Soluble CD4: anothertherapeutic option in HIV infection

Soluble CD4: anothertherapeutic option in HIV infection

1128 research techniques according to strength might only be applicable for certain well-defined problems. How could a study on HLA or DNA patterns b...

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research techniques according to strength might only be applicable for certain well-defined problems. How could a study on HLA or DNA patterns be randomised, the genetic dice having already been thrown by the patient’s parents? Even in studies of efficacy, one sees more and more case-controlling: examples include the efficacy of vaccines," screening, 18 and prophylaxis.l9 The precept to read only randomised controlled trials might make the reader miss all that is new, innovative, and exciting in medicine. Since the progress of science seldom follows a very orderly path2O it might be unwise to maintain the pretence of some universal rank order preference in theory. A scientific fact always needs to be incorporated into the existing scientific framework of the reader. 21,22 As already stated in the 1930s, even if a perfectly conducted randomised controlled trial yielded a result such as that some much diluted coloured water would cure typhoid, we would tend to dismiss the findings as an unlucky draw and remain faithful to mainline pharmacology.23 Conversely, some case-control studies on smoking and cancer of the 1950s-— poorly conducted by today’s standards-might ultimately change the face of our civilisation. So, should we case-control? The most universal answer might be that "it depends..." on the question addressed, the state of the problem, the speed of answer and accuracy needed, and some practical constraints. Thereby epidemiologists might concentrate on medical and biological substance, rather than on dismissing one another’s studies out-of-hand because of alleged methodological shortcomings.26 Nevertheless, we should remain critical and watchful, but not in terms of a priori convictions, however logical they might seem to the believer. We urgently need to analyse instances in which epidemiological methodology has failed, in either direction-by being too sceptical or too lenient,

by underemphasis or by overinterpretation. 1. Cole Ph. The evolving case-control study. In: Ibrahim MA, Spitzer WO, eds. The case-control study: consensus and controversy. Oxford: Pergamon, 1979: 15-34. 2. Cornfield J. A method of estimating comparative rates from clinical data. Applications to cancer of the lung, breast and cervix. J Natl Cancer Inst 1951; 11: 1269-75. 3. Mantel N, Haenszel W. Stastical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-48. 4. Miettinen OS. Theoretical epidemiology: principles of occurrence research in medicine. New York: Wiley, 1985. 5. Sackett DL, Haynes RB, Tugwell P. Clinical epidemiology: a basic science for clinical research. Boston: Little, Brown, 1985. 6. Bennet KJ, Sackett DL, Haynes RB, et al. A controlled trial of teaching critical appraisal of the clinical literature to medical students. JAMA 1987; 257: 2451-54. 7. Feinstein AR. Clinical judgment. Baltimore: Williams and Wilkins, 1967. 8. Feinstein AR. Clinical biostatistics. St Louis: Mosby, 1977. 9. Feinstein AR. Clinical epidemiology: the architecture of clinical research. Philadelphia: Saunders, 1985. 10. Hurwitz ES, Barrett MJ, Bergman D, et al. Public Health Service study on Reye syndrome and medication. JAMA 1987; 257: 1905-11. 11. Forsyth BW, Horwitz RI, Acompora D, et al. New epidemiologic evidence confirming that bias does not explain the aspirin/Reye syndrome association. JAMA 1989; 261: 2517-24.

Reye syndrome, salicylates, epidemiology and public health policy. JAMA 1987; 257: 1941. 13. Russell B. Sceptical essays. London: Allan and Unwin, 1977. 14. Savitz DA, Greenland S, Stolley PD, Kelsey JL. Scientific standards of criticism: a reaction to "Scientific standards in epidemiologic studies of the menace of daily life" by AR Feinstein. Epidemiology 1990; 1: 78-82 15. Feinstein AR. Scientific news and epidemiologic editorials: a reply to the critics. Epidemiology 1990; 1: 170-80. 16. Rahimtoola SH. Control of scientific research. In: Brugada P, Wellens HJJ. Cardiac arrythmias: where to go from here? Mount Kisco, NY:

12. Mortimer EA.

Future, 1987: 689-98. PG, Rodriguez LC, Fine PEM. Assessment of the protective

17. Smith

of vaccines against common diseases using case-control and cohort studies. Int J Epidemiol 1984; 13: 87-93. 18. Morrison AS. Screening in chronic disease. New York: Oxford University Press, 1985. 19. Imperiale TF, Horwitz RI. Does prophylaxis prevent postdental infective endocarditis? A controlled evaluation of protective efficacy. Am J Med 1990; 88: 131-36. 20. Feyerabend P. Against method. London: Verso, 1980. 21. Cornfield J. Statistical relationships and proof in medicine. Am Statistician 1954; 8: 19-21. (Reprinted in Greenland S, ed. Evolution of epidemiologic ideas: annotated readings on concepts and methods. Chestnut Hill, MA: Epidemiology Resources, 1987.) 22. Cornfield J. Recent methodological contributions to clinical trials. Am J Epidemiol 1976; 104: 408-21. 23. Woods HM, Russel WT. An introduction to medical statistics. London: Staples Press, 1948. 24. Doll R, Hill AB. Smoking and carcinoma of the lung. Br Med J 1950; 2: 739-48. (Reprinted in Buck C, Llopis A, Nájera E, Terris M, eds. The challenge of epidemiology: issues and selected readings. Washington, DC: Pan American Health Organization, 1988.) 25. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma: a study of six hundred and eighty-four cases. JAMA 1950; 143: 329-36. (Reprinted in Buck C, Llopis A, Nájera E, Terris M, eds. The challenge of epidemiology: issues and selected readings. Washington, DC: Pan American Health

efficacy

26.

Organization, 1988.) Stolley PD. Faith, evidence and the epidemiologist. J Publ Hlth Policy 1985; 6: 37-42.

Soluble CD4: anothertherapeutic option in HIV infection Very high affinity binding of the gp 120 envelope glycoprotein of human immunodeficiency virus (HIV) to the CD4 surface antigen of T "helper" lymphocytes, macrophages, and related cells provides the main (although not the only) route of cell attachment and entry for the virus. Binding also disrupts the interaction of T-cell CD4 with major histocompatibility complex (MHC) class II determinants on antigen-presenting cells, an essential early step in the generation of a normal immune response.1-5 Furthermore, CD4-positive cells with bound viral gpl20 may be targets for destruction mediated by cytotoxic T cells or by antibodydependent cellular cytotoxicity (ADCC) .2,6Thus there are at least three mechanisms whereby binding of gpl20 to CD4 may contribute to the pathogenesis of AIDS-enhancement of spread of infection from cell to cell, impairment of immune recognition, and triggering of destruction of helper T cells. For these reasons the concept of a "decoy" in the form of CD4 molecules in solution in the plasma or carried, for example, on red cell membranes has its attractions as a means of diverting at least a proportion of HIV particles and of free gp 120 molecules away from more vulnerable sites.

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A truncated version of the CD4 molecule carrying the gp120-binding domain has been synthesised by introducing the corresponding gene into cultured cells. Experiments with HIV in vitro have shown that this soluble CD4 does indeed reduce the infectivity and the cytopathic and immunomodulatory effects of the virus.8-13 Nevertheless, there are anxieties about using the material in man. Since CD4, in its normal setting, has such an important role, will an excess of soluble CD4 itself disrupt immune function? Alternatively, will it prove immunogenic and will antibodies to CD4 behave in much the same way as gpl20 itself, binding to the surface of T helper cells and inactivating them? The conventional route-ie, testing a new treatment in animals-is of limited help in this instance. Although there are CD4 equivalents in other mammals, gp 120 binding is restricted to man and the primates and, when it comes to detailed analysis of virus/cell interactions, even primate models of AIDS are usually too far removed from the human disease to provide data from which clinicians can extrapolate with confidence.13,14 The initial trials of soluble CD4 in man were therefore attended with some

trepidation.

Phase I studies in HIV-infected patients have been moderately reassuring. No serious adverse reactions have been recorded; immune function does not appear to deteriorate, at least in the short term; and although a few patients have produced measurable CD4 antibody, this is evidently well tolerated. Soluble CD4 can be given intramuscularly, subcutaneously, or by intravenous infusion and by any of these routes can attain serum levels shown to have antiviral effect in vitro. Numbers of patients included in trials are still limited and none has been on treatment for more than a few months. It is therefore too soon to expect evidence for the efficacy of this approach in arresting the progress of HIV-related disease, although there were indications of a reduction of circulating virus load in some of the patients on high-dose regimens in the phase I trials,15,16 Detailed analysis of the structure and function of the CD4 molecule provides further grounds for optimism. The N-terminal domains of the extracellular portion carry both gpl20-binding regions and determinants that interact with MHC class II on antigen-presenting cells. However, although there is some overlap between these elements, they are not identical. Moreover, the soluble form of CD4 does not appear to compete with the membrane-bound form for access to MHC class II molecules nor, in general, do antibodies raised against the soluble form inhibit cell-cell interactions based on CD4/MHC class II recognition.l’ Thus conformational differences between the soluble and membrane-bound forms seem to protect the uniqueness of the important functional domain of the 1 itter without compromising the ability of the former to mop up gp 120. This may be a fortuitous but

nonetheless crucial factor in determining the potential therapeutic index of soluble DC4. It is not yet clear how often antibodies to the soluble form may be directed to the gp 120 binding site but the affinity of the gpl20/CD4 interaction is so high that it may proceed efficiently even in the presence of some

specific antibody. Developments of the soluble CD4 concept have been proposed—eg, construction of a fusion protein comprising the Fc portion of immunoglobulin and the N-terminal CD4 domain. One intention is to prolong the biological half-life of the molecule. However, it is not certain that any modification will be required for this purpose since intramuscular injection of soluble CD4 itself appears to create a useful depot release system that achieves well-sustained blood levels. On the other hand, the fusion protein is able to mediate ADCC specifically towards HIV-infected T cells, which could be considerable advantage, and since it is transported across the placenta like authentic IgG it may have potential for preventing transmission of infection from mother to infant.18 Another approach, which has its champions, is to prepare or induce an anti-idiotype (ie, an antibody against the antigen-combining site of another antibody) against a monoclonal that recognises the gp 120 binding site of CD4. The rationale is that such a molecule would carry a mirror image of the antigencombining site-ie, a representation of the target portion of the CD4 molecule itself. That anti-idiotype should then behave very much like soluble CD4 in attracting gpl20 but would have no other CD4-like attributes and so would not interfere with the normal functions of that molecule. It is proving difficult to identify an anti-CD4 monoclonal with precisely the specificity required to generate an appropriate antiidiotypey but, in any event, the apparent lack of unwanted side-effects from soluble CD4 may render this alternative concept redundant. Perhaps the most promising aspect of soluble CD4 therapy is the fact that, by comparison with other agents already in use or under trial, it acts at an entirely different point in the virus life cycle. Thus combined therapy, with zidovudine or dideoxyinosine, for example, should show gains in efficacy without additive toxicity. 20 1.

Dalgleish AG, Beverely PCL, Clapham P, et al. The T4 (CD4) molecule is

an

essential component of the HTLV

III/LAV-1

receptor. Nature

1984; 312: 763-67. 2. Rozenberg ZF, Fauci AS. The immunopathogenesis of HIV infection. Adv Immunol 1989; 47: 377-431. 3. Homsy J, Meyer M, Tateno M, et al. The Fc and not CD4 receptor mediates antibody enhancement of HIV infection in human cells. Science 1989; 244: 1357-60. 4. Valentin A, Lundin K, Patarroyo M, Asjo B. The leukocyte adhesion glycoprotein CD18 participates in HIV-1-induced syncytia formation in monocytoid and T cells. J Immunol 1990; 144: 934-37. 5. Gay D, Maddon P, Sekaly R, et al. Functional interaction between human T cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature 1987; 328: 626-28. 6. Lyerly HK, Matthews TJ, Langlois AJ, et al. Human T cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as

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target for immune attack. Proc Natl Acad Sci USA 84:

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A, Roosnek E, Gregory T, et al. T cells can present antigens such as HIV gp120 targeted to their own surface molecules.

7. Lanzavecctioa

Nature 1988; 334: 530-32. 8.

Smith DH, Byrn RA, Marsters SA, et al. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science 1987; 228:

1704-07. 9. Fisher RA, Bertonis JM, Meier W, et al. HIV infection is blocked in vitro by recombinant soluble CD4. Nature 1988; 331: 76-78. 10. Hussey RE, Richardson NE, Kowalski M, et al. A soluble CD4 selectively inhibits HIV replication and syncytium formation. Nature 1988; 331: 78-81 11. Deen KC, McDougal JS, Macker R, et al. A soluble form of CD4 (T4) protein inhibits AIDS virus infection. Nature 1988; 331: 82-84. 12. Trannecker A, Luke W, Karjalian K. Soluble CD4 molecules neutralise human immunodeficiency virus type 1. Nature 1988; 331: 76-78. 13. Manca F, Habeshaw JA, Dalgleish AG. HIV envelope glycoprotein, antigen-specific T-cell responses, and soluble CD4. Lancet 1990; 335: 811-15. 14. Watanabe M, Reimann KA, De Long PA, et al. Effects of recombinant CD4 in rhesus monkeys infected with simian immunodeficiency virus of macaques. Nature 1989; 237: 267-70. 15. Schosley RT, Merigan TC, Gant P, et al. Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase I-II escalating dosage trial. Ann Intern Med 1990; 112: 247-53. 16. Kalm JO, Allan JD, Hodges TL, et al. The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired

immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study. Ann Intern Med 1990; 112: 254-61. 17. Lamarre D, Capon DJ, Karp DR, et at. Class II MHC molecules and the HIV gp120 envelope protein interact with functionally distinct regions of the CD4 molecule. EMBO J 1989; 8: 3271-77. 18. Bym RA, Mordenti J, Lucas C, et al. Biological properties of a CD4 immunoadhesin. Nature 1990; 344: 667-70. 19. Dalgleish AG, Thomson BJ, Chanh TC, Malkovsky M, Kennedy RC. Neutralisation of HIV isolates by anti-idiotypic antibodies which mimic the T4 (CD4) epitope: a potential AID S vaccine. Lancet 1987; ii: 1047-50. 20. Johnson VA, Barlow MA, Chanh TC, et al. Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by recombinant soluble CD4 and 3’ azido-3’ deoxythymidine. J Infect Dis 1989; 159: 837-44.

THE TRUST IN PULSE OXIMETERS Pulse oximeters give a non-invasive continuous readout of the oxygen saturation of haemoglobin in arterial blood. They are widely accepted as sensitive and accurate instruments that produce clinically useful data and are used extensively in anaesthetic practice. Are we becoming too complacent about the accuracy of such monitors? These instruments rely on spectrophotometric analysis of light transmitted through tissues to measure haemoglobin oxygen saturations. A microprocessor is used to isolate the pulsatile component of the light signal, which is assumed to be solely of arterial origin. Two specific wavelengths of light suited to the detection of haemoglobin and oxyhaemoglobin are used to generate the sensor output. Haemoglobin saturation values are calculated by use of an inbuilt algorithm derived from human experimental data. Current models are unable to distinguish between chromophores other than haemoglobin and oxyhaemoglobin, so in practice all pulsatile signals are attributed to these two

compounds. Since the introduction of pulse oximetry there have been several clinical reports of erroneous data generation. Oximeters process complex data from highly amplified signals and are therefore subject to interference from the hostile electromagnetic environment in which they are used. Sensor movement,l infrared2 and theatre lighting,3 and surgical diathermy may produce such interference, which is usually transient. However, a permanent instrument

readout error following diathermy was lately reported4 The assumptions that underlie the calculation of saturation may give rise to difficulties. Thus it is assumed that the pulsatile component of the sensor output indicates only events in the arterial circulation, yet venous pulsationl or anything that causes slight rhythmical changes in optical conduction can give spurious readings. Use of oximeters with a waveform display may allow the operator to reject artifactual readings obtained from non-arterial sources. The assumption that all absorption signals at the two wavelengths used by the instrument arise from haemoglobin or oxyhaemoglobin is potentially a more serious source of error since any other substance in the arterial blood that absorbs light at the detection wavelengths will be reported as being one of these two compounds. Substances of this type include carboxyhaemoglobin,s5 methaemoglobin,6 and certain dyes such as methylene blue.7 Exclusive reliance on pulse oximeter readings in patients with raised blood concentrations of these interfering chromophores may be dangerous and therefore confirmatory investigations such as co-oximetry should be used if there is uncertainty. Skin dyes,8 dried blood,9 and nail polishlO have also affected the accuracy of readings, despite the fact that the absorbance they produce would be expected to be non-pulsatile. Pulse oximeters are widely thought to provide a measurement of oxygen saturation throughout the body. This generalisation may be true in the steady state, but under dynamic conditions oximetry gives an accurate assessment of arterial oxygen saturation only at the point of measurement-ie, simultaneous pulse oximeter readings taken from tissues with different perfusion rates show different saturation values after induced changes in arterial oxygen tension. Thus Severinghaus" induced decreases in arterial oxygen tension in normal subjects and found response lags of 50 s and 10 s for saturation readings obtained from pulse oximeter sensors placed on the finger and earlobe, respectively. Any factors that impair blood flow to the tissues onto which the sensor is placed may increase this response lag and further delay detection of arterial hypoxaemia. These effects will be greater in instruments with long averaging times. A computer model of the cardiorespiratory system has been used to assess the importance of time delays on the detection of hypoxic events. 12 Various causes of oxygen supply failure were examined and in most cases pulse oximetry, even with a 60 s delay, gave adequate warning of a fall in brain oxygen tension. However, when arterial oxygen saturation fell most rapidly-ie, during ventilation with a gas mixture containing no oxygen-severe brain hypoxia could occur before a pulse oximeter with finger sensor would alarm. If this computer simulation accurately represents human pathophysiology, over-reliance on finger pulse oximetry may, in this circumstance, result in an unacceptable risk of

hypoxic damage. Pulse oximetry undoubtedly represents an important advance in patient monitoring technology and its use is strongly recommended by the Association of Anaesthetists.13 A survey of insurance claims resulting from over a thousand anaesthetic mishaps concluded that its addition to a monitoring system could have prevented over a third of avoidable incidents.14 Nevertheless, the limitations of the technique suggest that unqualified reliance on the values produced might sometimes be dangerously misleading. Technological advances may overcome some of these limitations; meanwhile, the effect of different

sensor