Department of Pathobiology, Texas A&M University Agricultural Experiment Station, San Angelo, TX, USA1
Department of Animal Science, Texas A&M University, College Station, TX, USA2
USDA/ARS Roman L. Hruska US Meat Animal Research Center, Clay Center, NE, USA3
Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX, USA4
Author for correspondence: Andrés de la Concha-Bermejillo. Present address: Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4467, USA. Fax +1 409 845 9231. e-mail adelaconcha{at}cvm.tamu.edu
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Chemotherapy during the early phase of HIV infection offers the opportunity to reduce lentivirus load in macrophages and lymphoid organs, therefore delaying the outcome of HIV-induced disease (Koup & Ho, 1994 ; Ho, 1996
). However, due to the emergence of drug-resistant HIV strains and the toxic side effects associated with continuous treatment of immuno-compromised patients (Carpenter et al., 1998
), alternative anti-retroviral drugs need to be developed.
Interferon- (IFN-
) is a multi-functional cytokine secreted by trophectoderm of ruminant conceptuses that has antiviral activity in vitro against HIV, feline immunodeficiency virus and OvLV (Pontzer et al., 1988
, 1997
; Dereuddre-Bosquet et al., 1996
; Juste et al., 1996
). In addition, IFN-
has antiproliferative and immuno-modulatory properties similar to those of classical type I IFNs (
,
and
), but has low cytotoxicity even at the high levels found within the uterus during early pregnancy (Dereuddre-Bosquet et al., 1996
; Bazer & Johnson, 1991
; Pontzer et al., 1991
). The unique antiviral and cell-friendly properties of IFN-
suggest that it may be useful as a therapeutic agent for treatment of lentivirus infections. The objective of the present study was to characterize the effects of recombinant ovine (ro) IFN-
on OvLV replication and the progression of disease.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cell-associated viraemia titres were determined every other week by an end-point dilution method. The OvLV serum antibody response was determined weekly by the AGID test and by ELISA. All experimental lambs were killed at 27 weeks p.i. and complete necropsies were performed. At this time, histological sections of lung were examined and scored for the degree of LIP and bronchus-associated lymphoid tissue (BALT).
Virus.
OvLV strain 85/34, a purified biological clone classified as lytic (rapid/high), was used for these experiments (Lairmore et al., 1988 ; de la Concha-Bermejillo et al., 1995b
). OvLV 85/34 was grown in primary cell cultures of mycoplasma-free goat synovial membrane (GSM) cells. Cells were propagated in Dulbeccos modified Eagles medium containing 10% foetal bovine serum, 100 U/ml penicillin, 100 µg/ml streptomycin and 2 µM L-glutamine (de la Concha-Bermejillo et al., 1995b
). The titre of the virus inoculum was calculated by the SpearmanKarber method (Villegas & Purchase, 1989
).
roIFN-
.
roIFN- was derived from a synthetic gene in P. pastoris (Ott et al., 1991
). It was harvested from the culture supernatant, concentrated tenfold by using Amicon Ultrafilters and a YM10 membrane at 4 °C and dialysed against 100 vols 10 mM TrisHCl (pH 7·5) at 4 °C. After purification by sequential ion exchange and size exclusion chromatography, proteins were visualized by Coomassie brilliant blue staining. roIFN-
was identified by immunoblotting with a rabbit polyclonal antiserum raised against native oIFN-
(Ott et al., 1991
). The proteins recovered from the supernatants of non-transformed P. pastoris cultures were used as the control material in our experiments.
Antiviral assay.
The antiviral activity of roIFN- was measured in the CPE inhibition assay described previously (Pontzer et al., 1988
), with MadinDarby bovine kidney (MDBK) cells challenged with vesicular stomatitis virus (VSV). Results were adjusted on the basis of results from a laboratory reference standard of a hybrid recombinant human IFN-
1/IFN-
8 kindly supplied by CibaGeigy which was run in parallel. One unit of antiviral activity (AVU) was defined as the reciprocal of the IFN dilution at which this standard reduced the CPE of VSV by 50%. The specific antiviral activity of roIFN-
produced in P. pastoris was 0·51x108 units/mg, similar to that of roIFN-
produced in S. cerevisiae (Ott et al., 1991
).
Virus isolation and titration.
OvLV was isolated and titrated from experimental animals as described previously (Juste et al., 1998 ). Briefly, every other week throughout the experiment, beginning before inoculation, Ficoll-separated peripheral blood mononuclear cells (PBMNC) were counted, aliquoted and inoculated both into disposable 25 cm2 tissue culture flasks and into 96-well tissue culture plates with confluent GSM cell monolayers. Tissue culture flasks were inoculated with 4x106 PBMNC per flask. Ninety-six well plates were inoculated with twofold dilutions of PBMNC ranging from 1·6x106 to 0·025x106 PBMNC per well (three wells per dilution). Cell co-cultures were maintained at 37 °C in a 5% CO2 atmosphere. After overnight incubation, non-adherent cells were removed by washing with Hanks balanced salt solution (HBSS) and adherent cells were incubated for 12 more days. At the end of this period, cells were washed with HBSS, fixed in methanol and stained with Giemsa. Flasks and wells were scored as positive or negative for syncytium formation, with a positive score being at least one cell containing five nuclei. The minimum number of syncytium-inducing PBMNC per million (Ficoll-separated PBMNC) was calculated as described previously (Juste et al., 1998
). At the time of necropsy, caudal mediastinal lymph node (CMLN) cells and bronchoalveolar lavage (BAL) cells were collected and OvLV was titrated in these cells as for PBMNC.
ELISA.
An ELISA was used to determine the antibody responses to the transmembrane (TM) and p25 OvLV structural proteins as described previously (Kwang et al., 1993 ). Briefly, microtitre plates were coated with 120 µg per well recombinant TM or p25 in 0·1 M sodium bicarbonate buffer (pH 9·6) and kept at 4 °C until further use. The plates were then washed three times in ELISA washing solution (0·15 M NaCl, 0·05% Tween 20) and excess binding sites were saturated with 100 µl 1% BSA in PBS (pH 7·2, 0·15 M) for 1 h at 37 °C. After three washes, 100 µl diluted sheep serum (1:50) in 1% BSA buffer was added to each well and plates were incubated at 37 °C for 1 h. After a subsequent washing of the wells, 100 µl anti-sheep immunoglobulin conjugated to horseradish peroxidase was added to each well and plates were incubated at 37 °C for 1 h. Wells were washed again and 100 µl substrate solution [citric acid; 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid); H2O2] was added. The colour reaction was allowed to proceed at room temperature for 30 min and the A405 of each well was determined by using an automatic ELISA plate reader.
Gross and histological assessment of lesions.
Twenty-seven weeks after inoculation, complete necropsies were performed on all lambs and macroscopic changes were recorded. Tissues for histology were fixed in 10% buffered neutral formalin solution, sectioned at 5 µm and stained with haematoxylin and eosin. The left lung was excised and insufflated with 10% buffered formalin solution at 30 cm of water pressure for 48 h before sectioning. Five lung sections from each lamb taken at the same places (ventral cranial lobe, ventral intermediate lobe, dorsal intermediate lobe, ventral caudal lobe and dorsal caudal lobe) were examined at 200x magnification and scored for four criteria in a logarithmic scale as follows. Presence of areas of interstitial pneumonia and of lymphoid perivascular or peribronchial infiltrate resulted in a score ranging from 0 to 32 in twofold steps. Presence of lymphoid follicles not associated with airways or blood vessels was considered to be the most specific lesion and was assigned the heaviest weight in the scoring (0, no lymphoid follicles; 24, 110 follicles per section; 48, more than 10 follicles per section). The final score for each section was determined by calculating a geometric mean for all four criteria. As a result, histopathological lesions were represented by a single score based on five replicate measurements per lamb.
Analysis of results.
Number of infected cells per million cells, ELISA A405 readings and the histopathological score from each lamb were transformed into logarithms and data were subjected to analysis of variance to determine differences in virus titrations from PBMC, BAL and CMLN, antibody responses and severity of lesions between treated and untreated lambs (SAS Institute Inc., version 6). Pearson correlations between pairs of variables were also calculated to evaluate the sign and significance of their relationship.
In most analyses, the control lambs for evaluating the effects of roIFN- treatment on OvLV infection were the infected, placebo-treated lambs. However, for analyses of effects on virus isolation during the first 16 weeks, results from both placebo- and late roIFN-
-treated groups were pooled into a single control group of 12 lambs, since the late-treated lambs did not receive roIFN-
during the first 16 weeks. This provided a larger sample size to evaluate the natural course of infection and reduced the variance. From the week the late-treatment lambs began receiving roIFN-
up to and including the end of the experiment, the control group was reduced to the six lambs that had only received non-transformed yeast supernatant.
Finally, the efficiency of the treatments on virus burden was estimated according to the following formula: percentage reduction=100(Vc-Vi)/Vc, where Vc is the mean viraemia in the control group and Vi is the mean viraemia in the treated group. A similar method was used to compare the effects of treatment on the severity of lesions, but in this case the mean score for uninfected lambs was subtracted from the mean of each group of infected lambs before calculating the percentage reduction.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
OvLV was never isolated from lambs in the mock-infected groups. On the other hand, OvLV was isolated from PBMNC on at least one occasion for all OvLV-inoculated lambs. The overall mean cell-associated viraemia titre was lower in the early roIFN- treatment group than in the late roIFN-
and placebo treatment groups (P<0·01). The pool of OvLV-infected lambs not receiving early roIFN-
treatment showed a peak in mean cell-associated viraemia titre between weeks 2 and 8 p.i., with the mean being greatest at week 2 p.i. (Fig. 1
). A 90% reduction in mean cell-associated viraemia was found at week 4 of the experiment in lambs that received early roIFN-
treatment when compared with the lambs not receiving early roIFN-
treatment (P<0·01). Lower (P<0·05) mean virus titres were also detected in the early roIFN-
-treated lambs at weeks 2 and 6. An increase in mean cell-associated viraemia titre was detected in the early roIFN-
-treated lambs 2 weeks after the roIFN-
treatment regime was changed from daily to twice a week (week 6). In both roIFN-
-treated and control lambs, the mean cell-associated viraemia titre declined by week 8 of the experiment. At week 18, 2 weeks after the late roIFN-
treatment group started to receive daily roIFN-
, a reduction in cell-associated viraemia was detected in this group when compared with the group receiving no roIFN-
. However, because viraemia titres were low in all groups at this time, the differences were not significant (P>>0·05). An increase in cell-associated viraemia titre was found in the late roIFN-
-treated group 3 weeks after the roIFN-
treatment regime was changed from daily to twice a week. The mean number of infected cells per million cells (ICMC) in the early roIFN-
-treated lambs at week 4 p.i. was 0·096, compared with 3·898 in the placebo-treated lambs. At week 22 p.i., when the maximum difference in cell-associated viraemia titre between late-roIFN-
- and placebo-treated lambs was observed, the mean number of ICMC was 0·005 for the former and 0·076 for the latter. Throughout the experiment, the highest mean number of ICMC was observed in the placebo-treated lambs during weeks 28 (range 2·2654·358).
|
All OvLV-infected lambs seroconverted by week 6 p.i., as determined by the AGID test, and remained seropositive until the end of the experiment. Precipitating antibodies were not detected in serum from any of the mock-infected lambs during the course of this experiment. Weekly mean ELISA A405 in the OvLV TM antibody assay increased slowly over time in all OvLV-infected groups (Fig. 2), and differences from the mock-infected lambs (controls not shown in graph) were significant (P<0·05) by week 5 p.i. The overall mean TM ELISA A405 was lower (P<0·05) in the early roIFN-
-treated group than in the late roIFN-
- and placebo-treated lambs. Weekly mean ELISA A405 in the OvLV p25 antibody assay also increased over time in all OvLV-infected groups, and became significant (P<0·05) in the mock-infected lambs by week 3 p.i. (data not shown). The overall mean p25 ELISA A405 was lower (P<0·05) in the late roIFN-
-treated lambs than in the early roIFN-
- and placebo-treated lambs. However, no differences (P<0·05) in weekly mean p25 ELISA A405 were detected between roIFN-
- and placebo-treated lambs.
|
Histologically, varying degrees of perivascular and peribronchiolar lymphoid infiltration or lymphoid follicles were observed in some lung sections from all groups. Lymphoid follicles not associated with airways were specific to OvLV-infected groups. Histopathological scoring of lung sections revealed no differences in the degree of mononuclear cell infiltration between the OvLV-infected, early roIFN--treated and mock-infected lambs. However, the degree of lung inflammation was more severe (P<0·01) in the OvLV-infected, placebo-treated and in the OvLV-infected, late roIFN-
-treated lambs than in the OvLV-infected, early roIFN-
-treated and mock-infected lambs (Fig. 3
). There were no differences (P<0·01) in histopathological scores between OvLV-infected, placebo-treated and OvLV-infected, late roIFN-
-treated lambs. After subtraction of the mean score for the mock-infected group, the OvLV-infected group that received early roIFN-
-treatment showed a reduction of 100% in histopathological score in comparison with the OvLV-infected, placebo-treated group. The late treatment group showed no reduction in histopathological score.
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A mild reduction in cell-associated viraemia titre was observed 2 weeks after daily roIFN- treatment was started in the late roIFN-
group (at week 16); however, because viraemia titres had already declined to a minimum in all groups as a result of the normal immune response against OvLV, differences among treatment groups were not significant. Nevertheless, daily treatment with roIFN-
starting 4 months after infection did not have significant beneficial effects on virus-induced LIP. The majority of HIV-infected individuals go through an acute phase of viraemia during the first few weeks after primary infection (Koup & Ho, 1994
; Pantaleo et al., 1994
; Daar et al., 1991
), when HIV is widely disseminated throughout the lymphoid system by infected macrophages (Pantaleo et al., 1993
). Subsequently, a specific HIV immune response leads to a decline in viraemia (Koup et al., 1994
). Therefore, reducing the initial peak of viraemia in the few weeks following infection is critical for preventing or delaying the pathological outcome of lentivirus infections.
In both early and late roIFN- treatments, mean viraemia titres increased after the frequency of treatment was changed from daily to biweekly, indicating that daily treatment is necessary to maintain a low virus load. Lentivirus biological clones, such as OvLV 85/34, are composed of a multitude of genetically diverse virus types or quasispecies (Cichutek et al., 1992
; Woodward et al., 1995
). The fact that roIFN-
did not give 100% inhibition of OvLV may suggest that some virus types within the strain are resistant to roIFN-
treatment. It is possible that roIFN-
treatment exerts selective pressure for replication of the resistant virus types. Primary isolates of HIV derived from donors at various stages of infection display a broad range of sensitivity to IFN-
2 (Kunzi et al., 1995
), but the prevalence of IFN-
2 resistance was low in the absence of AIDS and increased dramatically once the infection progressed to AIDS. For these reasons, further experiments are necessary to determine the role of roIFN-
-resistant virus types in lentivirus-induced disease and immune responses.
In the present study, individual viraemia titres were positively correlated with LIP scores, confirming previous observations that viraemia levels can predict disease progression in lentivirus infections (Katzenstein et al., 1996 ). The antibody response against OvLV TM protein was significantly lower in lambs that received the early roIFN-
treatment, suggesting that initial viraemia influences the magnitude of the antibody response against this protein. The antibody response to OvLV TM protein was also correlated positively with LIP scores. A previous report also suggested that the humoral response in OvLV infection plays a role in disease development (Petursson et al., 1992
). Therefore, the beneficial effect of early roIFN-
treatment may include reducing virus load, decreasing the TM antibody response and reducing immunopathology. Because the relationship between cell-associated viraemia and antibody response against OvLV p25 protein was negative, the reduction in anti-TM antibody levels was not likely to be the result of a suppressed humoral response caused by roIFN-
.
The levels of TM antibody were correlated positively with viraemia titres and lung lesions, suggesting that this antibody response may be used as a surrogate marker to estimate virus load and the outcome of OvLV-induced lung pathology. However, the relationship between TM antibody levels and viraemia titres is best described by a second-degree equation, because it is positive up to a transformed viraemia titre of approximately 0·35 and a transformed TM A405 of approximately 0·6, but thereafter the relationship becomes negative. Although OvLV does not cause clear immunodeficiency, as seen in humans with AIDS, opportunistic infections often occur during the terminal stages of this infection (de la Concha-Bermejillo, 1997 ). Therefore, the relationship between viraemia and TM antibody response suggests that OvLV may overwhelm the humoral response in sheep with extremely high virus load. In fact, other immune disregulations such as reduced delayed hypersensitivity reactions (Myer et al., 1988
; Pyrah & Watt, 1996
), failure of IgG2 response to the virus (Bird et al., 1995
), depressed levels of lymphocyte-generated interleukin-2 (Ellis & DeMartini, 1985a
), impaired pulmonary lymphocyte activation (Begara et al., 1995
) and decreased concanavalin A-induced activity of suppressor cells (Ellis & DeMartini, 1985b
) have been reported for OvLV-infected sheep. It is possible that opportunistic infections associated with OvLV-infection may be the result of a compromised immune function.
Virus load in BAL cells may correlate with the degree of LIP (de la Concha-Bermejillo et al., 1995b ; Brodie et al., 1992
), but the virus load in BAL cells was not decreased by roIFN-
treatment in the present study. However, virus load was highest in BAL cells in late roIFN-
-treated lambs, followed by early roIFN-
-treated and placebo lambs. Because treatment was administered subcutaneously, the concentration of roIFN-
in the alveolar space may have been limited. In addition, treatment with roIFN-
alters the integrity of the surface coat of pulmonary intravascular macrophages (PIMs), causing their disappearance from the lungs (Singh et al., 1998
). The same report showed that PIMs, cells that are not obtained regularly in lung lavages, play a role in lentivirus-induced lung pathology. Thus, the lack of LIP in lambs treated with roIFN-
early after OvLV infection may have been due in part to the effects of this cytokine on PIMs rather than on alveolar macrophages. In the case of CMLN, the early roIFN-
treatment group had the lowest virus load, followed by the late roIFN-
treatment group and then the placebo treatment group. While these differences were not significant (P>>0·05), the virus load in CMLN cells correlated positively with viraemia levels. Although the lung is the main target organ for OvLV-induced pathology, the impact of treatment in lentivirus infections can be better assessed in lymphoid tissue reservoirs, where most of the virus is produced in macrophages and stored in immune complexes on the surface of follicular dendritic cells (Cavert et al., 1997
). In HIV infection, the pool of virus on follicular dendritic cells is at least an order of magnitude greater than that in mononuclear cells (Haase et al., 1996
).
In summary, the results of this experiment demonstrated clearly that early roIFN- treatment decreased OvLV replication in vivo and prevented development of lentivirus-induced LIP. Although human recombinant IFN-
is active in vitro against HIV (Kornbluth et al., 1990
; Gendelman et al., 1990
) and has beneficial effects in the treatment of HIV-related Kaposis sarcoma and early HIV infection (Francis et al., 1992
; Lane, 1991
; Stuart-Harris et al., 1992
), treatment with rIFN-
also results in a high incidence of toxic side effects (Lane et al., 1990
). Because of its low toxicity and potent antiviral activity, roIFN-
may prove to be a promising new IFN therapy to delay the pathological outcome of lentivirus infections. However, because roIFN-
treatment did not reduce OvLV viraemia below the limit of detection, its effectiveness in combination with other antiretroviral agents needs to be investigated.
![]() |
Acknowledgments |
---|
![]() |
Footnotes |
---|
c Present address: Department of Animal and Veterinary Science, 216 Ag. Sci. Bldg, University of Idaho, Moscow, ID 83844-2330, USA.
d Present address: Institute of Molecular Agrobiology, 1 Research Link, National University of Singapore, Singapore 117604.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bazer, F. W. & Johnson, H. M. (1991). Type I conceptus interferons: maternal recognition of pregnancy signals and potential therapeutic agents. American Journal of Reproductive Immunology 26, 19-22.
Begara, I., Lujan, L., Hopkins, J., Collie, D. D., Miller, H. R. & Watt, N. J. (1995). A study on lymphocyte activation in maedi-visna virus induced pneumonia. Veterinary Immunology and Immunopathology 45, 197-210.[Medline]
Bird, P., Reyburn, H. T., Blacklaws, B. A., Allen, D., Nettleton, P., Yirrell, D. L., Watt, N., Sargan, D. & McConnell, I. (1995). The restricted IgG1 antibody response to maedi visna virus is seen following infection but not following immunization with recombinant gag protein. Clinical and Experimental Immunology 102, 274-280.[Medline]
Brodie, S. J., Marcom, K. A., Pearson, L. D., Anderson, B. C., de la Concha-Bermejillo, A., Ellis, J. A. & DeMartini, J. C. (1992). Effects of virus load in the pathogenesis of lentivirus-induced lymphoid interstitial pneumonia. Journal of Infectious Diseases 166, 531-541.[Medline]
Carpenter, C. C., Fischl, M. A., Hammer, S. M., Hirsch, M. S., Jacobsen, D. M., Katzenstein, D. A., Montaner, J. S., Richman, D. D., Saag, M. S., Schooley, R. T., Thompson, M. A., Vella, S., Yeni, P. G. & Volberding, P. A. (1998). Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society USA Panel. Journal of the American Medical Association 280, 78-86.
Cavert, W., Notermans, D. W., Staskus, K., Wietgrefe, S. W., Zupancic, M., Gebhard, K., Henry, K., Zhang, Z. Q., Mills, R., McDade, H., Schuwirth, C. M., Goudsmit, J., Danner, S. A. & Haase, A. T. (1997). Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276, 960-964.
Cichutek, K., Merget, H., Norley, S., Linde, R., Kreuz, W., Gahr, M. & Kurth, R. (1992). Development of a quasispecies of human immunodeficiency virus type 1 in vivo. Proceedings of the National Academy of Sciences, USA 89, 7365-7369.[Abstract]
Coffin, J. M., Essex, M., Gallo, R., Graf, T. M., Hinuma, Y., Hunter, E., Jaenisch, R., Nusse, R., Oroszlan, S., Svoboda, J., Teich, N., Toyoshima, K. & Varmus, H. (1995). Family Retroviridae. In Virus Taxonomy. Sixth Report of the International Committee on Taxonomy of Viruses, pp. 193-204. Edited by F. A. Murphy, C. M. Fauquet, D. H. L. Bishop, S. A. Ghabrial, A. W. Jarvis, G. P. Martelli, M. A. Mayo & M. D. Summers. Vienna & New York: Springer-Verlag.
Cutlip, R. C., Jackson, T. A. & Lehmkuhl, H. D. (1979). Lesions of ovine progressive pneumonia: interstitial pneumonitis and encephalitis.American Journal of Veterinary Research 40, 1370-1374.[Medline]
Cutlip, R. C., Lehmkuhl, H. D., Schmerr, M. J. & Brogden, K. A. (1988). Ovine progressive pneumonia (maedi-visna) in sheep. Veterinary Microbiology 17, 237-250.[Medline]
Daar, E. S., Moudgil, T., Meyer, R. D. & Ho, D. D. (1991). Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. New England Journal of Medicine 324, 961-964.[Abstract]
de la Concha-Bermejillo, A. (1997). Maedi-visna and ovine progressive pneumonia. Veterinary Clinics of North America Food Animal Practice 13, 13-33.
de la Concha-Bermejillo, A., Juste, R. A., Kretschmer, R. & Aguilar Setien, A. (1995a). Ovine lentivirus infection: an animal model for pediatric HIV infection. Archives of Medical Research 26, 345-354.[Medline]
de la Concha-Bermejillo, A., Brodie, S. J., Magnus-Corral, S., Bowen, R. A. & DeMartini, J. C. (1995b). Pathologic and serologic responses of isogeneic twin lambs to phenotypically distinct lentiviruses. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 8, 116-123.[Medline]
DeMartini, J. C., Brodie, S. J., de la Concha-Bermejillo, A., Ellis, J. A. & Lairmore, M. D. (1993). Pathogenesis of lymphoid interstitial pneumonia in natural and experimental ovine lentivirus infection. Clinical Infectious Diseases 17 (Suppl. 1), S236S242.[Medline]
Dereuddre-Bosquet, N., Clayette, P., Martin, M., Mabondzo, A., Fretier, P., Gras, G., Martal, J. & Dormont, D. (1996). Anti-HIV potential of a new interferon, interferon- (trophoblastin). Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11, 241-246.[Medline]
Ellis, J. A. & DeMartini, J. C. (1985a). Ovine interleukin-2: partial purification and assay in normal sheep and sheep with progressive pneumonia. Veterinary Immunology and Immunopathology 8, 15-25.[Medline]
Ellis, J. A. & DeMartini, J. C. (1985b). Evidence of decreased concanavalin A induced suppressor cell activity in the peripheral blood and pulmonary lymph nodes of sheep with ovine progressive pneumonia. Veterinary Immunology and Immunopathology 8, 93-106.[Medline]
Finzi, D., Hermankova, M., Pierson, T., Carruth, L. M., Buck, C., Chaisson, R. E., Quinn, T. C., Chadwick, K., Margolick, J., Brookmeyer, R., Gallant, J., Markowitz, M., Ho, D. D., Richman, D. D. & Siliciano, R. F. (1997). Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295-1300.
Francis, M. L., Meltzer, M. S. & Gendelman, H. E. (1992). Interferons in the persistence, pathogenesis, and treatment of HIV infection. AIDS Research and Human Retroviruses 8, 199-207.[Medline]
Gendelman, H. E., Baca, L., Turpin, J. A., Chester Kalter, D., Hansen, B. D., Orenstein, J. M., Friedman, R. M. & Meltzer, M. S. (1990). Restriction of HIV replication in infected T cells and monocytes by interferon-. AIDS Research and Human Retroviruses 6, 1045-1049.[Medline]
Haase, A. T., Henry, K., Zupancic, M., Sedgewick, G., Faust, R. A., Melroe, H., Cavert, W., Gebhard, K., Staskus, K., Zhang, Z. Q., Dailey, P. J., Balfour, H. H.Jr, Erice, A. & Perelson, A. S. (1996). Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 274, 985-989.
Ho, D. D. (1996). Viral counts count in HIV infection. Science 272, 1124-1125.[Medline]
Joshi, V. V., Oleske, J. M., Klein, K. M., Dadzie, C., Simpser, M. & Rapkin, R. H. (1985). Pathologic pulmonary findings in children with the acquired immunodeficiency syndrome: a study of ten cases. Human Pathology 16, 241-246.[Medline]
Joshi, V. V., Oleske, J. K. & Connor, E. M. (1990). Morphologic findings in children with acquired immunodeficiency syndrome: pathogenesis and clinical implications. Pediatric Pathology 10, 155-165.[Medline]
Juste, R. A., Ott, T. L., Kwang, J., Bazer, F. W. & de la Concha-Bermejillo, A. (1996). Effects of recombinant interferon- on ovine lentivirus replication. Journal of Interferon and Cytokine Research 16, 989-994.[Medline]
Juste, R. A., Kwang, J. & de la Concha-Bermejillo, A. (1998). Dynamics of cell-associated viremia and antibody response during the early phase of lentivirus infection in sheep. American Journal of Veterinary Research 59, 563-568.[Medline]
Katzenstein, D. A., Hammer, S. M., Hughes, M. D., Gundacker, H., Jackson, J. B., Fiscus, S., Rasheed, S., Elbeik, T., Reichman, R., Japour, A., Merigan, T. C. & Hirsch, M. S. (1996). The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. New England Journal of Medicine 335, 1091-1098.
Kornbluth, R. S., Oh, P. S., Munis, J. R., Cleveland, P. H. & Richman, D. D. (1990). The role of interferons in the control of HIV replication in macrophages. Clinical Immunology and Immunopathology 54, 200-219.[Medline]
Koup, R. A. & Ho, D. D. (1994). Shutting down HIV.Nature 370, 416.[Medline]
Koup, R. A., Safrit, J. T., Cao, Y., Andrews, C. A., McLeod, G., Borkowsky, W., Farthing, C. & Ho, D. D. (1994). Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. Journal of Virology 68, 4650-4655.[Abstract]
Kunzi, M. S., Farzadegan, H., Margolick, J. B., Vlahov, D. & Pitha, P. M. (1995). Identification of human immunodeficiency virus primary isolates resistant to interferon- and correlation of prevalence to disease progression. Journal of Infectious Diseases 171, 822-828.[Medline]
Kwang, J., Keen, J., Cutlip, R. C. & Littledike, E. T. (1993). Evaluation of an ELISA for detection of ovine progressive pneumonia antibodies using a recombinant transmembrane envelope protein. Journal of Veterinary Diagnostic Investigation 5, 189-193.[Medline]
Lairmore, M. D., Poulson, J. M., Adducci, T. A. & DeMartini, J. C. (1988). Lentivirus-induced lymphoproliferative disease. Comparative pathogenicity of phenotypically distinct ovine lentivirus strains. American Journal of Pathology 130, 80-90.[Abstract]
Lane, H. C. (1991). The role of -interferon in patients with human immunodeficiency virus infection. Seminars in Oncology 18 (Suppl. 7), 4652.[Medline]
Lane, H. C., Davey, V., Kovacs, J. A., Feinberg, J., Metcalf, J. A., Herpin, B., Walker, R., Deyton, L., Davey, R. T. J. & Falloon, J. (1990). Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Annals of Internal Medicine 112, 805-811.[Medline]
Levy, J. A. (1993). Pathogenesis of human immunodeficiency virus infection. Microbiology Reviews 57, 183-289.
Mellors, J. W., Rinaldo, C. R., Gupta, P., White, R. M., Todd, J. A. & Kingsley, L. A. (1996). Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272, 1167-1170.[Abstract]
Myer, M. S., Huchzermeyer, H. F., York, D. F., Hunter, P., Verwoerd, D. W. & Garnett, H. M. (1988). The possible involvement of immunosuppression caused by a lentivirus in the aetiology of jaagsiekte and pasteurellosis in sheep. Onderstepoort Journal of Veterinary Research 55, 127-133.[Medline]
OBrien, W. A., Hartigan, P. M., Daar, E. S., Simberkoff, M. S. & Hamilton, J. D. (1997). Changes in plasma HIV RNA levels and CD4+ lymphocyte counts predict both response to antiretroviral therapy and therapeutic failure. VA Cooperative Study Group on AIDS. Annals of Internal Medicine 126, 939-945.
Ott, T. L., van Heeke, G., Johnson, H. M. & Bazer, F. W. (1991). Cloning and expression in Saccharomyces cerevisiae of a synthetic gene for the type-I trophoblast interferon ovine trophoblast protein-1: purification and antiviral activity. Journal of Interferon Research 11, 357-364.[Medline]
Pantaleo, G., Graziosi, C. & Fauci, A. S. (1993). The immunopathogenesis of human immunodeficiency virus infection. New England Journal of Medicine 328, 327-335.
Pantaleo, G., Demarest, J. F., Soudeyns, H., Graziosi, C., Denis, F., Adelsberger, J. W., Borrow, P., Saag, M. S., Shaw, G. M., Sekaly, R. P. & Fauci, A. S. (1994). Major expansion of CD8+ T cells with a predominant V usage during the primary immune response to HIV. Nature 370, 463-467.[Medline]
Petursson, G., Andresdottir, V., Andresson, O. S., Georgsson, G., Palsson, P. A., Rafnar, B. & Torsteinsdottir, S. (1992). Lentivirus diseases of sheep and goats: maedi-visna and caprine arthritis encephalitis. In Progress in Sheep and Goat Research, pp. 107-129. Edited by A. W. Speedy. Wallingford, UK: CAB International.
Pontzer, C. H., Torres, B. A., Vallet, J. L., Bazer, F. W. & Johnson, H. M. (1988). Antiviral activity of the pregnancy recognition hormone ovine trophoblast protein-1.Biochemical and Biophysical Research Communications 152, 801-807.[Medline]
Pontzer, C. H., Bazer, F. W. & Johnson, H. M. (1991). Antiproliferative activity of a pregnancy recognition hormone, ovine trophoblast protein-1. Cancer Research 51, 5304-5307.[Abstract]
Pontzer, C. H., Yamamoto, J. K., Bazer, F. W., Ott, T. L. & Johnson, H. M. (1997). Potent anti-feline immunodeficiency virus and anti-human immunodeficiency virus effect of IFN-tau. Journal of Immunology 158, 4351-4357.[Abstract]
Pyrah, I. T. G. & Watt, N. J. (1996). Immunohistological study of the depressed cutaneous DTH response in sheep naturally infected with an ovine lentivirus (maedi-visna virus). Clinical and Experimental Immunology 104, 32-36.[Medline]
Rivero, J., Fraga, M., Cancio, I., Cuervo, J. & Lopez-Saura, P. (1997). Long-term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy 10, 107-113.[Medline]
Scott, G. B. (1991). HIV infection in children: clinical features and management. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 4, 109-115.
Simberkoff, M. S., Hartigan, P. M., Hamilton, J. D., Day, P. L., Diamond, G. R., Dickinson, G. M., Drusano, G. L., Egorin, M. J., George, W. L., Gordin, F. M., Hawkes, C. A., Jensen, P. C., Kilmas, N. G., Labriola, A. M., OBrien, W. A., Oster, C. N., Weinhold, K. J., Wray, N. P. & Pazner, S. B. (1996). Long-term follow-up of symptomatic HIV-infected patients originally randomized to early versus later zidovudine treatment; report of a Veterans Affairs Cooperative Study. VA Cooperative Study Group on AIDS Treatment.Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 11, 142-150.[Medline]
Singh, B., Ott, T. L., Bazer, F. W. & de la Concha-Bermejillo, A. (1998). Structural responses of pulmonary intravascular macrophages in lentivirus-infected and/or recombinant ovine interferon--treated lambs. Anatomical Record 251, 472-485.[Medline]
Stuart-Harris, R. C., Lauchlan, R. & Day, R. (1992). The clinical application of the interferons: a review. Medical Journal of Australia 156, 869-872.[Medline]
Villegas, P. & Purchase, H. G. (1989). Titration of biological suspensions. In A Laboratory Manual for the Isolation and Identification of Avian Pathogens, pp. 186-191. Edited by H. G. Purchase, L. H. Arp, C. H. Domermuth & J. E. Pearson. Dubuque, IA: Kendall/Hunt Publishing.
Woodward, T. M., Carlson, J. O., de la Concha-Bermejillo, A. & DeMartini, J. C. (1995). Biological and genetic changes in ovine lentivirus strains following passage in isogeneic twin lambs. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 8, 124-133.[Medline]
Received 1 July 1999;
accepted 28 October 1999.
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
INT J SYST EVOL MICROBIOL | MICROBIOLOGY | J GEN VIROL |
J MED MICROBIOL | ALL SGM JOURNALS |