AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 8, Number 2, 1992 Mary Ann Liebert, Inc., Publishers
Interferons in the Persistence, Pathogenesis, and Treatment of HIV Infection MARK L. FRANCIS, MONTE S. MELTZER, and HOWARD E. GENDELMAN
ABSTRACT Interferon (IFN) plays an important role in the treatment and pathogenesis of HIV disease. Recent studies show beneficial effects of IFNa in the treatment of HIV-associated Kaposi's Sarcoma and early HIV-infection. Moreover, cell culture studies support these beneficial effects. HIV infection of monocytes is blocked by IFNa administered at the time of viral challenge. The IFNa-treated cells show no evidence of HIV infection. Viral gene products produced in monocytes infected with HIV then treated with IFNa gradually decrease to baseline. Large quantities of proviral DNA are seen in the HIV-infected IFNa-treated cells with little evidence for viral transcription suggesting true microbiological latency. While most viral infections of cells result in IFN production, HIV is a notable exception. Indeed, HIV does not induce monocytes to produce IFNa and blocks its production following poly(I)-poly (c) stimulation. This allows HIV yet another mechanism to evade an important host antiviral response. Paradoxically, the appearance of IFN activity in sera of HIV-infected patients is associated with disease progression, not resolution. Recent observations showing that the interaction between HIV-infected monocytes and PBMC results in the production of IFNas with reduced anti-HIV activity may help explain this paradox. Thus, IFNa plays an important but complex role in HIV disease. The elucidation of cellular factors that regulate the antiretroviral effects of IFNa may lead to the development of novel therapeutic strategies for HIV infection.
INTRODUCTION with human immunodeficiency virus (HIV) prodisease only after a relatively long incuduces bation period that can exceed 10 years. During the interval of subclinical infection, virus replication is apparently held in check by host immune reactions and certain regulatory factors intrinsic to the viral genome. Recent studies document high level viremia ( 10-104 TCID50/ml plasma) in acute HIV infection that rapidly (6-8 weeks) subsides to undetectable levels.1 The frequency of productively infected cells in blood after this early viremia is 0.01 to 0.001% and remains at a low level through end-stage disease.2 Components of the host immune response that constrain virus replication after the acute viremic interval are still incompletely defined. Vigorous humoral and cellular immune reactions are easily demonstrated against both struc-
Infectionsymptomatic
tural and regulatory HIV gene products. Which of these immune reactions effect the long-lasting antiviral response in the infected patient are not known. It is likely that interferons are key participants in the antiviral response to HIV. Experimental and clinical observations show significant changes in interferon (IFN) activity during HIV 3~13 disease. Many of these changes parallel similar observations in the animal lentivirus systems. I4~16 The role of IFN in HIV infection is complex and only incompletely understood. Strong antiviral activity is reported with addition of IFNa, IFNß, and IFN-y to HIV-infected T cells and macrophages. Preliminary reports document efficacy of rIFNa in patients with early stage HIV infection or with Kaposi's sarcoma.4-7 However, IFN activity or surrogate markers for IFN activity (2',5'-oligoade-
nylate synthetase activity, neopterin, ß2-microglobulin) are paradoxically found in cells or sera of patients with late stage
HIV Immunopathogenesis Program, Department of Cellular Immunology, Walter Reed Foundation for the Advancement of Military Medicine, Rockville, MD 20805.
199
Army Institute of Research and the Henry M.
Jackson
FRANCIS ET AL.
200 HIV disease, and are an index of a poor prognosis.8"13 Numerclinical studies with HIV-infected patients and parallel disease suggest an adverse role for findings in animal lentivirus14~16 Identification of the factors that IFN in disease progression. allow effective antiviral responses for IFN in HIV disease may lead to the development of novel therapeutic strategies for control of viral infection.
ous
THE INTERFERONS: AN OVERVIEW More than 30 years ago, Isaacs and Lindenmann found that cell cultures exposed to influenza virus produced a soluble factor that protected other cultures from infection.'7 This factor was termed IFN and has been the subject of basic and applied research for several decades.182'' IFNs are grouped into two distinct types based on their cell receptors and modes of action. Type 1 IFNs include IFNa (leukocyte-derived), IFNß (fibroblast-derived), and IFNfi (trophoblast-derived) and share a common receptor. Type II IFN, or IFN7, is produced by antigen or mitogen-stimulated T cells and natural killer (NK) cells and has a different receptor. IFNa and IFNß are acid-stable while IFN7 is acid labile. While there is only one each of IFNß and IFN7 genes, there are >20 IFNa genes, at least 16 of which encode separate protein products. In addition to IFN-mediated antiviral activities, IFN also affects cell growth and differentiation. Type I IFNs, typified by IFNa, remain the most widely investigated and most intimately involved in the regulation of viral gene expression.
IFN INDUCTION
During viral infections, IFNs play important roles in host antiviral responses. Within hours following systemic exposure to virus, high levels of IFN are observed in different body fluids. The induction of IFN by virus is complex but common mechanisms underlie diverse classes of viruses including dengue, mumps, respiratory syncytial, influenza, sendai, and herpes simplex virus. Following viral infection there is a rapid transcriptional upregulation of IFN. Productive viral infection is not an absolute requirement for IFN induction. Newcastle disease virus (NDV), a virus whose life cycle is aborted at an early stage following mammalian cell infection, induces high levels of IFN in the absence of productive viral replication. Moreover, one of the most potent inducers of IFN is poly(I) poly(C), a synthetic dsRNA. After exposure to virus, the molecular regulation of IFN is complex and involves both positive and negative eis and transacting elements.21 Recently, Fujita et al. isolated a hexanucleotide sequence, AA(A/G)(T/G)GA, within the IFN promoter element responsible for virus induction of IFN.26 When four or more copies of this hexanucleotide sequence are placed upstream from heterologous promoters (e.g., IL-2), they also become virus inducible.21 In addition to rii-acting regulatory elements, IFN induction also involves fra«s-acting factors. ' The IFN regulatory factor-1 (IRF-1 ) is a nuclear factor that binds to the Fujita hexanucleotide sequence. Transfection of the mouse IRF-1 gene into monkey COS cells not only leads to IRF-1 protein expression but to induction of IFNß.27 Other, •
cw-acting DNA binding proteins (e.g., NFkB) can activate expression of IFN in cooperation with IRF-1. NFkB, a protein first described for its ability to bind the immunoglobulin k enhancer in B cells, also binds to a positive regulatory domain in the IFNß gene. The negative regulation of IFN involves the IFN regulatory' factor-2 (IRF-2) and the viral regulatory element
( VRE).2 The VRE is located 5 to IFNa genes and also contains the hexanucleotide sequence. Both the IRF-2 and the VRE are involved in the down-regulation of IFN mRNA following activation. Indeed, soon after induction of IFN, IFN mRNAs are selectively degraded and new production ceases. Posttranscriptional regulation of IFN mRNA also plays a pivotal role in modifying IFN mRNA after virus infection. Mammalian cells constructed to retain 40 bp 5' to the transcriptional start site of the IFNß gene constitutively produce a functionally unstable IFNß mRNA. This mRNA, however, becomes more stable following treatment of cells with poly(I) poly(C).28 Moreover, a UA-rich sequence similar to that found with cytokine and oncogene mRNAs is found in the 3', untranslated regions of the IFN mRNA.29'30 The presence of this sequence leads to a translational blockade of IFN mRNA. Thus, the regulation of IFN production following virus infection involves eis and trans-acting factors (e.g., IRF-1 and/or NFkB) and a specific hexanucleotide sequence. Subsequent inhibition of IFN production occurs following induction and is mediated by IRF-2 or VRE and/or other post-transcriptional modifications of the IFN mRNAs. '
•
HIV-induced block in IFN
Monocytes are major producers of IFNa in humans; NK cells and, to a lesser extent, B and T cells also produce IFNa. During the course of viral infection, however, the cell types that produce IFN and the IFN
species produced by virus are highly variable.
Furthermore, not all viruses induce IFN following productive infection. Indeed, HIV infection of its principal target cells, the CD4+ T cell and monocyte does not lead to IFN production. In a survey of 15 different virus isolates, IFN activity was not
detected in culture fluids following productive HIV infection.3 Indeed, direct induction of IFN by any retrovirus in animal or human systems is not described. Further, certain viruses can subvert the induction of IFN by unrelated infectious and noninfectious agents. For example, during hepatitis B virus (HBV) infections, the HBV core antigen acts as a viral rra/ti-acting factor that suppresses transcription of the human IFNß gene.31 Similar mechanisms are likely operative in HIV infections.32 Indeed, HIV infection in monocytes results in a block in production of IFNa. Moreover, poly(I) poly(C)-treated monocytes persistently infected with HIV also produce little or no IFNa. The block in IFNa production in HIV-infected monocytes is mediated at the level of IFNa mRNA. While IFNa mRNAs are readily apparent in cell lysates of uninfected monocytes 8-24 hours following poly(I) poly(C) treatment, no IFN mRNA is found in cell lysates of HIV-infected monocyte cultures treated under identical conditions and for identical time intervals as the uninfected cells (Table 1). The specificity of the HIV-associated block at the level of IFN mRNA was shown by analysis of mRNAs for several other cytokines induced in monocytes by poly(I) poly(C). The levels of mRNAs for IL-lß, IL-6, and TNFa in cell lysates of uninfected and •
•
INTERFERON AND HIV
201
Table 1. Cytokine Activity and mRNA in HIV-Infected Monocyte Cultures
Uninfected monocytes treated with
IFNa (IU/ml) mRNA
IL-lj8(pg/ml)
mRNA IL-6 (pg/ml) mRNA TNFa (pg/ml) mRNA
IFN/3 (IU/ml) mRNA
treated with
Medium
Poly (I)-(C)
Medium
Poly (IXC)
0 0 0 0 0
1250 +++ 20 +++ 300 +++
0 0 0
10 x 106 units daily) additional toxicities include nausea, vomiting, somnolence, anemia, cough, rhinorrhea, diarrhea, altered sense of taste, mouth sores, depression, anxiety, hypotension, thrombocytopenia, leukopenia, and elevated transaminase levels.719 Fortunately, almost all the adverse signs and symptoms are quickly reversible with discontin-
205
ACKNOWLEDGMENTS We thank Drs. Jim A. Turpin, Robert Friedman, Gaines Sen, Robert Silverman, Carl Dieffenbach, and Doug Testa for helpful discussions, Victoria Hunter for excellent graphics, and the Military Medical Consortium for Applied Retroviral Research for excellent patient management. These studies were supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD. Dr. H. E. Gendelman is a Carter-Wallace fellow of The Johns Hopkins University School of Public Health and Hygiene in the Department of Immunology and Infectious Diseases. The opinions expressed are not necessarily those of the U.S. Army or Department of Defense.
REFERENCES 1. Clark SJ,
flu-like
uation of the IFNa.19 However, when IFNa is discontinued in
patients responding to therapy, a significant portion (50-90%) will experience relapse as is noted during treatment of hepatitis C infections.66,67 Future prospects of IFN therapy for HIV disease likely involve discovery of more effective preparations (e.g., not all subtypes of IFNa are equally effective in restricting HIV infection in its target cells) or in its use in combination chemotherapy. Indeed, IFNa acts synergistically with RT inhibitors in the treatment HIV-infected cells in vitro.68
2.
Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, Kappes JC, Hahn BH, and Shaw GM: High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med 1991;324:954-960. Lifson AR, Rutherford GW, and Jaffe HW: The natural history of human immunodeficiency virus infection. J Infect Dis 1988;
158:1360-1367. 3. Gendelman HE, Baca LM, Turpin J, Kalter DC, Hansen B, Orenstein JM, Dieffenbach CW, Friedman RM, and Meltzer MS: Regulation of HIV Replication in infected monocytes by IFN-a: Mechanisms for viral restriction. J Immunol 1990;145:2669-2676. 4. Krown SE, Real FX, Cunningham-Rundles S, Myskowski PL, Koziner B, Fein S, Mittelman A, Oettgen HF, and Safai B: Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with Kaposi's sarcoma. N Engl J Med 1983;308:1071-1076. 5. DeWit R, Schattenkerk JKME, Boucher CAB, Bakker PJM, Veenhof KHN, and Danner SA: Clinical and virological effects of high-dose recombinant interferon-a in disseminated AIDS-related Kaposi's sarcoma. Lancet 1988;2:1214-1217. 6. Lane HC, Kovacs JA, Feinberg J, Herpin B, Davey V, Walker R, Deyton L, Metcaf JA, Baseler M, Salzman N, Manischewitz J, Quinnan G, Masur H, and Fauci AS: Anti-retroviral effects of interferon-a in AIDS-associated Kaposi's sarcoma. Lancet
1988;2:1218-1222.
CONCLUSIONS
Components of the immune response that constrain virus replication and affect long-lasting antiviral immunity following HIV infection are incompletely defined. It is likely that interferons (IFNs) are critical participants in these host antiviral processes. IFNs induce significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its target cells. Several reports now document the efficacy of rIFNa in the treatment of patients with early stage HIV infection and Kaposi's sarcoma. Moreover, a specific defect in induction of IFNa from PBMC of HIVinfected individuals parallels advancing clinical disease. IFN or surrogate markers for IFN activity are found in sera of patients with advancing HIV disease and predict poor clinical outcomes. Thus, the role of IFN in HIV disease is complex and seemingly paradoxical. The diminished capacity of blood cells from HIVinfected patients to produce IFN likely reflect a specific viral adaptive mechanisms for persistent HIV replication.
7. Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Davey R, Falloon J, Polis MA, Salzman NP, Baseler M, Masur H, and Fauci AS: Interferon-a in patients with asymptomatic human immunodeficiency virus (HIV) infection: A randomized, placebo-controlled trial. Ann Int Med 1990;112:805— 811. 8. Witt PL, Spear GT, Lindstrom MJ, Kessler HA, Borden EC, Phair J, and Landay AL: 2',5-Oligoadenylate synthetase, neopterin and b2-microglobulin in asymptomatic HIV-infected individuals. AIDS
1991;5:289-293. 9. Fuchs D, Shearer GM, Boswell RN, Lucey DR, Clerici M, Reibnegger G, Werner ER, Zajac RA, and Wächter H: Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection. AIDS 1991;5:209-213. 10. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC, Drummond JE, Vaidya K, Mann DL, Eyster ME, Ragni MV, Lederman MM, Cohen AR, Bray GL, Rosenberg PS, Friedman RM, Hillgartner MW, Blattner WA, Kroner B, and Gail MH: A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 1989;321:1141-1148.
206
FRANCIS ET AL.
11. DeStefano E, Friedman RM, Friedman-Kien AE, Goedert JJ, Henriksen D, Preble OT, Sonnabend JA, and Vilcek J: Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy. J Infect Dis 1982;146:451-455. 12. Preble OT, Rook AH, Quinnan QV, Vilcek J, Friedman RM, Steis R, Gelmann EP, and Sonnabend JA: Role of interferon in AIDS. Ann NY Acad Sei 1985;437:65-75. 13. Vadhan R, Wong G, Gnecco C, Cunningham-Rundles S, Krim M, Real FX, Oettgen HF, and Krown SE: Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome. Cancer Res 1986;46:417425. 14. Narayan O, Sheffer D, Clements JE, and Teenekoon G: Restricted replication of lentivirus Visna viruses induce a unique interferon during interaction between lymphocytes and infected macrophages. J ExpMed 1985;162:1954-1969. 15. Zinc MC and Narayan O: Lentivirus-induced interferon inhibits maturation and proliferation of monocytes and restricts the replication of caprine arthritis encephalitis virus. J Virol 1989;63:2578-
2584. 16. Lairmore MD, Butera ST, Callahan GN, and DeMartini JC: Spontaneous interferon production by pulmonary leukocytes is associated with lentivirus-induced lymphoid interstitial pneumonia. J Immunol 1988;140:779-785. 17. Isaacs A and Lendenmann J: Virus interference. 1. The interferon. Proc R Soc Lond B 1957;147:258-267. 18. Samuel CE: Antiviral actions of interferon: lnterferon-regulated cellular proteins and their surprisingly selective antiviral activities.
Virology 1991;183:1-11. Tyring SK, Fleischmann WR, Coppenhaver DH, Niesel DW, Klimpel GR, Stanton J, and Hughes TK: The interferons: Mechanisms of action and clinical applications. JAMA
32.
33.
34.
35.
36.
labile human interferon alpha production by peripheral blood mononuclear cells stimulated by HIV-infected cells. Arch Virol
1988;99:9-19.
37. Kurane I and Ennis FA: Induction of interferon a from human lymphocytes by autologous, dengue virus-infected monocytes. J 38.
19. Baron S,
1991;266:1375-1383.
20. Laurence J: Immunology of HIV infection, I: Biology of the interferons. AIDS Res Human Retroviruses 1990;6:1149-1156. 21. Taylor JL and Grossberg SE: Recent progress in interferon research: Molecular mechanisms of regulation, action, and virus circumvention. Virus Res 1990;15:1-26. 22. Kornbluth RS, Oh PS, Munis JR, Cleveland PH, and Richman DD: The role of interferons in the control of HIV replication in macrophages. Clin Immunol Immunopathol 1990;54:200-219. 23. Pestka S, Langer JA, Zoon KC, and Samuel CE: Interferons and their actions. Ann Rev Biochem 1987;56:727-777. 24. Zoon KC: Human interferons: Structure and function. Interferon
1988;103:219-229.
1981;54:293-299. 41.
42.
Kruys V, Marinz O, Shaw G, Deschamps J, and Huez G: Translational blockade imposed by cytokine-derived UA-rich sequences.
Science 1989;245:852-855. Beutler B, Hartog K, Thayer R, Brown-Schimer S, and Cerami A: Identification of a common nucleotide sequence in the 3' untranslated region of mRNA molecules specifying inflammatory mediators. Proc Nati Acad Sei (USA) 1986;83:1670-1674. 31. Whilten TM, Quets AT, and Schloemer RH: Identification of the 30.
Capul D,
Kushnaryov VM, MacDonald HS, LeMense GP, DeBruin J, Sedmak JJ, and Grossberg SE: Quantitative analysis of mouse interferon-beta receptor-mediated endocytosis and nuclear entry. Cytobioscience 1988;53:185-197. Kushnaryov VM, MacDonald HS, DeBruin J, LeMense GP, Sedmak JJ, and Grossberg SE: Internalization and transport of mouse
beta-interferon into the cell nucleus. J Interferon Res
1986;6:241-245. 43. Arnheiter H and Meier E: Mx proteins: Antiviral proteins by chance or by necessity? New Biologist 1990;2:851-857. 44. Roy S, Agy M, Hovanessian AG, Sonenberg N, and Katze MG: The integrity of the stem structure of human immunodeficiency virus type 1 Tat-responsive sequence RNA is required for interaction with the interferon-induced 68,000-Mr protein kinase. J Virol
1991;65:632-640. 45.
1984;12:6979-6993.
29.
ExpMed 1987;166:999-1010. Capobianchi MR, Malavasi F, DiMarco P, and Dianzani F: Differences in the mechanism of induction of interferon-alpha by herpes simplex virus and herpes simplex virus-infected cells. Arch Virol
39. Gobi AE, Funa K, and Alm GV: Different induction patterns of mRNA for IFN-a and -ß in human mononuclear leukocytes after in vitro stimulation with herpes simplex virus-infected fibroblasts and sendai virus. J Immunol 1988;140:3605-3609. 40. Kato T and Minagawa T: Cellular source of interferon induced in human peripheral blood mononuclear leukocytes by mumps virus or by tumour cells persistently infected with mumps virus. J Gen Virol
1987;9:1-12. 25. Pomerantz RJ and Hirsch MS: Interferon and human immunodeficiency virus infection. Interferon 1987;9:114-127. 26. FujitaT, OhnoS, Yasumitsu H, and Taniguchi T: Delimitation and properties of DNA sequences required for the regulated expression of human interferon-ß gene. Cell 1985;41:489-496. 27. Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, and Taniguchi T: Induction of endogenous IFN-a and IFN-ß genes by a regulatory transcription factor, IRF-1. Nature 1989;337:270-272. 28. Nir U, Cohen B, Chen L, and Revel MA: Human IFN-ßl gene deleted of promoter sequences upstream from the TATA box is controlled post-transcriptionally by dsRNA. Nucl Acid Res
hepatitis B virus factor that inhibits expression of the beta interferon gene. J Virol 1991;65:4699-4704. Gendelman HE, Friedman RM, Joe S, Baca LM, Turpin JA, Dveksler G, Meltzer MS, and Dieffenbach C: A selective defect of interferon a production in human immunodeficiency virus-infected monocytes. J Exp Med 1990;172:1433-1442. Voth R, Rossol S, Klein K, Hess G, Schutt KH, Schroder HC, Buschenfelde K-HMZ, and Muller WEG: Differential gene expression of IFN-a and tumor necrosis factor-a in peripheral blood mononuclear cells from patients with AIDS related complex and AIDS. J Immunol 1990;144:970-975. Lopez C, Fitzgerald PA, and Siegal FP: Severe acquired immunodeficiency syndrome in male homosexuals: Diminished capacity to make interferon-a in vitro associated with severe opportunistic infections. J Infect Dis 1983;148:962-966. Gendelman HE, Baca LM, Kubrak CA, Genis P, Burrous S, Friedman RM, Munch D, and Meltzer MS: Induction of interferon a in peripheral blood mononuclear cells by human immunodeficiency virus (HlV)-infected monocytes: Restricted antiviral activity of the HIV-induced interferons. J Immunol 1992, in press. Capobianchi MR, DeMarco F, DiMarco P, and Dianzani F: Acid-
46.
SenGupta DN and Silverman RH: Activation of interferon-regulated, dsRNA-dependent enzymes by human immunodeficiency virus-1 leader RNA. Nucl Acids Res 1989;17:969-978. Edery I, Petryshyn R, and Sonenberg N: Activation of doublestranded RNA-dependent kinase (dsl) by the TAR region of HIV-1
mRNA: A novel translational control mechanism. Cell 1989; 56:303-312. 47. Poli G, Orenstein JM, Kinter A, Folks TM, and Fauci AS: Interferon-a but not AZT suppresses HIV expression in chronically infected cell lines. Science 1989;244:575-577. 48. Yasuda Y, Miyake S, Kato S, Kita M, Kishida T, Kimura T, and
INTERFERON AND HIV Kutz K: Interferon-a treatment leads to accumulation of virus
particles on the surface of cells persistently infected with the human
immunodeficiency virus. J AIDS 1990;3:1046-1051. Landsberger FR, and Tamm I: Beta-interferon induced pure dependent changes in plasma membrane lipid bilayer of
49. Pfeffer LM,
cultured cells. J Interferon Res 1982;4:431-440. 50. Pfeffer LM, Wang E, and Tamm I: Interferon effects on microfilament organization, cellular fibronectin distribution, and cell motility in human fibroblasts. J Cell Biol 1980;85:9-17. 51. Faltynek CR, Finch LR, Miller P, and Overton WR: Treatment with recombinant IFN-7 decreases cell surface CD4 levels on peripheral blood monocytes and on myelomonocyte cell lines. J Immunol
1989;142:500-508. 52.
53.
54.
55.
56.
and Miller R: Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J Clin Invest 1983:72:393397. MentzerSJ, Faller DV, and Burakoff SJ: Interferon--y induction of LFA-1-mediated homotypic adhesion of human monocytes. J Immunol 1986;137:108-113. Mokoena T and Gordon S: Human macrophage activation: modulation of mannosyl, fucosyl receptor activity in vitro by lymphokines, gamma and alpha interferons, and dexamethasone. J Clin Invest 1985;75:624-631. Lavie G, Zucker-Franklin D, and Franklin EC: Elastase-type proteases on the surface of human blood monocytes: possible role in amyloid formation. J Immunol 1980;125:175-180. Gerfaux J, Rousseet S, Chany-Fournier F, and Chany C: Interferon effect on collagen and fibronectin distribution in the extracellular matrix of murine sarcoma virus-transformed cells. Cancer Res
Guyre PM, Morganelli PM,
1981;41:3629-3634. 57. Ratner L, Sen GC, Brown GE, Lebleu B, Kawakita M, Cabrer B, Slattery E, and Lengyel P: Interferon, double-stranded RNA and RNA degradation: characteristics of an endonuclease activity. Eur J Biochem 1977;79:565-577. 58. Mitchell WM, Montefiori DC, Sobol RW, Li SW, Reichenbach SW, Reichenbach NL, Charabula R, Pfeiderer W, Robinson WE, and Suhadolnik RJ: Structure/function relationships of 2-5A analogues for inhibition of HIV-1 reverse transcriptase and infection in vitro. JCell Biochem 1989;13B:305. 59. Liu DK and Owens CF: Inhibition of Viral reverse transcriptase by 2',5'-oligoadenylates. Biochem Biophys Res Commun 1987; 145:291-297. 60. Abb J, Zachoval R, Zachoval V, and Deinhardt F: HIV antigen, HIV antibody and serum interferon in a patient with encephalopathy. Infection 1987;15:425-426.
207 61. Fuchs D, Hausen A, ReibneggerG, Werner ER, Werner-Felmayer G, Dierich MP, and Wächter H: Interferon--y concentrations are increased in sera from individuals infected with human immunodeficiency virus type 1. J AIDS 1989;2:158-162. 62. Minagawa T, Mizuno K, Hirano S, Asano M, Numata A, Kohanawa M, Nakane A, Hachimori K, Tamagawa S, Negishi M, Yamazaki S, and Satoh Y: Detection of high levels of immunoreactive human beta-1 interferon in sera from HIV-infected patients. Life Sei 1989;45:iii-vii. 63. Yarchoan R, Venzon DJ, Pluda JM, Lietzau J, Wyvill KM, Tsiatis AA, Steinberg SM, and Broder S: CD4 count and the risk for death in patients infected with HIV receiving antiretroviral therapy. Ann IntMed 1991;115:184-189. 64. Preble OT, Black RJ, Friedman RM, Klippel JH, and Vilcek J: Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science 1982:216:429431. 65. Lau AS, Read SE, and Williams BRG: Downregulation of interferon a but not g receptor expression in vivo in the acquired immunodeficiency syndrome. J Clin Invest 1988;82:1415-1421. 66. Davis GL, Baiart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, VanThiel DH, Tamburro C, Lefkowitch J, Albrecht J, Meschievitz C, Ortego TJ, Gibas A, and the Hepatitis Interventional Therapy Group: Treatment of chronic hepatitis C with recombinant interferon alpha: A multicenter randomized controlled trial. N Engl J Med 1989;321:1501-1506. 67. DiBisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, Banks SM, and Hoofnagle JH: Recombinant interferon alpha therapy for chronic hepatitis C: A randomized, double-blind, placebo-controlled trial. N Engl J Med
1989;321:1506-1510. 68. Johnson VA, Merrill DP, Videler JA, Chou T-C, Byington RE, Eron JJ, D'Aquila RT, and Hirsh MS: Two-drug combinations of zidovudine, didanosine, and recombinant interferon-a inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis 1991;164:646-655.
Address reprint requests to: Mark L. Francis, M.D. Department of Cellular Immunology Walter Reed Army Institute of Research 9620 Medical Center Drive, Suite 200 Rockville, MD 20850
Interferons in the Persistence, Pathogenesis, and Treatment of HIV Infection MARK L. FRANCIS, MONTE S. MELTZER, and HOWARD E. GENDELMAN
ABSTRACT Interferon (IFN) plays an important role in the treatment and pathogenesis of HIV disease. Recent studies show beneficial effects of IFNa in the treatment of HIV-associated Kaposi's Sarcoma and early HIV-infection. Moreover, cell culture studies support these beneficial effects. HIV infection of monocytes is blocked by IFNa administered at the time of viral challenge. The IFNa-treated cells show no evidence of HIV infection. Viral gene products produced in monocytes infected with HIV then treated with IFNa gradually decrease to baseline. Large quantities of proviral DNA are seen in the HIV-infected IFNa-treated cells with little evidence for viral transcription suggesting true microbiological latency. While most viral infections of cells result in IFN production, HIV is a notable exception. Indeed, HIV does not induce monocytes to produce IFNa and blocks its production following poly(I)-poly (c) stimulation. This allows HIV yet another mechanism to evade an important host antiviral response. Paradoxically, the appearance of IFN activity in sera of HIV-infected patients is associated with disease progression, not resolution. Recent observations showing that the interaction between HIV-infected monocytes and PBMC results in the production of IFNas with reduced anti-HIV activity may help explain this paradox. Thus, IFNa plays an important but complex role in HIV disease. The elucidation of cellular factors that regulate the antiretroviral effects of IFNa may lead to the development of novel therapeutic strategies for HIV infection.
INTRODUCTION with human immunodeficiency virus (HIV) prodisease only after a relatively long incuduces bation period that can exceed 10 years. During the interval of subclinical infection, virus replication is apparently held in check by host immune reactions and certain regulatory factors intrinsic to the viral genome. Recent studies document high level viremia ( 10-104 TCID50/ml plasma) in acute HIV infection that rapidly (6-8 weeks) subsides to undetectable levels.1 The frequency of productively infected cells in blood after this early viremia is 0.01 to 0.001% and remains at a low level through end-stage disease.2 Components of the host immune response that constrain virus replication after the acute viremic interval are still incompletely defined. Vigorous humoral and cellular immune reactions are easily demonstrated against both struc-
Infectionsymptomatic
tural and regulatory HIV gene products. Which of these immune reactions effect the long-lasting antiviral response in the infected patient are not known. It is likely that interferons are key participants in the antiviral response to HIV. Experimental and clinical observations show significant changes in interferon (IFN) activity during HIV 3~13 disease. Many of these changes parallel similar observations in the animal lentivirus systems. I4~16 The role of IFN in HIV infection is complex and only incompletely understood. Strong antiviral activity is reported with addition of IFNa, IFNß, and IFN-y to HIV-infected T cells and macrophages. Preliminary reports document efficacy of rIFNa in patients with early stage HIV infection or with Kaposi's sarcoma.4-7 However, IFN activity or surrogate markers for IFN activity (2',5'-oligoade-
nylate synthetase activity, neopterin, ß2-microglobulin) are paradoxically found in cells or sera of patients with late stage
HIV Immunopathogenesis Program, Department of Cellular Immunology, Walter Reed Foundation for the Advancement of Military Medicine, Rockville, MD 20805.
199
Army Institute of Research and the Henry M.
Jackson
FRANCIS ET AL.
200 HIV disease, and are an index of a poor prognosis.8"13 Numerclinical studies with HIV-infected patients and parallel disease suggest an adverse role for findings in animal lentivirus14~16 Identification of the factors that IFN in disease progression. allow effective antiviral responses for IFN in HIV disease may lead to the development of novel therapeutic strategies for control of viral infection.
ous
THE INTERFERONS: AN OVERVIEW More than 30 years ago, Isaacs and Lindenmann found that cell cultures exposed to influenza virus produced a soluble factor that protected other cultures from infection.'7 This factor was termed IFN and has been the subject of basic and applied research for several decades.182'' IFNs are grouped into two distinct types based on their cell receptors and modes of action. Type 1 IFNs include IFNa (leukocyte-derived), IFNß (fibroblast-derived), and IFNfi (trophoblast-derived) and share a common receptor. Type II IFN, or IFN7, is produced by antigen or mitogen-stimulated T cells and natural killer (NK) cells and has a different receptor. IFNa and IFNß are acid-stable while IFN7 is acid labile. While there is only one each of IFNß and IFN7 genes, there are >20 IFNa genes, at least 16 of which encode separate protein products. In addition to IFN-mediated antiviral activities, IFN also affects cell growth and differentiation. Type I IFNs, typified by IFNa, remain the most widely investigated and most intimately involved in the regulation of viral gene expression.
IFN INDUCTION
During viral infections, IFNs play important roles in host antiviral responses. Within hours following systemic exposure to virus, high levels of IFN are observed in different body fluids. The induction of IFN by virus is complex but common mechanisms underlie diverse classes of viruses including dengue, mumps, respiratory syncytial, influenza, sendai, and herpes simplex virus. Following viral infection there is a rapid transcriptional upregulation of IFN. Productive viral infection is not an absolute requirement for IFN induction. Newcastle disease virus (NDV), a virus whose life cycle is aborted at an early stage following mammalian cell infection, induces high levels of IFN in the absence of productive viral replication. Moreover, one of the most potent inducers of IFN is poly(I) poly(C), a synthetic dsRNA. After exposure to virus, the molecular regulation of IFN is complex and involves both positive and negative eis and transacting elements.21 Recently, Fujita et al. isolated a hexanucleotide sequence, AA(A/G)(T/G)GA, within the IFN promoter element responsible for virus induction of IFN.26 When four or more copies of this hexanucleotide sequence are placed upstream from heterologous promoters (e.g., IL-2), they also become virus inducible.21 In addition to rii-acting regulatory elements, IFN induction also involves fra«s-acting factors. ' The IFN regulatory factor-1 (IRF-1 ) is a nuclear factor that binds to the Fujita hexanucleotide sequence. Transfection of the mouse IRF-1 gene into monkey COS cells not only leads to IRF-1 protein expression but to induction of IFNß.27 Other, •
cw-acting DNA binding proteins (e.g., NFkB) can activate expression of IFN in cooperation with IRF-1. NFkB, a protein first described for its ability to bind the immunoglobulin k enhancer in B cells, also binds to a positive regulatory domain in the IFNß gene. The negative regulation of IFN involves the IFN regulatory' factor-2 (IRF-2) and the viral regulatory element
( VRE).2 The VRE is located 5 to IFNa genes and also contains the hexanucleotide sequence. Both the IRF-2 and the VRE are involved in the down-regulation of IFN mRNA following activation. Indeed, soon after induction of IFN, IFN mRNAs are selectively degraded and new production ceases. Posttranscriptional regulation of IFN mRNA also plays a pivotal role in modifying IFN mRNA after virus infection. Mammalian cells constructed to retain 40 bp 5' to the transcriptional start site of the IFNß gene constitutively produce a functionally unstable IFNß mRNA. This mRNA, however, becomes more stable following treatment of cells with poly(I) poly(C).28 Moreover, a UA-rich sequence similar to that found with cytokine and oncogene mRNAs is found in the 3', untranslated regions of the IFN mRNA.29'30 The presence of this sequence leads to a translational blockade of IFN mRNA. Thus, the regulation of IFN production following virus infection involves eis and trans-acting factors (e.g., IRF-1 and/or NFkB) and a specific hexanucleotide sequence. Subsequent inhibition of IFN production occurs following induction and is mediated by IRF-2 or VRE and/or other post-transcriptional modifications of the IFN mRNAs. '
•
HIV-induced block in IFN
Monocytes are major producers of IFNa in humans; NK cells and, to a lesser extent, B and T cells also produce IFNa. During the course of viral infection, however, the cell types that produce IFN and the IFN
species produced by virus are highly variable.
Furthermore, not all viruses induce IFN following productive infection. Indeed, HIV infection of its principal target cells, the CD4+ T cell and monocyte does not lead to IFN production. In a survey of 15 different virus isolates, IFN activity was not
detected in culture fluids following productive HIV infection.3 Indeed, direct induction of IFN by any retrovirus in animal or human systems is not described. Further, certain viruses can subvert the induction of IFN by unrelated infectious and noninfectious agents. For example, during hepatitis B virus (HBV) infections, the HBV core antigen acts as a viral rra/ti-acting factor that suppresses transcription of the human IFNß gene.31 Similar mechanisms are likely operative in HIV infections.32 Indeed, HIV infection in monocytes results in a block in production of IFNa. Moreover, poly(I) poly(C)-treated monocytes persistently infected with HIV also produce little or no IFNa. The block in IFNa production in HIV-infected monocytes is mediated at the level of IFNa mRNA. While IFNa mRNAs are readily apparent in cell lysates of uninfected monocytes 8-24 hours following poly(I) poly(C) treatment, no IFN mRNA is found in cell lysates of HIV-infected monocyte cultures treated under identical conditions and for identical time intervals as the uninfected cells (Table 1). The specificity of the HIV-associated block at the level of IFN mRNA was shown by analysis of mRNAs for several other cytokines induced in monocytes by poly(I) poly(C). The levels of mRNAs for IL-lß, IL-6, and TNFa in cell lysates of uninfected and •
•
INTERFERON AND HIV
201
Table 1. Cytokine Activity and mRNA in HIV-Infected Monocyte Cultures
Uninfected monocytes treated with
IFNa (IU/ml) mRNA
IL-lj8(pg/ml)
mRNA IL-6 (pg/ml) mRNA TNFa (pg/ml) mRNA
IFN/3 (IU/ml) mRNA
treated with
Medium
Poly (I)-(C)
Medium
Poly (IXC)
0 0 0 0 0
1250 +++ 20 +++ 300 +++
0 0 0
10 x 106 units daily) additional toxicities include nausea, vomiting, somnolence, anemia, cough, rhinorrhea, diarrhea, altered sense of taste, mouth sores, depression, anxiety, hypotension, thrombocytopenia, leukopenia, and elevated transaminase levels.719 Fortunately, almost all the adverse signs and symptoms are quickly reversible with discontin-
205
ACKNOWLEDGMENTS We thank Drs. Jim A. Turpin, Robert Friedman, Gaines Sen, Robert Silverman, Carl Dieffenbach, and Doug Testa for helpful discussions, Victoria Hunter for excellent graphics, and the Military Medical Consortium for Applied Retroviral Research for excellent patient management. These studies were supported in part by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, MD. Dr. H. E. Gendelman is a Carter-Wallace fellow of The Johns Hopkins University School of Public Health and Hygiene in the Department of Immunology and Infectious Diseases. The opinions expressed are not necessarily those of the U.S. Army or Department of Defense.
REFERENCES 1. Clark SJ,
flu-like
uation of the IFNa.19 However, when IFNa is discontinued in
patients responding to therapy, a significant portion (50-90%) will experience relapse as is noted during treatment of hepatitis C infections.66,67 Future prospects of IFN therapy for HIV disease likely involve discovery of more effective preparations (e.g., not all subtypes of IFNa are equally effective in restricting HIV infection in its target cells) or in its use in combination chemotherapy. Indeed, IFNa acts synergistically with RT inhibitors in the treatment HIV-infected cells in vitro.68
2.
Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, Kappes JC, Hahn BH, and Shaw GM: High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med 1991;324:954-960. Lifson AR, Rutherford GW, and Jaffe HW: The natural history of human immunodeficiency virus infection. J Infect Dis 1988;
158:1360-1367. 3. Gendelman HE, Baca LM, Turpin J, Kalter DC, Hansen B, Orenstein JM, Dieffenbach CW, Friedman RM, and Meltzer MS: Regulation of HIV Replication in infected monocytes by IFN-a: Mechanisms for viral restriction. J Immunol 1990;145:2669-2676. 4. Krown SE, Real FX, Cunningham-Rundles S, Myskowski PL, Koziner B, Fein S, Mittelman A, Oettgen HF, and Safai B: Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with Kaposi's sarcoma. N Engl J Med 1983;308:1071-1076. 5. DeWit R, Schattenkerk JKME, Boucher CAB, Bakker PJM, Veenhof KHN, and Danner SA: Clinical and virological effects of high-dose recombinant interferon-a in disseminated AIDS-related Kaposi's sarcoma. Lancet 1988;2:1214-1217. 6. Lane HC, Kovacs JA, Feinberg J, Herpin B, Davey V, Walker R, Deyton L, Metcaf JA, Baseler M, Salzman N, Manischewitz J, Quinnan G, Masur H, and Fauci AS: Anti-retroviral effects of interferon-a in AIDS-associated Kaposi's sarcoma. Lancet
1988;2:1218-1222.
CONCLUSIONS
Components of the immune response that constrain virus replication and affect long-lasting antiviral immunity following HIV infection are incompletely defined. It is likely that interferons (IFNs) are critical participants in these host antiviral processes. IFNs induce significant antiretroviral activities that affect the ability of human immunodeficiency virus (HIV) to infect and replicate in its target cells. Several reports now document the efficacy of rIFNa in the treatment of patients with early stage HIV infection and Kaposi's sarcoma. Moreover, a specific defect in induction of IFNa from PBMC of HIVinfected individuals parallels advancing clinical disease. IFN or surrogate markers for IFN activity are found in sera of patients with advancing HIV disease and predict poor clinical outcomes. Thus, the role of IFN in HIV disease is complex and seemingly paradoxical. The diminished capacity of blood cells from HIVinfected patients to produce IFN likely reflect a specific viral adaptive mechanisms for persistent HIV replication.
7. Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Davey R, Falloon J, Polis MA, Salzman NP, Baseler M, Masur H, and Fauci AS: Interferon-a in patients with asymptomatic human immunodeficiency virus (HIV) infection: A randomized, placebo-controlled trial. Ann Int Med 1990;112:805— 811. 8. Witt PL, Spear GT, Lindstrom MJ, Kessler HA, Borden EC, Phair J, and Landay AL: 2',5-Oligoadenylate synthetase, neopterin and b2-microglobulin in asymptomatic HIV-infected individuals. AIDS
1991;5:289-293. 9. Fuchs D, Shearer GM, Boswell RN, Lucey DR, Clerici M, Reibnegger G, Werner ER, Zajac RA, and Wächter H: Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection. AIDS 1991;5:209-213. 10. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC, Drummond JE, Vaidya K, Mann DL, Eyster ME, Ragni MV, Lederman MM, Cohen AR, Bray GL, Rosenberg PS, Friedman RM, Hillgartner MW, Blattner WA, Kroner B, and Gail MH: A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med 1989;321:1141-1148.
206
FRANCIS ET AL.
11. DeStefano E, Friedman RM, Friedman-Kien AE, Goedert JJ, Henriksen D, Preble OT, Sonnabend JA, and Vilcek J: Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy. J Infect Dis 1982;146:451-455. 12. Preble OT, Rook AH, Quinnan QV, Vilcek J, Friedman RM, Steis R, Gelmann EP, and Sonnabend JA: Role of interferon in AIDS. Ann NY Acad Sei 1985;437:65-75. 13. Vadhan R, Wong G, Gnecco C, Cunningham-Rundles S, Krim M, Real FX, Oettgen HF, and Krown SE: Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome. Cancer Res 1986;46:417425. 14. Narayan O, Sheffer D, Clements JE, and Teenekoon G: Restricted replication of lentivirus Visna viruses induce a unique interferon during interaction between lymphocytes and infected macrophages. J ExpMed 1985;162:1954-1969. 15. Zinc MC and Narayan O: Lentivirus-induced interferon inhibits maturation and proliferation of monocytes and restricts the replication of caprine arthritis encephalitis virus. J Virol 1989;63:2578-
2584. 16. Lairmore MD, Butera ST, Callahan GN, and DeMartini JC: Spontaneous interferon production by pulmonary leukocytes is associated with lentivirus-induced lymphoid interstitial pneumonia. J Immunol 1988;140:779-785. 17. Isaacs A and Lendenmann J: Virus interference. 1. The interferon. Proc R Soc Lond B 1957;147:258-267. 18. Samuel CE: Antiviral actions of interferon: lnterferon-regulated cellular proteins and their surprisingly selective antiviral activities.
Virology 1991;183:1-11. Tyring SK, Fleischmann WR, Coppenhaver DH, Niesel DW, Klimpel GR, Stanton J, and Hughes TK: The interferons: Mechanisms of action and clinical applications. JAMA
32.
33.
34.
35.
36.
labile human interferon alpha production by peripheral blood mononuclear cells stimulated by HIV-infected cells. Arch Virol
1988;99:9-19.
37. Kurane I and Ennis FA: Induction of interferon a from human lymphocytes by autologous, dengue virus-infected monocytes. J 38.
19. Baron S,
1991;266:1375-1383.
20. Laurence J: Immunology of HIV infection, I: Biology of the interferons. AIDS Res Human Retroviruses 1990;6:1149-1156. 21. Taylor JL and Grossberg SE: Recent progress in interferon research: Molecular mechanisms of regulation, action, and virus circumvention. Virus Res 1990;15:1-26. 22. Kornbluth RS, Oh PS, Munis JR, Cleveland PH, and Richman DD: The role of interferons in the control of HIV replication in macrophages. Clin Immunol Immunopathol 1990;54:200-219. 23. Pestka S, Langer JA, Zoon KC, and Samuel CE: Interferons and their actions. Ann Rev Biochem 1987;56:727-777. 24. Zoon KC: Human interferons: Structure and function. Interferon
1988;103:219-229.
1981;54:293-299. 41.
42.
Kruys V, Marinz O, Shaw G, Deschamps J, and Huez G: Translational blockade imposed by cytokine-derived UA-rich sequences.
Science 1989;245:852-855. Beutler B, Hartog K, Thayer R, Brown-Schimer S, and Cerami A: Identification of a common nucleotide sequence in the 3' untranslated region of mRNA molecules specifying inflammatory mediators. Proc Nati Acad Sei (USA) 1986;83:1670-1674. 31. Whilten TM, Quets AT, and Schloemer RH: Identification of the 30.
Capul D,
Kushnaryov VM, MacDonald HS, LeMense GP, DeBruin J, Sedmak JJ, and Grossberg SE: Quantitative analysis of mouse interferon-beta receptor-mediated endocytosis and nuclear entry. Cytobioscience 1988;53:185-197. Kushnaryov VM, MacDonald HS, DeBruin J, LeMense GP, Sedmak JJ, and Grossberg SE: Internalization and transport of mouse
beta-interferon into the cell nucleus. J Interferon Res
1986;6:241-245. 43. Arnheiter H and Meier E: Mx proteins: Antiviral proteins by chance or by necessity? New Biologist 1990;2:851-857. 44. Roy S, Agy M, Hovanessian AG, Sonenberg N, and Katze MG: The integrity of the stem structure of human immunodeficiency virus type 1 Tat-responsive sequence RNA is required for interaction with the interferon-induced 68,000-Mr protein kinase. J Virol
1991;65:632-640. 45.
1984;12:6979-6993.
29.
ExpMed 1987;166:999-1010. Capobianchi MR, Malavasi F, DiMarco P, and Dianzani F: Differences in the mechanism of induction of interferon-alpha by herpes simplex virus and herpes simplex virus-infected cells. Arch Virol
39. Gobi AE, Funa K, and Alm GV: Different induction patterns of mRNA for IFN-a and -ß in human mononuclear leukocytes after in vitro stimulation with herpes simplex virus-infected fibroblasts and sendai virus. J Immunol 1988;140:3605-3609. 40. Kato T and Minagawa T: Cellular source of interferon induced in human peripheral blood mononuclear leukocytes by mumps virus or by tumour cells persistently infected with mumps virus. J Gen Virol
1987;9:1-12. 25. Pomerantz RJ and Hirsch MS: Interferon and human immunodeficiency virus infection. Interferon 1987;9:114-127. 26. FujitaT, OhnoS, Yasumitsu H, and Taniguchi T: Delimitation and properties of DNA sequences required for the regulated expression of human interferon-ß gene. Cell 1985;41:489-496. 27. Fujita T, Kimura Y, Miyamoto M, Barsoumian EL, and Taniguchi T: Induction of endogenous IFN-a and IFN-ß genes by a regulatory transcription factor, IRF-1. Nature 1989;337:270-272. 28. Nir U, Cohen B, Chen L, and Revel MA: Human IFN-ßl gene deleted of promoter sequences upstream from the TATA box is controlled post-transcriptionally by dsRNA. Nucl Acid Res
hepatitis B virus factor that inhibits expression of the beta interferon gene. J Virol 1991;65:4699-4704. Gendelman HE, Friedman RM, Joe S, Baca LM, Turpin JA, Dveksler G, Meltzer MS, and Dieffenbach C: A selective defect of interferon a production in human immunodeficiency virus-infected monocytes. J Exp Med 1990;172:1433-1442. Voth R, Rossol S, Klein K, Hess G, Schutt KH, Schroder HC, Buschenfelde K-HMZ, and Muller WEG: Differential gene expression of IFN-a and tumor necrosis factor-a in peripheral blood mononuclear cells from patients with AIDS related complex and AIDS. J Immunol 1990;144:970-975. Lopez C, Fitzgerald PA, and Siegal FP: Severe acquired immunodeficiency syndrome in male homosexuals: Diminished capacity to make interferon-a in vitro associated with severe opportunistic infections. J Infect Dis 1983;148:962-966. Gendelman HE, Baca LM, Kubrak CA, Genis P, Burrous S, Friedman RM, Munch D, and Meltzer MS: Induction of interferon a in peripheral blood mononuclear cells by human immunodeficiency virus (HlV)-infected monocytes: Restricted antiviral activity of the HIV-induced interferons. J Immunol 1992, in press. Capobianchi MR, DeMarco F, DiMarco P, and Dianzani F: Acid-
46.
SenGupta DN and Silverman RH: Activation of interferon-regulated, dsRNA-dependent enzymes by human immunodeficiency virus-1 leader RNA. Nucl Acids Res 1989;17:969-978. Edery I, Petryshyn R, and Sonenberg N: Activation of doublestranded RNA-dependent kinase (dsl) by the TAR region of HIV-1
mRNA: A novel translational control mechanism. Cell 1989; 56:303-312. 47. Poli G, Orenstein JM, Kinter A, Folks TM, and Fauci AS: Interferon-a but not AZT suppresses HIV expression in chronically infected cell lines. Science 1989;244:575-577. 48. Yasuda Y, Miyake S, Kato S, Kita M, Kishida T, Kimura T, and
INTERFERON AND HIV Kutz K: Interferon-a treatment leads to accumulation of virus
particles on the surface of cells persistently infected with the human
immunodeficiency virus. J AIDS 1990;3:1046-1051. Landsberger FR, and Tamm I: Beta-interferon induced pure dependent changes in plasma membrane lipid bilayer of
49. Pfeffer LM,
cultured cells. J Interferon Res 1982;4:431-440. 50. Pfeffer LM, Wang E, and Tamm I: Interferon effects on microfilament organization, cellular fibronectin distribution, and cell motility in human fibroblasts. J Cell Biol 1980;85:9-17. 51. Faltynek CR, Finch LR, Miller P, and Overton WR: Treatment with recombinant IFN-7 decreases cell surface CD4 levels on peripheral blood monocytes and on myelomonocyte cell lines. J Immunol
1989;142:500-508. 52.
53.
54.
55.
56.
and Miller R: Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes. J Clin Invest 1983:72:393397. MentzerSJ, Faller DV, and Burakoff SJ: Interferon--y induction of LFA-1-mediated homotypic adhesion of human monocytes. J Immunol 1986;137:108-113. Mokoena T and Gordon S: Human macrophage activation: modulation of mannosyl, fucosyl receptor activity in vitro by lymphokines, gamma and alpha interferons, and dexamethasone. J Clin Invest 1985;75:624-631. Lavie G, Zucker-Franklin D, and Franklin EC: Elastase-type proteases on the surface of human blood monocytes: possible role in amyloid formation. J Immunol 1980;125:175-180. Gerfaux J, Rousseet S, Chany-Fournier F, and Chany C: Interferon effect on collagen and fibronectin distribution in the extracellular matrix of murine sarcoma virus-transformed cells. Cancer Res
Guyre PM, Morganelli PM,
1981;41:3629-3634. 57. Ratner L, Sen GC, Brown GE, Lebleu B, Kawakita M, Cabrer B, Slattery E, and Lengyel P: Interferon, double-stranded RNA and RNA degradation: characteristics of an endonuclease activity. Eur J Biochem 1977;79:565-577. 58. Mitchell WM, Montefiori DC, Sobol RW, Li SW, Reichenbach SW, Reichenbach NL, Charabula R, Pfeiderer W, Robinson WE, and Suhadolnik RJ: Structure/function relationships of 2-5A analogues for inhibition of HIV-1 reverse transcriptase and infection in vitro. JCell Biochem 1989;13B:305. 59. Liu DK and Owens CF: Inhibition of Viral reverse transcriptase by 2',5'-oligoadenylates. Biochem Biophys Res Commun 1987; 145:291-297. 60. Abb J, Zachoval R, Zachoval V, and Deinhardt F: HIV antigen, HIV antibody and serum interferon in a patient with encephalopathy. Infection 1987;15:425-426.
207 61. Fuchs D, Hausen A, ReibneggerG, Werner ER, Werner-Felmayer G, Dierich MP, and Wächter H: Interferon--y concentrations are increased in sera from individuals infected with human immunodeficiency virus type 1. J AIDS 1989;2:158-162. 62. Minagawa T, Mizuno K, Hirano S, Asano M, Numata A, Kohanawa M, Nakane A, Hachimori K, Tamagawa S, Negishi M, Yamazaki S, and Satoh Y: Detection of high levels of immunoreactive human beta-1 interferon in sera from HIV-infected patients. Life Sei 1989;45:iii-vii. 63. Yarchoan R, Venzon DJ, Pluda JM, Lietzau J, Wyvill KM, Tsiatis AA, Steinberg SM, and Broder S: CD4 count and the risk for death in patients infected with HIV receiving antiretroviral therapy. Ann IntMed 1991;115:184-189. 64. Preble OT, Black RJ, Friedman RM, Klippel JH, and Vilcek J: Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science 1982:216:429431. 65. Lau AS, Read SE, and Williams BRG: Downregulation of interferon a but not g receptor expression in vivo in the acquired immunodeficiency syndrome. J Clin Invest 1988;82:1415-1421. 66. Davis GL, Baiart LA, Schiff ER, Lindsay K, Bodenheimer HC, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, VanThiel DH, Tamburro C, Lefkowitch J, Albrecht J, Meschievitz C, Ortego TJ, Gibas A, and the Hepatitis Interventional Therapy Group: Treatment of chronic hepatitis C with recombinant interferon alpha: A multicenter randomized controlled trial. N Engl J Med 1989;321:1501-1506. 67. DiBisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J, Goodman Z, Banks SM, and Hoofnagle JH: Recombinant interferon alpha therapy for chronic hepatitis C: A randomized, double-blind, placebo-controlled trial. N Engl J Med
1989;321:1506-1510. 68. Johnson VA, Merrill DP, Videler JA, Chou T-C, Byington RE, Eron JJ, D'Aquila RT, and Hirsh MS: Two-drug combinations of zidovudine, didanosine, and recombinant interferon-a inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis 1991;164:646-655.
Address reprint requests to: Mark L. Francis, M.D. Department of Cellular Immunology Walter Reed Army Institute of Research 9620 Medical Center Drive, Suite 200 Rockville, MD 20850
