contrast, a Scandinavian trials with 8(56Hlv-positive symptomatic ARC patients with mean CD4 counts greater than 425 showed a significant reduction in ARC to AlDS conversion (4% to 0.5%) over a six month period, although no significant immune correlates were obtained. tn Italy, from a trial with 553 asymptomatic HIV-positive iqlividualsx+, isoprmosine treatment -wdb8ssociakd with no new infections; 12 controls developed infections. In this study, decreawd symptoms, preservation

of 08 ratios and an increase in natural killer cells were observed in the treated group. No toxicity was observed. These studies indicate that isoprinosine treatment benefits HIV-positive patients by preventing the development of infection only when CD4’ lymphocyte counts are greater than 400 mm-‘. Thyrnopentir. is the pentapeptide active site of thymopoietin, a chemically defined thymusderived peptide having thymomimetic activitv irr vitro and in viuo. Initial co&roRed studiessr2B with thymopentin showed positive effects. On the basis of these findings, a blind multicenter tintrial- involving 47 thymo treated asymptomatic H Jen-positive and ARC patients and 44 placebo-treated controls was set up. Preliminary results indicated that four controLs m to constitutional symptoms or AIDS, while none of the treated patients progressed (p

Immunotherapy of human immunodeficiency virus infection.

HIV infection results in the destruction of the thymus-dependent cellular immune system and death due to opportunistic infection and malignancy. Immun...
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