Differences Between Human c¢ (Leukocyte) and ~ (Fibroblast) Interferons Brief Review

267 1 tif Archives of Virology 67, 267 281 (1981) Archives of Virology © by Springer Verlag 1981 Differences Between Human c¢ (Leukocyte) and ~ (Fibroblast) Interferons Brief Review By TERESA G HAYES.

Archives of Virology 67, 267 281 (1981) Archives of Virology

© by Springer-Verlag 1981

Differences Between Human c¢ (Leukocyte)

and ~ (Fibroblast) Interferons

Brief Review

By

TERESA G HAYES

Department of Microbiology, New York University School of Medicine,

New York, U.S.A

Accepted November 24, 1980

Introduction

H u m a n interferons are divided into three major classes based on antigenic and physieochemieal criteria The major product of peripheral blood leukoeytes induced with Sendai virus is called :¢ interferon (4, 47) Tissue culture foreskin fibroblasts stimulated with polyinosinie acid-polycytidylie acid [poly (I) • poty (C)] synthesize predominantly ~ interferon (49) ¥ interferon is made by lymphoeytes exposed t~) various mitogenic and immune-specific stimuli, including phyto- hemagglutinin (40, 114), anti-lymphocyte globulins (39), and viral antigens (8,

45, 109)

Recent advances in biochemistry and molecular biology have led to the clon- ing of the structural genes for some ~ and ~ interferon species (24, 78, 79, 106) The present review is a summary of the various known characteristics of the native a and ~ interferon molecules The review will not a t t e m p t to evaluate all

of the data obtained in the last few months with cloned interferon DNA sequences,

as much of t h a t information has not y e t been published Also, as y interferon has been less well characterized than the other two interferon types, it will not be included in the comparison

Structural Comparison of Human Intederons

Antigenic Properties

The first reported demonstrations of human interferon production were per- formed with primary cultures of amnion and kidney cells stimulated with polio- virus (61, 62) and leukemic bone marrow cell cultures inoculated with several myxo- and paramyxoviruses (56) I t was subsequently established t h a t other human cells could synthesize interferon, including embryonic fibroblasts, cultures from the lung and thyroid, transformed cell lines such as H e L a and KB, and peripheral blood leukocytes (15, 23, 43, 95)

19 Arch Vitol 67/4

0304-860S/81/0067/0267/$ 03.00

As information accumulated about interferons from various sources, it be- came evident t h a t the products of induced cells were not uniform with respect to their biological and physicochemical characteristics LEvY-KoE~IG et al (70) ob- served t h a t antibodies raised in rabbits against NDV-induced leukocyte inter- feron neutralized interferon made by leukocytes to a higher degree than inter- feron produced in foreskin fibroblasts or amnion cells They concluded t h a t

" h u m a n interferons derived h'om several types of human cells m a y exhibit dif- ferences in antigenic constitution" This finding was corroborated by Duc- GoI~A~ et al (28), who noted t~hat rabbit antiserum against white blood cell inter- feron did not neutralize the antivirM activity of human amniotic membrane inter- feron in monkey cells

A series of experiments employing affinity chromatography with interferon or anti-interferon globulins demonstrated t h a t there are indeed antigenic differences among human interferons An affinity column made of sheep antiserum against interferon from leukocytes did not bind a portion of the interferon activity pro- duced b y induced fibroblasts, although leukocyte interferon was completely re- tained b y the column (3) In contrast, Sepharose-couplcd rabbit antiserum against leukocyte interferon bound both leukocyte and fibroblast interferons (4) How- ever, an affinity column prepared with antiserum against fibroblast interferon retained only 4 percent of the activity of a leukocyte interferon preparation (4)

To explain these findings, BERG et al (4) suggested that a minor component with the specificity of fibroblast interferon was present in preparations of leukocyte interferon This hypothesis was supported by the work of HAVELL et al (48), who demonstrated t h a t antiserum against leukocyte interferon contains two physically separable antibody populations, one of which binds specifically to an affinity column of fibroblast interferon coupled to Sepharose This indicated t h a t there are

at least two antigenically distinct forms of interferon The major antigenic species

in leukocyte interferon was designated L~ interferon, while the main component

in fibroblast interferon was called F interferon (48) The two interferons are presently called g and ~, respectively (18)

When antisera monospecifie for ~ and ~ interferons became available, certain interferon preparations were shown to contai~ varying proportions of the two antigenic types of interferon Interferon induced in peripheral blood leukocytes by Sendal virus had primarily the antigenic specificity- of ~ interferon, with ~ inter- feron making up less than 1 percent of the total (4, 47) In contrast, ~ interferon comprised 10 to 20 percent of the total interferon activity produced b y the Namalva line of lymphoblastoid cells after virus stimulation, with the remMning interferon activity of the ~ antigenic type (i9, 53) Foreskin fibroblasts stimulated with poly (I) • poly (C) synthesized almost exclusively ~ interferon (49, 55)

Physicochemieal Properties

The g and ~ antigenic types of interferons exhibit certain similarities, as well as

m a n y differences, in their physicochemical characteristics The molecular weights

of both interferons fall in the same general range, close to 20~000 daltons B y mdleeular sieving techniques, ~ interferon appeared to be a homogeneous popula- tion with a molecular weight of 25,000 26,000 (6, 14, 38, 107) On sodium dodecyl snifate-polyacrylamide gel electrophoresis (SDS-PAGE), however; ~ interferon

Differences Between Human e and ~ Interferons 269

migrated as two fairly broad bands with molecular weights of 15,000 18,500 and 19,000 23,000 (7, 53, 88, 107, t11) Purified ~ interferon produced in lympho- btastoid cells was separated b y SDS-PAGE into multiple bands with a p p a r e n t molecular weights of 18,500 and 22,000; peptide mapping indicated the presence

of at least five different ~ interferon subspecies (2)

Crude fibroblast interferon was found to have a molecular weight of 26,000 b y sucrose density gradient ultracentrifugation (74) Purified ~ interferon migrated

as a single sharp peak of molecular weight 20,000 on SDS-PAGE (65, 99) I n cor~trast to ~ interferon, only one type of ~ interferon has been definitely identified

as yet However, the ~ interferon produced b y FS-4 tissue culture fibroblasts h a d

a different affinity for the ligand Blue Sepharose t h a n the ~ interferon synthesized

b y lymphoblastoid cells (37) Two distinct m R N A s coding for ~ interferon h a v e been isolated (85) Thus, there m a y be more t h a n one ~ interferon subspecies as well

Both ~ and ~ interferons are highly active molecules The specific activity of

a n d ~ interferons purified to near or complete homogeneity is in ~ h e range of

2 - - 8 × 10 s units per milligram of protein (65, 66, 82, 99, 118) By definition, a single unit of interferon has antiviral activity Thus, with estimated molecular weights

of 20,000, the two interferons are each active on cells at concentrations of about i0 -12 ~ I n some highly sensitive cell-virus systems (e.g., GM-258 cells infected with encephMomyocarditis virus), interferon activity is detectable at 10 -I4 M (J VILS~K, unpublished observations)

Studies with chemical reagents suggest t h a t intact disulfide bonds are essential

to the activity of both ~ and ~ interferons After reduction of disulfide bonds with

~-mereaptoethano], the two interferons lost antiviral activity (10, 76) Blockage

of the reduced sulfhydryl groups b y c a r b o x y m e t h y l a t i o n with iodoacetamide resulted in a further loss of activity for both interferons (76, 99) On the other hand, intact sulfhydryl groups are not likely to be necessary for the action of either interferon, as reagents such as p-ehloromercuribenzoate or N-ethyl- maleimide t h a t react with free sulfhydryl groups had no effect, on their activities (10, 76, 99)

Despite their general similarities in interactions with sulfur group reagents, and ~ interferons m a y differ when interacting with reducing agents in the presence of denaturants I n a boiling t percent SDS solution, ~ interferon was more stable in the presence of 1 percent ~-mercaptoethanol and 5 ~ Urea t h a n in their absence, whereas ~ interferon had the opposite characteristics (89, 111) The two interferons Mso have different patterns of reaction with several proteolytic enzymes Leueine amino peptidase inactivated a partially purified preparation of interferon to a greater extent t h a n a similar preparation of ~ interferon; e inter- feron was also much more sensitive t h a n ~ interferon to the actions of carboxy- peptidase A and chymotrypsin (80)

I n general, crude ~ interferon is more stable to heat t h a n crude ~ interferon (reviewed in r d 42) Preparations of ~ interferon were more rapidly inactivated

at 56 ° C t h a n preparations of e interferon (12) Studies on purified interferons are difficult to interpret, as t h e r m a l inactivation of both interferons is closely de- pendent on protein concentration, which is not always specified in published reports (65, 84.) However, pa,rtiallh- purified ~ interferon retained all of its antiviral activity

after three days at 56 ° C (75), while partially purified ~ interferon test 57 percent

of its activity in 24 hours at 37 ° C (84) Thus, it is likely that in the pure form interferon is more sensitive than ~ to the effects of high temperature

In addition, ~ interferon appears to be more susceptible to inactivation by mechanical stress than ~ interferon Vigorous stirring of a crude preparation of interferon resulted in about 80 percent loss of activity after five minutes (50) Rotation end-over-end in a stoppered tube (32) or revolving in a rotational visco- meter (11) largely inactivated ~ interferon, whereas z interferon was completely stable to the same treatments The effect seemed to be due to shear forces lead- ing to aggregation of protein molecules, rather than to adsorption to surfaces (10, 11)

Both ~ and ~ interferons attach to certain immobilized aromatic ligands The two interferons were retained by a column of the dipeptide L-tryptophyl-L-

t r y p t o p h a n covalently linked to agarose Each required ethylene glycol for elution, confirming the hydrophobic nature of the interaction (93) Nonetheless, there is evidence that ~ interferon has a higher intrinsic hydrophobicity than ~ interferon (64) After binding to the immobilized polyaromatic dye Cibacron Blue F 3 G A (Blue Dextran), ~ interferon could be eluted simply by increasing the ionic strength of the elution buffer, while ~ interferon was not released until after the addition of ethylene glycol (64) In addition, ~ but not ~ interferon bound to CH- Sepharose (63), L-tryptophyl agarose (93), and controlled-pore glass (33)

There is conflicting evidence on whether ~ interferon is a glycoprotein Treat- ment of ~ interferon with glycosidases resulted in a reduction in molecular weight

of all or part of the preparation (6, 7) and a changed pattern on isoeleetric focus- ing (6, 7, 80) Production of ~ interferon was impaired in the presence of the glycosylation inhibitors tunieamyein (13), glucosamine, and 2-deoxy-D-glueose (91) In addition, sodium periodate treatment of ~ interferon was reported to con- vert all of the interferon to the lower molecular weight form (90)

However, RUBr~ST~I~ et al (82) found at best a very small effect of sodium periodate on the 17,500 molecular weight species of ~ interferon There was little

or no binding of ~ interferon to Coneanavalin A, a ]ectin with specificity for D- mannose residues (21, 63, ¥ K YIP, personal communication) Nor did a inter- feron bind to lectins with affinity for fucose, galactose, N-acetyl neuraminic acid, N-acetylgalaetosamine, ~nd N-acety]glueosamine (63) Furthermore, glueosamine and galactosamine could not be detected in a purified preparation of lympho- blastoid interferon (2) Thus, there is no direct evidence for the presence of sugar residues in z¢ interferon, although it cannot be entirely ruled out at present The data on the glycosylation of ~ interferon are more clear-cut Inhibitors of glycosylation decreased the synthesis of biologically active ~ interferon (51) and elicited the appearance of a smaller molecular weight form of the interferon (52) Treatment of ~ interferon with glycosidases reduced charge heterogeneity and removed sialic acid and N-acetylglucosamine (6) ~ interferon was completely bound b y immobilized Concanavalin A (20, 21) In addition, after oxidation with periodic acid, purified ~ interferon stained with Fuchsin base, directly confirming the presence of carbohydrate (65) A portion of an acid hydrolyzate of purified interferon migrated coincidently with galactosamine and/or mannosamine standards (99) Thus, it appears quite certain that ~ interferon is a glyeoprotein

Differences Between Human ~ and ~ Interferons Biological Comparison of Human Interferons

271

Antiviral Activity on H u m a n Cells I n vitro The first indication t h a t human interferons from distinct sources showed dif- ferences in their biological activities came from a study by SUTTOZ¢ and TYRI~LL {95) Using crude preparations of interferon, they found that interferon produced

in amnion cells had antiviral activity in amnion cells but not in cells from the thyroid, embryonic lung, or kidney Subsequently it was realized t h a t ~ and interferons are both able to protect human fibroblasts against virus challenge, but patterns of antiviral activity differ for the two interferons I n human embryo fibroblasts, there was a difference in the slopes of the two dose-response curves (30) I n foreskin fibroblasts, the slopes of the dose-response curves for leukocyte and fibrobIast interferons were the same but the cells were much less sensitive

to leukocyte than t/o fibroblast interferon (25) Similarly, ~ interferon was general-

ly more efficient than ~ at inhibiting the yield of vesicular stomatitis virus in FS-4 foreskin fibroblast cells; development of the antiviral state was more rapid with interferon in these cells (41, 47)

As such studies indicate, the difference in activity between ¢~ and ~ interferons appears to be a characteristic of the cells employed in the assay system A direct comparison of cell strains showed t h a t ~ and ~ interferons had identical dose- response curves in U (human amnion) cells, but in FS-4 cells ~ interferon was more efficient t h a n c~ at producing the antiviral state (11 t) When a standard prepara- tion of ~ interferon was assigned an equal antiviral titer in both cell types, the relative titer of ~ interferon was about ten-fold higher in FS-4 cells than in U cells (59) This indicates that human cells can be preferentially sensitive to one or the other interferon type

Antiviral Activity on Heterologous Cells I n vitro The differential sensitivity to ~ and ~ interferons is even more pronounced in cells from several non-human species Some heterologous cells appear to be more re- sponsive to ~ interferon t h a n to ~ interferon Interferon induced in human foreskin fibroblasts by Newcastle disease virus was reported to be highly active on primary cultures of rabbit kidney cells, while NDV-induccd human leukocyte interferon had lower levels of activity on these cells (25, 26, 69) A parallel situation was found in rat cells Interferon produced in human amniotic membrane cell cultures induced an antiviral state in rat embryonic fibroblasts, whereas white blood cell interferon was inactive except at very high doses (28)

I n contrast, m a n y heterologous cells are more sensitive to the ~ type of inter- feron than to the ~ type H u m a n virus-induced leukocyte interferon had a con- siderably higher antivirat titer on several bovine and porcine cell cultures t h a n did interferon induced in human embryonic fibroblasts (44, 55) Similarly, a series

of feline cell lines was reported to be more sensitive to ~ than to ~ interferon (27)

I t should be noted t h a t cells from m a n y heterologous species are insensitive

to both c~ and ~ interfcrons (reviewed in ref 87)

Non-Antiviral Activities I n vitro Both ~ and ~ interferons are able to produce the non-antiviral activities as- sociated with interferon Leukocyte and fibroblast interferons were equally ef- fective in enhancing the toxic effect of poly ( I ) poly(C) on fibroblasts (22) Both types of interferon increased cytotoxic T cell activity (58, 117) and augmented the activity of natural killer cells (108, 116) When compared directly, ~ interferon from leukocytes or lymphoblastoid cells caused a similar increase in natural killer activity as ~ interferon from fibroblasts (57)

However, the two interferons show certain differences in their non-antivirat actions, especially in their ability to inhibit the multiplication of cells HILFEN-

~A~rS et al (60) observed t h a t the slopes of the dose-response curves for growth inhibition b y ~ and ~ interferons in Daudi cells were different, although the amounts of the two interferons needed for 50 percent growth inhibition were close Later, it was shown t h a t c~ interferon inhibited the multiplication of Daudi cells and another lymphoblastoid cell line to a greater extent t h a n ~ interferon (34) Similarly, g interferon was more inhibitory t h a n ~ to the growth of myeloid progenitor cells (110)

I n contrast, ~ interferon was more effective t h a n ~ at suppressing the growth

of two osteosarcoma lines (34), virus transformed h u m a n embryo fibrohlasts (68), and several non-transformed fibroblast strains (97) ~ interferon prolonged the G1 stage in the life cycle of h u m a n fetal skin fibroblasts more strongly t h a n did interferon (71) Thus, as firs~ suggested by EINI~oR~ and STI~ANDEg (3~), the capacity of interferon to inhibit growth m a y be tissue specific: c< interferon could

be more effective on lymphoid eells, whereas ~ interferon m a y act preferentially

on cells of fibroblast origin

Activity o / H u m a n Inter/eron In vivo

I n the living organism as well as in vitro, ~ and ~ interferons differ in certain

of their characteristics When injected intravenously into rabbits, serum levels of and ~ interferons were comparable (5, 112) However, after intramuscular in- jection, the circulating levels of ~ interferon were higher t h a n those achieved with ~ interferon (5, 46, 112) An analogous situation m a y exist in man, as after intramuscular administration of 3 × 106 units, ~ interferon was not detectable in the circulation (31) ; the same amount of c~ interferon produced good serum levels when administered intramuscularly or intravenously (35)

I n the limited n u m b e r of clinical trials t h a t have been r u n with interferon, a few studies have directly compared the efficacy of ~ a n d ~ interferons SCUD-

MACgER et al (94) tested the two interferons applied topically after debridement for t h e r a p y of dendritic keratitis They concluded t h a t there was no significant difference in the clinical healing curve for ~ and ~ interferons Upon closer ex- amination of the data, however, it appears t h a t the more resista:at infections took longer to heal with ~ interferon WEIMA~ et al (113) treated three patients with HBsAg-positive chronic active hepatitis sequentially, for two weeks each, with and ~ interferons ~ interferon induced a decrease in serum transaminase activity,

b u t a consistent decline in D N A polymerase was seen only with ~ interferon As the interferons were administered intramuscularly in this study and serum inter-

Differences Between Human e and ~ Interferons 273

feron levels were not specified, the possible difference in circulating interferon levels makes comparison of the effects of ~ and, ~ interferons difficult Other clinical trials using ~ and ~ interferons for the sam~ disease usually differed in their experimental protocols (reviewed in refs 29 a n d ~7) and so cannot be directly compared

Geneties of the Interferon System

Sensitivity to ]nter/eron Action

Several laboratories have investigated what determines a cell's capacity to develop an antiviral state after t r e a t m e n t with interferon The first indication

t h a t interaction with interferon is determined b y a chromosomM locus came from studies with somatic cell hybrids As hybrid cells derived from the fusion of rodent and h u m a n cells often tend to preferentially segregate h u m a n chromosomes, one

m a y correlate a specific phenotype with the presence or absence of particular

h u m a n chromosomes (discussed in ref 83)

Using mouse-human hybrids, T A x et al (104) demonstrated t h a t the antivirM

protection induced b y interferon was syntenic with expression of the enzyme indophenol oxidase and concordant with the presence of chromosome 21 When

h u m a n fibroblasts containing one, two or three copies of chromosome 21 Were tested for their ability to develop an antivirM state after t r e a t m e n t with inter- feron, a clear gene dosage effect was apparent (17, 96, 102) With the aid of fibre- blasts containing translocations of parts of chromosome 21, it was demonstrated

t h a t the gene(s) for interferon sensitivity is (are) located on the long a r m of chromosome 21 (36, 101) l~esponses to ~ and ~ interferons have both been local- ized to this region (36, 97, 98)

The interferon-related gene functions specified b y chromosome 21 are still in dispute TAn- and his colleagues suggested t h a t chromosome 21 codes for an anti- viral protein t h a t inhibits the translation of exogenous m R N A (96, 102, 104): A more likely expla.nation, however, is t h a t chromosome 21 codes for an interferon receptor on the cell m e m b r a n e (16, 17, 81)

The latter hypothesis is supported b y several lines of evidence AGv~T (t) demonstrated t h a t mouse interferon binds specifically and with high affinity to a receptor on the surface of mouse L 1210 cells A wealth of indirect evidence sug- gests t h a t a similar receptor exists for h u m a n interferon (summarized in ref 87) The involvement of chromosome 21 in production of the interferon receptor was suggested in a s t u d y employing mouse antiserum raised against a m o u s e - h u m a n hybrid cell line containing h u m a n chromosomes 4, 21, and 22 The antiserum was adsorbed on hybrid cells containing h u m a n chromosomes 4 and 22 to eliminate reaction to cellular antigens coded b y these two chromosomes Preincubation with the adsorbed antiserum inhibited the subsequent a n t i v i r a l response of

h u m a n fibroblasts to interferon, indicating t h a t chromosome 21 codes for a cell- surface antigen (81) The hypothesis t h a t this antigen was an interferon receptor

is supported b y the finding t h a t cells with trisomy 21 bound more interferon t h a n normal diploid cells, and a smaller amount still was bound b y cells with mono- somy 21 (115)

At this point, there is no evidence as to whether h u m a n 0¢, ~, and y interferons share a common receptor on the cell surface This type of information should be- come available as soon as pure preparations of interferon are readily obtainable

Production o/ Inter/eron

Information on the chromosomal location of the genes for the production of interferon is more complex than t h a t for sensitivity to its action At present, there are conflicting data on the exact chromosomal location of interferon production Studies with somatic cell hybrids and aneuploid cells established that the ability

to produce interferon was asyntenic with sensitivity to its antiviral action (17, 102) Working with mouse-human hybrids, TA~- et al (t00) concluded t h a t chromosomes 2 and 5 together were necessary for the production of h u m a n inter- feron This result was confirmed with a series of hamster-human hybrids (C C~IANY, cited in ref 103) However, with other rodent-human hybrids, it was determined that chromosome 2 (86), chromosome 5 (77, 86) and/or chromosome 9 (9, 72, 73) each contained information sufficient for the production of h u m a n interferon The sites were further localized to the long arm of chromosome 2 (86), the short arm of chromosome 5 (86), the long arm of chromosome 5 (98, 103),

or the short arm of chromosome 9 (9)

The human interferon produced by these hybrids was identified as ~ inter- feron, based on its reaction with specific anti-interferon sera and its activity on heterologous cells (73, 86) The chromosomal loci for the production of ~ and ?, interferons have not been determined,

Conelusions

I n this review information obtained with native human c¢ and ~ interferon molecules was presented A summary of this and other data is s h o ~ a in Table i

A great deal of additional information is now emerging from cloning studies For instance, there is a substantial amount of homology in the amino acid sequence of and ~ interferons (92, 105) The resemblance m a y extend to the level of second-

a r y structure (54) I n addition, h u m a n genc bank analysis indicates that there are

at least eight distinct genes for ~ interferon (78) c~ interferon subspecies differ not only in structure but in some of their biological properties (92)

Table 1 Some distinguishing properties o] I_FN.u (leukocyte) and ItZN -~ (]ibroblast)

Activity in bovine EBTr cells

Rate of induction of antiviral state

Stability after 0.1 percent SDS

Binding to ConA-Sepharose

Binding" to hydrophobic ligands

Susceptibility to mechanical stress

Approximate pI

Number of known subspecies

Stable Partially stable Mostly not bound Binds

5.0 to 7.0 6.5

Differences Between H u m a n u and ~ Interferons 275

S u c h r e s e a r c h opens u p a n e n t i r e l y n e w a r e a for f u t u r e s t u d y W h a t is t h e

f u n c t i o n a l significance of each of t h e i n t e r f e r o n t y p e s ? One p o s s i b i l i t y is t h a t t h e

d i f f e r e n t i n t e r f e r o n s could h a v e d i s t i n c t sites of a c t i o n w i t h i n t h e o r g a n i s m F o r

e x a m p l e , ~ i n t e r f e r o n c o u l d p e r f o r m s y s t e m i c f u n c t i o n s w h e r e a s ~ i n t e r f e r o n m a y

a c t l o c a l l y n e a r t h e site of synthesis Or, each of t h e i n t e r f e r o n subspecies could

h a v e a f i x e d t a r g e t t i s s u e or o r g a n specificity T h e t w o i d e a s a r e n o t m u t u a l l y ex- clusive, as s e v e r a l ~ i n t e r f e r o n species a r e p r o d u c e d c o n c u r r e n t l y i n r e s p o n s e t o a single s t i m u l u s (2) a n d so could p r o t e c t a n e n t i r e o r g a n i s m On t h e o t h e r h a n d , t h e

v a r i o u s i n t e r f e r o n t y p e s could p r o t e c t t h e h o s t a g a i n s t challenge b y d i f f e r e n t viruses

T h e s e q u e s t i o n s a r e l i k e l y t o b e a d d r e s s e d in t h e v e r y n e a r f u t u r e w i t h t h e a i d

of s o p h i s t i c a t e d b i o c h e m i c a l t e c h n i q u e s A f t e r i d e n t i f i c a t i o n a n d sequencing of

t h e D N A for atl of t h e i n t e r f e r o n s a n d p r o d u c t i o n of s u f f i c i e n t l y large a m o u n t s

of t h e v a r i o u s i n t e r f e r o n p r o t e i n s , r e s e a r c h in t h i s a r e a will be g r e a t l y f a c i l i t a t e d

Aeknowledflments

I would like to t h a n k Dr J a n VilSek for helpful advice and discussion T G H

is s u p p o r t e d b y Medical Scientist Training Grant GM-07308 from the National

I n s t i t u t e s of Health

Referenees

1 AGUET, M : High-affinity binding of l~I-labelled mouse interferon to a specific cell surface receptor N a t u r e 284, 459 461 (1980)

2 A L L E N , G., F A N T E S , K i.: A family of structural genes for h u m a n l y m p h o - blastoid (leukocyte-type) interferon N a t u r e 287, 408 411 (1980)

3 A N F I N S E N , C B., B O S E , S., C O R L E ¥ , L., G U R A a I - R O T ~ A ~ , I) : 10artial purifica- tion of h u m a n interferon b y affinity c h r o m a t o g r a p h y Proe Nat Aead Sci U.S.A 71, 3139 3142 (1974)

4 BER~, K., OGBUR~, C A., PAUC~ER, K., MOGENSE~, K E., CAZ*~:ELL, K : Affin-

i t y c h r o m a t o g r a p h y of h u m a n leukocyte and diploid cell interferons on Sepharose- bound antibodies J I m m u n o l 114, 640 644 (1975)

5 BILLIAU, A., D E S O M E R , P., E D ¥ , V G., D E C L E R C Q , E., I-IEEEMANS, H : H u m a n fibroblast interferon for clinical trials: Pharmacokineties a n d tolerability in experimental animals a n d h u m a n s Antimicrob Agts C h e m o t h e r 16, 5 6 - 6 3 (1979)

6 BOSE, S., GURAR.I~RO~AN, D., R~'EGG, U T., CoR.IaS¥, L., ANFINSE~ ~, C B :

A p p a r e n t dispensability of the c a r b o h y d r a t e m o i e t y of h u m a n interferon for

a n t i v i r a l activity J biol Chem 251, 1659 1662 (t976)

7 BRIDGEI~-, 1 ° J., A N F I N S E N , C B., C O R L E Y , L., B O S E , S., Z O O N , I~ C., RI~EGG,

U T., B U C K L E R , C E : H u m a n lymphoblastoid interferon L a r g e scale produc- tion a n d partial purification J biol C h e m 252, 6 5 8 5 - - 6 5 8 7 (1977)

8 B U I M O V I C I - K L E I N , E., W E I S S , E., C O O P E R , L Z.: Interferon production in

l y m p h o c y t e cultures after rubella infection in h u m a n s J inf Dis 135, 3 8 0 - - 3 8 5 (1977)

9 B U R K E , I) C., M E A G E R , A.: Genetic control of interferon formation A n n N Y Acad Sci 350, 179 -187 (1980)

10 CAR~WRIGHT, T., SE~rUSSI, O., GRADY, M I) : Reagents which inhibit disulphide

b o n d formation stabilize h u m a n fibroblast interferon J gem Virol 36, 323 327 (1977)

11 CJkRTWI%IC-HT, T., SELNUSSI, 0 , GI~AD¥, M I) : The mechanism of the inactivation

of h u m a n fibroblast interferon b y mechanical stress J t e n Virol 36, 317 321

12 CESARIO, T C., SCHRYEa, P J., TILL~S, J G : Relationship bet, ween the physico- chemical nature of h u m a n interferon, the cell induced, and the inducing agent Antimicrob Agts Chemother 11, 291 298 (1977)

13 CI-IADHA, K C., GROB, P M., HAMILL, R L., SULKOWSKI, E : Glycosylation of

h u m a n leukocyte interferon: Effects of Tunieamycin Arch ViroI 64, 109 117 (1980)

t4 C~AD~A, K C., SCLAm, M., SLu, KowsI~I, E., CARTER, W A.: Molecular size heterogeneity of h u m a n leukocyte interferon Biochem, 17, 196 200 (1978)

15 CI4ANY, C : l~Tn facteur inhibiteur de la multiplication intraeellulaire des virus rappelant l'interfgron, p r o v e n a n t de cellules canc6reuses Le ph6nom~ne d'auto- inhibition vJrale C R Acad Sei 150, 3903 3905 (1960)

16 CI~AN¥, C.: Membrane-bound interferon specific cell receptor system: l~ole in the establishment and amplification of the antiviral state Biomedicine 24, 148

to 157 (1976)

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