Media/ Hypotheses (1990) 32,157-158 @ Longman Group UK Ltd 1990
An Alternative Cure? C.A.L.S.
03CK-9877/9010032-0157/$10.00
Strategy for Therapy
COLACO
Quadrant Research Foundation, Cambridge CB3 ODJ, UK
Abstract recognition the disease preventing
Cambridge
Research Laboratories,
The acquired immunodeficiency syndrome (AIDS), first recognised in 1981 in the USA is now a global pandemic (1). It has been estimated that l-2 million Americans and scores of people in every country of the world have been infected the pathogenic with agent, human immunodeficiency virus (HIV) (2). At least two forms of the retrovirus have been isolated and the cellular receptor for the virus has been shown to be the lymphocyte surface antigen CD4 (3-5). As the immunodeficiency characteristic of AIDS is associated with the observed selective depletion of CD4+ T lymphocytes, the direct cytopathic effects of HIV infection might explain the pathology of the disease. However, in seropositive patients, only a small fraction of the CD4-t population are productively infected with HIV (6).Other explanations are thus required to
received accepted
181a Huntingdon
Road,
Present therapeutic strategies in AIDS require continuous treatment. The of the major contribution of an ‘autoimmune’ component to the pathology opens up the possibility of ablation of specific T-cell sets as a means of and reversing the disease.
Introduction
Date Date
of AIDS; A
26 April 1989 21 August 1989
account loss.
for the majority
The ‘autoimmune’
of the CD4+
component
of
T-Cell
of AIDS
Recently it has been shown that uninfected CD4+ T cells expressing products of the Class II locus of the major histocompatibility complex when exposed to soluble gp120 of HIV are killed by virus specific cytotoxic T-cells (7). This cytotoxicity is CD4+ T-cell specific as CD8+ infected cells are not killed and this cytopathic mechanism probably accounts for the majority of the CD4+ T-cell loss seen in AIDS (8). It has been pointed out that this observation has important implications for therapy and vaccines; namely that soluble CD4 may be more important than previously thought as a therapy and that vaccines should be directed towards Class I restricted responses and that Class II restricted responses to gp120 should be avoided (8). The implication for therapy has recently been borne out by studies using soluble CD4 molecules reinforcing the validity of the (9-11)
157
158 ‘autoimmune’ component factor in the pathogenesis
MEDICAL HYPOTHESES
of AIDS as a major of the disease.
Therapeutic strategies As human IgG has failed to confer passive immunity in experimental animals, two main strategies have been pursued for the development of therapeutic agents to control AIDS. The first is the use of antiviral chemotherapy using compound such as AZT which despite their toxicity do help some patients (12). The second is the use of soluble CD4 molecules to block virus infectivity (10). This has been further refined by the use of ‘CD4 immunoadhesives’ which also block virus infectivity and by their antibody-like properties should prove useful therapeutic agents (11). However, the limitation of both approaches is that the treatments have to be administered continuously and do not cure the disease. A strategy towards a cure contribution of the the major Given ‘autoimmune’ component of the pathology of AIDS recent work on the prevention and reversal of murine experimental autoimmune encephalomyelitis (EAE) suggests an alternative approach to AIDS therapy that if successful could lead to a cure for the disease. EAE has been shown to be an autoimmune disease mediated by CD4+ T-cells in the experimental murine model (13-15). Analysis of the T-cell receptors of these cells has shown that they utilize only a restricted set of V-genes and treatment of the affected animals with monoclonal antibodies specific for this V-gene family resulted in the prevention and reversal of the disease (1617). As the restricted use of T-cell receptor V-genes is probably due to the restricted number of antigenic determinants recognized by specific T-cells it is likely that the specific cytotoxic Tcells that kill uninfected CD4+ T-cells presenting soluble HIV antigens in AIDS will be -similarly restricted in recognition and V-gene family usage. Antibodies to these V-genes of the T-cell receptor could thus be used to selectively ablate the cytopathic T-cell subsets and thus reverse and prevent AIDS in a situation parallel to that in EAE.
Conclusion
The analysis of the use of T-cell receptor V-genes by HIV specific cytotoxic T-cells that can kill uninfected CD4+ T-cells presenting soluble viral antigens should evaluate the possible use of antibodies to these V-region -- :-genes as a therapy and possible cure for AIDS m a situation parallel to that in the murine EAE model for a CD4+ T-cell mediated autoimmune disease.
References
5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
M.R.C. Annual Report 198711988 Curran, J. W. et al. The epidemology of AIDS. Science 229, 1352, 1985 Ho, D. D. et al. Pathogenesis of infection with HIV. N. Eng. J. Med. 317. 763,-1984 Dalgleish. A. et al. The CD4 CT41antigen is an essential component of the receptor for- the AIDS retrovirus. Nature 312, 763, 1984 Sattentau, Q. J. and Robin A. Weiss. The CD4 antigen; physiological ligand and HIV receptor. Cell 52, 631, 1988 Harper, M. E. et al. Detection of lymphocytes expressing human T-lymphotrophic virus type III in lymph modes and peripheral blood from infected individuals by in situ hvbridization. P.N.A.S. 83, 772, 1986 $lic&o, !, F. et_ al,&iysis of Host-virus interacti9ns in AIDS with anti-go120 T-cell clones. Cell 54.561. 1988 Germain, R. N. &igen processing and CD4+ T-cell depletion in AIDS. Cell 54, 441, 1988 Smith, D. H. et al. Blocking of HIV 1 infectivity by a soluble secreted form of the CD4 antigen. Science 238, 1704, 1982 Traunecker, A. et al. Soluble CD4 molecules neutralize HIV 1. Nature 331, 84, 1988 Canon, D. J. et al. Designing CD4 immunoadhesives for AIDS therapy. Nature 327, 525, 1989 Mitsuva. H. & Broder. S. Strategies for antiviral theranv .. in AIDS. Nature 325, ‘773, 1987Mokhtarian, F. et al. Adoptive transfer for MBP-sensitised T-cells produces chronic relapsing demyelinating disease in mice. Nature 309, 356, 1984 _ Zamvil. S. et al. T-cell clones snecific for MBP induce chronic relapsing peralysis and ‘demyelination. Nature 317, 365, 1985 Zamvil, S. et al. T-cell epitope of the autoantigen MBP that mediates encephalomyclitis. Nature 324, 258 Urban. J. L. et al. Restricted use of T-cell receptor Vgenes in murine autoimmune encephalomyelitis raises possibilities for antibodv therapy. Cell 54, 577, 1988 Dacha-Orbea, A. et al.* Limited heterogeneity of T-cell receptors from lymphocytes mediating autoimmune enceplalomyelitis allows specific immune intervention. Cell 54, 263, 1988
An Alternative Cure? C.A.L.S.
03CK-9877/9010032-0157/$10.00
Strategy for Therapy
COLACO
Quadrant Research Foundation, Cambridge CB3 ODJ, UK
Abstract recognition the disease preventing
Cambridge
Research Laboratories,
The acquired immunodeficiency syndrome (AIDS), first recognised in 1981 in the USA is now a global pandemic (1). It has been estimated that l-2 million Americans and scores of people in every country of the world have been infected the pathogenic with agent, human immunodeficiency virus (HIV) (2). At least two forms of the retrovirus have been isolated and the cellular receptor for the virus has been shown to be the lymphocyte surface antigen CD4 (3-5). As the immunodeficiency characteristic of AIDS is associated with the observed selective depletion of CD4+ T lymphocytes, the direct cytopathic effects of HIV infection might explain the pathology of the disease. However, in seropositive patients, only a small fraction of the CD4-t population are productively infected with HIV (6).Other explanations are thus required to
received accepted
181a Huntingdon
Road,
Present therapeutic strategies in AIDS require continuous treatment. The of the major contribution of an ‘autoimmune’ component to the pathology opens up the possibility of ablation of specific T-cell sets as a means of and reversing the disease.
Introduction
Date Date
of AIDS; A
26 April 1989 21 August 1989
account loss.
for the majority
The ‘autoimmune’
of the CD4+
component
of
T-Cell
of AIDS
Recently it has been shown that uninfected CD4+ T cells expressing products of the Class II locus of the major histocompatibility complex when exposed to soluble gp120 of HIV are killed by virus specific cytotoxic T-cells (7). This cytotoxicity is CD4+ T-cell specific as CD8+ infected cells are not killed and this cytopathic mechanism probably accounts for the majority of the CD4+ T-cell loss seen in AIDS (8). It has been pointed out that this observation has important implications for therapy and vaccines; namely that soluble CD4 may be more important than previously thought as a therapy and that vaccines should be directed towards Class I restricted responses and that Class II restricted responses to gp120 should be avoided (8). The implication for therapy has recently been borne out by studies using soluble CD4 molecules reinforcing the validity of the (9-11)
157
158 ‘autoimmune’ component factor in the pathogenesis
MEDICAL HYPOTHESES
of AIDS as a major of the disease.
Therapeutic strategies As human IgG has failed to confer passive immunity in experimental animals, two main strategies have been pursued for the development of therapeutic agents to control AIDS. The first is the use of antiviral chemotherapy using compound such as AZT which despite their toxicity do help some patients (12). The second is the use of soluble CD4 molecules to block virus infectivity (10). This has been further refined by the use of ‘CD4 immunoadhesives’ which also block virus infectivity and by their antibody-like properties should prove useful therapeutic agents (11). However, the limitation of both approaches is that the treatments have to be administered continuously and do not cure the disease. A strategy towards a cure contribution of the the major Given ‘autoimmune’ component of the pathology of AIDS recent work on the prevention and reversal of murine experimental autoimmune encephalomyelitis (EAE) suggests an alternative approach to AIDS therapy that if successful could lead to a cure for the disease. EAE has been shown to be an autoimmune disease mediated by CD4+ T-cells in the experimental murine model (13-15). Analysis of the T-cell receptors of these cells has shown that they utilize only a restricted set of V-genes and treatment of the affected animals with monoclonal antibodies specific for this V-gene family resulted in the prevention and reversal of the disease (1617). As the restricted use of T-cell receptor V-genes is probably due to the restricted number of antigenic determinants recognized by specific T-cells it is likely that the specific cytotoxic Tcells that kill uninfected CD4+ T-cells presenting soluble HIV antigens in AIDS will be -similarly restricted in recognition and V-gene family usage. Antibodies to these V-genes of the T-cell receptor could thus be used to selectively ablate the cytopathic T-cell subsets and thus reverse and prevent AIDS in a situation parallel to that in EAE.
Conclusion
The analysis of the use of T-cell receptor V-genes by HIV specific cytotoxic T-cells that can kill uninfected CD4+ T-cells presenting soluble viral antigens should evaluate the possible use of antibodies to these V-region -- :-genes as a therapy and possible cure for AIDS m a situation parallel to that in the murine EAE model for a CD4+ T-cell mediated autoimmune disease.
References
5. 6.
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
M.R.C. Annual Report 198711988 Curran, J. W. et al. The epidemology of AIDS. Science 229, 1352, 1985 Ho, D. D. et al. Pathogenesis of infection with HIV. N. Eng. J. Med. 317. 763,-1984 Dalgleish. A. et al. The CD4 CT41antigen is an essential component of the receptor for- the AIDS retrovirus. Nature 312, 763, 1984 Sattentau, Q. J. and Robin A. Weiss. The CD4 antigen; physiological ligand and HIV receptor. Cell 52, 631, 1988 Harper, M. E. et al. Detection of lymphocytes expressing human T-lymphotrophic virus type III in lymph modes and peripheral blood from infected individuals by in situ hvbridization. P.N.A.S. 83, 772, 1986 $lic&o, !, F. et_ al,&iysis of Host-virus interacti9ns in AIDS with anti-go120 T-cell clones. Cell 54.561. 1988 Germain, R. N. &igen processing and CD4+ T-cell depletion in AIDS. Cell 54, 441, 1988 Smith, D. H. et al. Blocking of HIV 1 infectivity by a soluble secreted form of the CD4 antigen. Science 238, 1704, 1982 Traunecker, A. et al. Soluble CD4 molecules neutralize HIV 1. Nature 331, 84, 1988 Canon, D. J. et al. Designing CD4 immunoadhesives for AIDS therapy. Nature 327, 525, 1989 Mitsuva. H. & Broder. S. Strategies for antiviral theranv .. in AIDS. Nature 325, ‘773, 1987Mokhtarian, F. et al. Adoptive transfer for MBP-sensitised T-cells produces chronic relapsing demyelinating disease in mice. Nature 309, 356, 1984 _ Zamvil. S. et al. T-cell clones snecific for MBP induce chronic relapsing peralysis and ‘demyelination. Nature 317, 365, 1985 Zamvil, S. et al. T-cell epitope of the autoantigen MBP that mediates encephalomyclitis. Nature 324, 258 Urban. J. L. et al. Restricted use of T-cell receptor Vgenes in murine autoimmune encephalomyelitis raises possibilities for antibodv therapy. Cell 54, 577, 1988 Dacha-Orbea, A. et al.* Limited heterogeneity of T-cell receptors from lymphocytes mediating autoimmune enceplalomyelitis allows specific immune intervention. Cell 54, 263, 1988
