1007
COMPARISON OF INVESTIGATIONS THAT USED WHO/CDC CRITERIA FOR AIDS
Monoclonal CD4 antibodies after accidental HIV infection SIR,-What should be done when a nurse, doctor, laboratory or other health-care worker is exposed to HIV-infected blood through a needlestick or other hazardous injury? Prophylactic zidovudine has been proposed but this may not always prevent HIV infection.3 This drug interferes with HIV replication; once viral DNA has been integrated into cellular DNA it can, at best, prevent progression of infection but not infection itself. Where an apparently minute amount of virus, free or cell-bound, has gained parenteral access to the body an intervention aimed at rapid interference with cellular uptake of the virus is required. To do this, we suggest blocking cellular CD4 receptors, removing or inactivating CD4 + cells temporarily, and neutralising free virus by rapidly released endogenous CD4 glycoprotein. High-affinity monoclonal CD4 antibodies (mAb) are good candidates for achieving these goals. As demonstrated in more than 30 patients with rheumatoid arthritis treated with murine CD4 antibodies a serum concentration of 2-5 /lg/ml mAb is obtained within 1 h of the infusion of 20 mg mAb, and the nadir of circulating CD4 + cells is seen 2-3 h after infusion (4 and unpublished). Soluble CD4 is detected at peak concentrations 3 h after infusion (figure). More importantly, however, high affinity CD4 mAb are now available which can interfere in vitro with productive infection of susceptible cells when added as late as 60 min after exposure of the cells to a high dose of infectious HIV. The table gives data of one of four experiments with almost identical results and shows that there is a time lag between the binding of HIV to the CD4 receptor and its irreversible uptake into the cell. During this period, it is still possible to interfere with viral infection by displacing the virus from the CD4 receptor. CD4 mAb, like the M-T413 used in these experiments, can block infection of cells by free virus and recruitment of uninfected cells into syncytia formation by infected cells. Thus, mAb M-T413 at a concentration of 0-03 ug/ml can inhibit syncytia formation of C8166 cells after addition of HIV-infected H9 cells. Therefore, these antibodies may be useful in counteracting infection by free as well as by cell-bound virus. Inoculated HIV-positive allogenic cells are assumed to be destroyed within two weeks after inoculation. In contrast to the intravenous administration of other monoclonal anti-T-cell antibodies such as CD3 the infusion of CD4 mAb is well tolerated. Temporary blockade of the cellular CD4 receptor with high-affinity CD4 mAb for several days after accidental exposure to HIV may be a rational procedure for interfering with the initial stage of HIV infection. The immunosuppression induced is of short duration and is completely reversible, as demonstrated in the rheumatoid arthritis patients. Given the dire situation of an occupational exposed individual, even though the calculated risk of infection is only small,s immediate infusion of CD4 mAb should be considered as a means of counteracting virus invasion. The
worker,
Inpt= inpatients; Outpt= outpatients; n=number of subjects 7 *Denved from data in ref
The sensitivity and specificity for these WHO/CDC criteria are in broad agreement with those of earlier reports2-5 despite being measured in a more rigorously defmed study population. Although such agreement might be expected a valid estimate of these indices, as well as of PPV, can be derived only from a study that looks at whether criteria can discriminate between those who are unwell because of HIV-related immunodeficiency and those with an infectious illness and/or malnutrition. A study using other types of patients as controls merely serves to artificially increase the specificity and PPV of the test.2-7 PPV is an unstable characteristic determined by the prevalence of the diagnosis that the test is designed to detect. 8 In Zaire, Tanzania, and Uganda the population seroprevalence rates for HIV carriage were 7%, 5-2%, and 15%, respectively,3,9,lo and hospital seroprevalence rates for HIV were 29-52% (table). In Cameroon the low background population seroprevalence, with the low rate of HIV carriage (9%) in the study population, may have contributed to the low PPV of 33% in our study. In addition, the clinical criteria have been measured against an imperfect "gold standard". Patients with AIDS represent the few patients who are HIV-1carriers (and have seroconverted). Seroconversion is not synonymous with AIDS. The number of patients who are classed as false negatives by the clinical criteria (5 % of our population) will therefore reflect the number of AIDS patients that the criteria failed to identify, as well as the large number of people who are symptom-free carriers. The apparent sensitivity of the criteria will therefore be negatively influenced by increases in the background seroprevalence of HIV. Subjective clinical assessment may be a further source of error. For instance, a 10% reduction in body weight and asthenia could not be accurately documented in the study conditions. Nuffield Department of Clinical Medicine and Department of Virology, John Radcliffe Hospital, Oxford 0X3 9DU, UK
I. M. J. MACKENZIE R. EGLIN G. PASVOL
1. Anon Acquired immunodeficiency syndrome (AIDS): WHO/CDC case definition for AIDS. Wkly Epidem Rec 1986; 61: 61-76. 2. Colebunders R, Mann JM, Francis H, et al. Evaluation of clinical case-definition of acquired immunodeficiency syndrome in Africa. Lancet 1987; i: 492-94. 3. Mugerwa R, Widy-Kirski R, Okware S, Downing R, Berkey S. Assessment of a provisional WHO clinical case definition of HIV related illness in the referral hospital of Uganda. Second international symposium of AIDS and associated cancers in Africa, Oct 7-9, 1987, Naples, Italy. Abstract TH-89. 4 De Cock KM, Colebunders R, Francis H, et al. Evaluation of the WHO clinical case definition m rural Zaire AIDS 1988; 2: 219-21. 5 Widy-Wirski R, Berkley S, Downing R, et al Evaluation of the WHO clinical case definition for AIDS m Uganda. JAMA 1988; 260: 3286-89. 6 Wabwire-Mangen F, Serwadda D, Sewankambo NK, et al. Further experience with the World Health Organization clinical case definition for AIDS in Uganda. AIDS
1989; 3: 462-63. 7
Schiodt M, Bakilana PB, Hiza JF, et al. Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. Oral Surg Oral Med Oral Pathol 1990; 69: 591-96.
8
Haynes RB. How to read clinical journals: II, to learn about a diagnostic test. Can Med Assoc J 1981; 124: 703-52 9. Mann JM, Snider DE, Francis H, et al Association between HTLV-III/LAV infection and tuberculosis in Zaire. JAMA 1986; 256: 346. 10 Mhalu F, Bradberg-Raden U, Mbena E, et al. Prevalence of HIV infection in healthy subjects and groups of patients in Tanzania. AIDS 1987; 1: 217-21 11 Colebunders RL, Braun MM, Nzila N, Dikilu K, Muepu K, Ryder R. Evaluation of the World Health Organization clinical case definition of AIDS among tuberculosis patients in Kinshasa, Zaire J Infect Dis 1989; 160: 902-03.
Soluble CD4 in
of
patients treated with CD4 mAb M-T151. Within a controlled study approved by the ethical committee, University of Munich, patients with active rheumatoid arthritis received sera
20 mg munne CD4 mAb M-T151 as a 30 min infusion Soluble CD4 concentrations measured by capture ELISA with two non-crosscompeting CD4 mAb (unpublished) Data as mean and SD (n=55
patients)
1008
INHIBITION OF HIV INFECTION OF H9 CELLS BY DELAYED ADDITION OF M-T413
3x10’ H9 cells Incubated with HIV-1 strain M899 (Dr L Gúrtler, Munich) Minimum time of virus contact required for productive infection by defined virus dose was evaluated in experiments where no mAb was added. At indicated time points cells were washed 3 x with phospate-buffered saline cultivated for 6 days To find out for how long after H IV addition CD4 mAb can still prevent H IV-1 infection In vitro, M-T413 was added at 10 g/ml at the times indicated. After 1 day cells were washed and cultures continued for 5 days. CD4 mAb M-T413 is directed against the V1 domain of human CD4. It has an affinity of 8 x 10" mol-’ and proved to bethe most potent inhibitor of HIV-1 infection of 108 CD4 mAb prepared m our laboratory, most of which had been generated in an effort to define new antigens on human T cells.’ Infection determined by measuring p24 concentration in supernatant (SN) (Abbott ELISA) or by immunostaining fixed cells with high-titre human anti-HIV antiserum and labelled rabbit antibody as second antibody.’ In immunostaining test 20 000 cells were evaluated. Infection scored as: - no cell stained, (+)=1-5 cells, + = 6-20, + + =21-100, and + + + = 100 cells stained.
availability of chimaeric (human Fc and mouse Fv) CD4 antibodies with a lowered risk of sensitising the patient towards a heterologous immunoglobulin could further facilitate the decision to adopt CD4 antibodies as a post-exposure measure against HIV infection. We thank C. Federle and A. Knop for technical assistance. This work was supported by the Ministry of Research and Technology (FVP/BGA
Munich I).
Institute for Immunology and Max von Pettenkofer Institute, Ludwig Maximilian University, D-8000 Munich, West Germany
E. P. RIEBER C. REITER L. GÜRTLER F. DEINHARDT G. RIETHMÜLLER
1. Henderson DK, Gerberding JL. Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: an interim analysis. J Infect Dis 1989; 160: 321-27. 2. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including consideration regarding zidovudine postexposure use. MMWR 1990; 39 (suppl RR1). 3. Looke DFM, Grove DI. Failed prophylactic zidovudine after needlestick injury. Lancet 1990; 335: 72-80. 4. Herzog C, Walker C, Muller W, et al. Anti-CD4 antibody treatment of patients with rheumatoid arthritis I: effect on clinical course and circulating T cells. J Autoimmun
attempt to identify HIV in these seronegative haemophiliacs, we have been able to study sixteen peripheral blood samples from 12 patients. Mononuclear cells were separated by ’Ficoll-Hypaque’ gradient and tested as follows in two ways. Cells were co-cultivated with phytohaemagglutinin-stimulated donor cells in RPM medium with 10% fetal calf serum and interleukin-2 10 units/ml. Culture supernatants were harvested weekly for 4 weeks and tested for HIV p24 antigen (Coulter). DNA was extracted from mononuclear cell pellets with lysis buffer (EDTA, 50, NaCl 0’ 1, "tris" HC150 mmol/1) containing 10%’Sarcosyl’and 100 jg/ml proteinase K, followed by phenol chloroform and ethanol precipitation. The DNA was amplified with 0.015 U/ml Taq polymerase (Cetus) in a double polymerase chain reaction (PCR) with nested gag and pol primers with a heating block (Techne PMC-2). The outer and inner primer pairs were as previously described.4 The product of the second amplification was subjected to electrophoresis on 3% agarose gels containing ethidium bromide. Appropriate controls were also tested. All samples were negative by both culture and PCR. We conclude therefore that, despite presumed exposure to an infected batch of factor VIII, these seronegative patients are not silent carriers of HIV. This is in agreement with the results of other laboratory tests (T4 and T8 cell counts, &bgr;2-microglobulin, neopterin, and IgA levels.5 The major difference between those who became infected and those who did not is that the seronegative group had been given less factor VI I 1.5 The two groups also differed in circulating IgM, those who seroconverted having a higher mean level than those who remained seronegative. An analysis of this finding in relation to other measures of immunological function in the members of the cohort before and after exposure to HIV is in preparation. Failure to infect 14 of the 32 patients may be due, therefore, to a low concentration of virus in the implicated batch of clotting factor and to subtle differences in susceptibility to a low challenge dose of virus. In
an
1989; 2: 627-42. 5. Centers for Disease Control. Guidelines for the prevention of transmission of human immunodeficiency virus and hepatitis B virus to health care and public safety workers. MMWR 1989; 38 (suppl S6). 6. Rieber EP. T cell section report. In: Knapp W, Doerken P, Gilks WR, et al, eds. Leukocyte typing IV, white cell differentiation antigens. Oxford: Oxford University Press, 1989: 229. 7. Erfle V, Hehlmann R, Mellert W, et al. Prevalence of antibodies to HTLV-III in AIDS risk groups m West Germany. Cancer Res 2985; 45: 4627-29.
Confirmation of non-infection in
persistently HIV-seronegative recipients
of
This work was supported Research Council.
by
a
special project grant from the Medical
Department of Medical Microbiology, University of Edinburgh, Edinburgh EH8 9AG, UK
J. F. PEUTHERER S. REBUS P. BARR
Department of Haematology, Royal Infirmary of Edinburgh,
C. A. LUDLAM H. G. WATSON
MRC Human Genetics Unit, Western General Hospital, Edinburgh
M. C. STEEL
contaminated factor VIII SIR,-We have described a cohort of patients with haemophilia in Edinburgh who were probably infected with HIV from a single batch of factor VIII.1 The implicated batch was transfused between March and May, 1984, to 32 patients who had been maintained solely on locally produced (Scottish National Blood Transfusion Service) factor VIII concentrates. 18 recipients seroconvenerted, and their clinical and laboratory features have been described.2,3 The other 14 have remained negative for antibody to HIV (Abbott ’Combi 1 /2’ and ’Wellcozyme’ ELI SAs). It is of great importance to establish that these anti-HIV negative patients are not infected silently.
1. Ludlam CA, Tucker J, Steel CM, et al. HTLV-III infection in seronegative haemophiliacs following transfusion of factor VIII. Lancet 1985 ii: 233-36 2. Simmonds P, Lainson FAL, Cuthbert R, Steel CM, Peutherer JF, Ludlam CA. HIV antigen and antibody detection, variable responses to infection in the Edinburgh haemophiliac cohort. Br Med J 1988; 296: 593-98. 3. Cuthbert RJG, Ludlam CA, Rebus S, et al. Human immunodeficiency virus detection: correlation with clinical progression in the Edinburgh haemophiliac cohort. Br J Haematol 1989; 72: 387-90 4. Simmonds P, Balfe P, Peutherer JF, Ludlam CA, Bishop JO, Leigh Brown AJ Human immunodeficiency virus—infected individuals contain provirus m small numbers of peripheral mononuclear cells and at low copy number J Virol 1990, 64: 864-72. 5. Cuthbert RJG, Ludlam CA, Steel CM, et al. Five year prospective study infection m the Edinburgh haemophiliac cohort. Br Med J(in press).
of HIV
COMPARISON OF INVESTIGATIONS THAT USED WHO/CDC CRITERIA FOR AIDS
Monoclonal CD4 antibodies after accidental HIV infection SIR,-What should be done when a nurse, doctor, laboratory or other health-care worker is exposed to HIV-infected blood through a needlestick or other hazardous injury? Prophylactic zidovudine has been proposed but this may not always prevent HIV infection.3 This drug interferes with HIV replication; once viral DNA has been integrated into cellular DNA it can, at best, prevent progression of infection but not infection itself. Where an apparently minute amount of virus, free or cell-bound, has gained parenteral access to the body an intervention aimed at rapid interference with cellular uptake of the virus is required. To do this, we suggest blocking cellular CD4 receptors, removing or inactivating CD4 + cells temporarily, and neutralising free virus by rapidly released endogenous CD4 glycoprotein. High-affinity monoclonal CD4 antibodies (mAb) are good candidates for achieving these goals. As demonstrated in more than 30 patients with rheumatoid arthritis treated with murine CD4 antibodies a serum concentration of 2-5 /lg/ml mAb is obtained within 1 h of the infusion of 20 mg mAb, and the nadir of circulating CD4 + cells is seen 2-3 h after infusion (4 and unpublished). Soluble CD4 is detected at peak concentrations 3 h after infusion (figure). More importantly, however, high affinity CD4 mAb are now available which can interfere in vitro with productive infection of susceptible cells when added as late as 60 min after exposure of the cells to a high dose of infectious HIV. The table gives data of one of four experiments with almost identical results and shows that there is a time lag between the binding of HIV to the CD4 receptor and its irreversible uptake into the cell. During this period, it is still possible to interfere with viral infection by displacing the virus from the CD4 receptor. CD4 mAb, like the M-T413 used in these experiments, can block infection of cells by free virus and recruitment of uninfected cells into syncytia formation by infected cells. Thus, mAb M-T413 at a concentration of 0-03 ug/ml can inhibit syncytia formation of C8166 cells after addition of HIV-infected H9 cells. Therefore, these antibodies may be useful in counteracting infection by free as well as by cell-bound virus. Inoculated HIV-positive allogenic cells are assumed to be destroyed within two weeks after inoculation. In contrast to the intravenous administration of other monoclonal anti-T-cell antibodies such as CD3 the infusion of CD4 mAb is well tolerated. Temporary blockade of the cellular CD4 receptor with high-affinity CD4 mAb for several days after accidental exposure to HIV may be a rational procedure for interfering with the initial stage of HIV infection. The immunosuppression induced is of short duration and is completely reversible, as demonstrated in the rheumatoid arthritis patients. Given the dire situation of an occupational exposed individual, even though the calculated risk of infection is only small,s immediate infusion of CD4 mAb should be considered as a means of counteracting virus invasion. The
worker,
Inpt= inpatients; Outpt= outpatients; n=number of subjects 7 *Denved from data in ref
The sensitivity and specificity for these WHO/CDC criteria are in broad agreement with those of earlier reports2-5 despite being measured in a more rigorously defmed study population. Although such agreement might be expected a valid estimate of these indices, as well as of PPV, can be derived only from a study that looks at whether criteria can discriminate between those who are unwell because of HIV-related immunodeficiency and those with an infectious illness and/or malnutrition. A study using other types of patients as controls merely serves to artificially increase the specificity and PPV of the test.2-7 PPV is an unstable characteristic determined by the prevalence of the diagnosis that the test is designed to detect. 8 In Zaire, Tanzania, and Uganda the population seroprevalence rates for HIV carriage were 7%, 5-2%, and 15%, respectively,3,9,lo and hospital seroprevalence rates for HIV were 29-52% (table). In Cameroon the low background population seroprevalence, with the low rate of HIV carriage (9%) in the study population, may have contributed to the low PPV of 33% in our study. In addition, the clinical criteria have been measured against an imperfect "gold standard". Patients with AIDS represent the few patients who are HIV-1carriers (and have seroconverted). Seroconversion is not synonymous with AIDS. The number of patients who are classed as false negatives by the clinical criteria (5 % of our population) will therefore reflect the number of AIDS patients that the criteria failed to identify, as well as the large number of people who are symptom-free carriers. The apparent sensitivity of the criteria will therefore be negatively influenced by increases in the background seroprevalence of HIV. Subjective clinical assessment may be a further source of error. For instance, a 10% reduction in body weight and asthenia could not be accurately documented in the study conditions. Nuffield Department of Clinical Medicine and Department of Virology, John Radcliffe Hospital, Oxford 0X3 9DU, UK
I. M. J. MACKENZIE R. EGLIN G. PASVOL
1. Anon Acquired immunodeficiency syndrome (AIDS): WHO/CDC case definition for AIDS. Wkly Epidem Rec 1986; 61: 61-76. 2. Colebunders R, Mann JM, Francis H, et al. Evaluation of clinical case-definition of acquired immunodeficiency syndrome in Africa. Lancet 1987; i: 492-94. 3. Mugerwa R, Widy-Kirski R, Okware S, Downing R, Berkey S. Assessment of a provisional WHO clinical case definition of HIV related illness in the referral hospital of Uganda. Second international symposium of AIDS and associated cancers in Africa, Oct 7-9, 1987, Naples, Italy. Abstract TH-89. 4 De Cock KM, Colebunders R, Francis H, et al. Evaluation of the WHO clinical case definition m rural Zaire AIDS 1988; 2: 219-21. 5 Widy-Wirski R, Berkley S, Downing R, et al Evaluation of the WHO clinical case definition for AIDS m Uganda. JAMA 1988; 260: 3286-89. 6 Wabwire-Mangen F, Serwadda D, Sewankambo NK, et al. Further experience with the World Health Organization clinical case definition for AIDS in Uganda. AIDS
1989; 3: 462-63. 7
Schiodt M, Bakilana PB, Hiza JF, et al. Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania. Oral Surg Oral Med Oral Pathol 1990; 69: 591-96.
8
Haynes RB. How to read clinical journals: II, to learn about a diagnostic test. Can Med Assoc J 1981; 124: 703-52 9. Mann JM, Snider DE, Francis H, et al Association between HTLV-III/LAV infection and tuberculosis in Zaire. JAMA 1986; 256: 346. 10 Mhalu F, Bradberg-Raden U, Mbena E, et al. Prevalence of HIV infection in healthy subjects and groups of patients in Tanzania. AIDS 1987; 1: 217-21 11 Colebunders RL, Braun MM, Nzila N, Dikilu K, Muepu K, Ryder R. Evaluation of the World Health Organization clinical case definition of AIDS among tuberculosis patients in Kinshasa, Zaire J Infect Dis 1989; 160: 902-03.
Soluble CD4 in
of
patients treated with CD4 mAb M-T151. Within a controlled study approved by the ethical committee, University of Munich, patients with active rheumatoid arthritis received sera
20 mg munne CD4 mAb M-T151 as a 30 min infusion Soluble CD4 concentrations measured by capture ELISA with two non-crosscompeting CD4 mAb (unpublished) Data as mean and SD (n=55
patients)
1008
INHIBITION OF HIV INFECTION OF H9 CELLS BY DELAYED ADDITION OF M-T413
3x10’ H9 cells Incubated with HIV-1 strain M899 (Dr L Gúrtler, Munich) Minimum time of virus contact required for productive infection by defined virus dose was evaluated in experiments where no mAb was added. At indicated time points cells were washed 3 x with phospate-buffered saline cultivated for 6 days To find out for how long after H IV addition CD4 mAb can still prevent H IV-1 infection In vitro, M-T413 was added at 10 g/ml at the times indicated. After 1 day cells were washed and cultures continued for 5 days. CD4 mAb M-T413 is directed against the V1 domain of human CD4. It has an affinity of 8 x 10" mol-’ and proved to bethe most potent inhibitor of HIV-1 infection of 108 CD4 mAb prepared m our laboratory, most of which had been generated in an effort to define new antigens on human T cells.’ Infection determined by measuring p24 concentration in supernatant (SN) (Abbott ELISA) or by immunostaining fixed cells with high-titre human anti-HIV antiserum and labelled rabbit antibody as second antibody.’ In immunostaining test 20 000 cells were evaluated. Infection scored as: - no cell stained, (+)=1-5 cells, + = 6-20, + + =21-100, and + + + = 100 cells stained.
availability of chimaeric (human Fc and mouse Fv) CD4 antibodies with a lowered risk of sensitising the patient towards a heterologous immunoglobulin could further facilitate the decision to adopt CD4 antibodies as a post-exposure measure against HIV infection. We thank C. Federle and A. Knop for technical assistance. This work was supported by the Ministry of Research and Technology (FVP/BGA
Munich I).
Institute for Immunology and Max von Pettenkofer Institute, Ludwig Maximilian University, D-8000 Munich, West Germany
E. P. RIEBER C. REITER L. GÜRTLER F. DEINHARDT G. RIETHMÜLLER
1. Henderson DK, Gerberding JL. Prophylactic zidovudine after occupational exposure to the human immunodeficiency virus: an interim analysis. J Infect Dis 1989; 160: 321-27. 2. Centers for Disease Control. Public health service statement on management of occupational exposure to human immunodeficiency virus, including consideration regarding zidovudine postexposure use. MMWR 1990; 39 (suppl RR1). 3. Looke DFM, Grove DI. Failed prophylactic zidovudine after needlestick injury. Lancet 1990; 335: 72-80. 4. Herzog C, Walker C, Muller W, et al. Anti-CD4 antibody treatment of patients with rheumatoid arthritis I: effect on clinical course and circulating T cells. J Autoimmun
attempt to identify HIV in these seronegative haemophiliacs, we have been able to study sixteen peripheral blood samples from 12 patients. Mononuclear cells were separated by ’Ficoll-Hypaque’ gradient and tested as follows in two ways. Cells were co-cultivated with phytohaemagglutinin-stimulated donor cells in RPM medium with 10% fetal calf serum and interleukin-2 10 units/ml. Culture supernatants were harvested weekly for 4 weeks and tested for HIV p24 antigen (Coulter). DNA was extracted from mononuclear cell pellets with lysis buffer (EDTA, 50, NaCl 0’ 1, "tris" HC150 mmol/1) containing 10%’Sarcosyl’and 100 jg/ml proteinase K, followed by phenol chloroform and ethanol precipitation. The DNA was amplified with 0.015 U/ml Taq polymerase (Cetus) in a double polymerase chain reaction (PCR) with nested gag and pol primers with a heating block (Techne PMC-2). The outer and inner primer pairs were as previously described.4 The product of the second amplification was subjected to electrophoresis on 3% agarose gels containing ethidium bromide. Appropriate controls were also tested. All samples were negative by both culture and PCR. We conclude therefore that, despite presumed exposure to an infected batch of factor VIII, these seronegative patients are not silent carriers of HIV. This is in agreement with the results of other laboratory tests (T4 and T8 cell counts, &bgr;2-microglobulin, neopterin, and IgA levels.5 The major difference between those who became infected and those who did not is that the seronegative group had been given less factor VI I 1.5 The two groups also differed in circulating IgM, those who seroconverted having a higher mean level than those who remained seronegative. An analysis of this finding in relation to other measures of immunological function in the members of the cohort before and after exposure to HIV is in preparation. Failure to infect 14 of the 32 patients may be due, therefore, to a low concentration of virus in the implicated batch of clotting factor and to subtle differences in susceptibility to a low challenge dose of virus. In
an
1989; 2: 627-42. 5. Centers for Disease Control. Guidelines for the prevention of transmission of human immunodeficiency virus and hepatitis B virus to health care and public safety workers. MMWR 1989; 38 (suppl S6). 6. Rieber EP. T cell section report. In: Knapp W, Doerken P, Gilks WR, et al, eds. Leukocyte typing IV, white cell differentiation antigens. Oxford: Oxford University Press, 1989: 229. 7. Erfle V, Hehlmann R, Mellert W, et al. Prevalence of antibodies to HTLV-III in AIDS risk groups m West Germany. Cancer Res 2985; 45: 4627-29.
Confirmation of non-infection in
persistently HIV-seronegative recipients
of
This work was supported Research Council.
by
a
special project grant from the Medical
Department of Medical Microbiology, University of Edinburgh, Edinburgh EH8 9AG, UK
J. F. PEUTHERER S. REBUS P. BARR
Department of Haematology, Royal Infirmary of Edinburgh,
C. A. LUDLAM H. G. WATSON
MRC Human Genetics Unit, Western General Hospital, Edinburgh
M. C. STEEL
contaminated factor VIII SIR,-We have described a cohort of patients with haemophilia in Edinburgh who were probably infected with HIV from a single batch of factor VIII.1 The implicated batch was transfused between March and May, 1984, to 32 patients who had been maintained solely on locally produced (Scottish National Blood Transfusion Service) factor VIII concentrates. 18 recipients seroconvenerted, and their clinical and laboratory features have been described.2,3 The other 14 have remained negative for antibody to HIV (Abbott ’Combi 1 /2’ and ’Wellcozyme’ ELI SAs). It is of great importance to establish that these anti-HIV negative patients are not infected silently.
1. Ludlam CA, Tucker J, Steel CM, et al. HTLV-III infection in seronegative haemophiliacs following transfusion of factor VIII. Lancet 1985 ii: 233-36 2. Simmonds P, Lainson FAL, Cuthbert R, Steel CM, Peutherer JF, Ludlam CA. HIV antigen and antibody detection, variable responses to infection in the Edinburgh haemophiliac cohort. Br Med J 1988; 296: 593-98. 3. Cuthbert RJG, Ludlam CA, Rebus S, et al. Human immunodeficiency virus detection: correlation with clinical progression in the Edinburgh haemophiliac cohort. Br J Haematol 1989; 72: 387-90 4. Simmonds P, Balfe P, Peutherer JF, Ludlam CA, Bishop JO, Leigh Brown AJ Human immunodeficiency virus—infected individuals contain provirus m small numbers of peripheral mononuclear cells and at low copy number J Virol 1990, 64: 864-72. 5. Cuthbert RJG, Ludlam CA, Steel CM, et al. Five year prospective study infection m the Edinburgh haemophiliac cohort. Br Med J(in press).
of HIV
