Glutathione deficiency and HIV infection

1603

Mode of delivery in HIV-1-infected

women

SiR,—The European Collaborative Study group (April 25, 1007) have analysed the risk factors for mother-to-child transmission of HIV-1 infection. A higher transmission rate was seen in patients with vaginal deliveries in which scalp electrodes, forceps, or vacuum extractors were used, and there was some evidence that a protective effect of operative delivery reduced the p

risk of HIV-1 transmission about threefold compared with vaginal delivery. Goedert et aP earlier reported similar results in an investigation of twins and triplets born to HIV-1-infected women. We feel that it is too early to recommend a specific mode of delivery in HIV-1-infected women, but not just because of insufficient data, as the European Collaborative Study group states. Before advising obstetricians to do elective caesarean sections, not only the risk factors for the virus transmission, but also the effect of

Mean values of

serum

iron and transferrin saturation.

Data from 26 patients and 52 courses of a combination of thiotepa, cyclophosphamide, and mitoxantrone given daily over 4 days.’

surgery on maternal course of disease should be emphasised. To what degree pregnancy itself should be regarded as a risk factor in the subsequent course of disease of mothers with HIV-1infection is still unclear.2,3 However, it is well established that anaesthesia and -5 surgery can induce important changes of the immune system.4,5 How such alterations may interfere with HIV pathogenesis is unknownbut a possible contribution of anaesthetic agents and operative trauma to initiate virus replication and hence to accelerate disease progression should be considered. Thus, the mode of delivery in HIV-1-infected women has to be evaluated in a randomised controlled study that also includes monitoring of possible changes of the mothers’ clinical and immunological status. Department of Obstetrics and Gynaecology, Eisenstadt

the process of catalase decrease, haem entry, scission, iron release, and catalysis of oxidative degradation of cells can follow-and thus account for the occasional report of pulmonary toxicity. We have completed 85 patient-courses with 5 days of desferrioxamine at 15 mg/kg per h x 8 h without any adverse reactions, and presume that these patients were not iron overloaded. We propose that patients with high serum iron and transferrin saturation levels avoid transfusions, iron supplements, and chemotherapy for at least 2 weeks before administration of desferrioxamine alone8 or in protocols such as D-CECaT.9 In patients who cannot afford a treatment-free interval, we suggest the 5 day intravenous course be given as a maximum of 15 mg/kg per h alone for 8 h daily for 2 days, then withhold all medications for 24 h to permit elimination of excess iron and normal pulmonary tissue repletion of catalase. This will allow a decrease in haem synthesis, and limit potential oxidant damage to the immediate 3-day period of desferrioxamine treatment. Chemotherapy and blood transfusions can be given afterwards where necessary. Department of Medicine, Division of Neoplastic Diseases, New York Medical College, Westchester County Medical Center, Valhalla, New York 10595, USA

LAWRENCE HELSON CHRISTIANS HELSON SUSAN BRAVERMAN GlOVANNI DEB ALBERTO DONFRANCESCO

Jacob HS, Craddock PR, Hammerschmidt DE, Modow CF. Complement-induced granulocyte aggregation. An unsuspected mechanism of disease. N Engl J Med 1980; 302: 789. 2. Gannon DE, Varani J, Phan SH, et al. Source of iron in neutrophil mediated killing of endothelial cells. Lab Invest 1987; 57: 37. 3. Sadrzadeh SMH, Anderson DK, Panter SS, Hallaway PE, Eaton JW. Hemoglobin potentiates central nervous system damage. J Clin Invest 1988; 79: 662. 4. Balla G, Vercellotti GM, Muller-Eberhard, Eaton J, Jacob HS. Exposure of endothelial cells to free heme potentiates damage mediated by granulocytes and toxic oxygen species. Lab Invest 1990; 64: 648-55. 5. Varani J, Fligiel SEG, Till GO, Kunkel RG, Ryan US, Ward PA. Pulmonary endothelial cell killing by human neutrophils. Possible involvement of hydroxyl radical. Lab Invest 1985; 53: 656. 6. Haurowitz F, Schwerin P, Yenson M. Destruction of hemin and hemoglobin by the action of unsaturated fatty acids and oxygen. J Biol Chem 1941; 140: 353. 7. Helson L, Helson C, Ahmed T, et al. Mitoxantrone, cytoxan, thiotepa, and stem cell 1.

boost for breast cancer. Proc Am Assoc Cancer Res 1992; abstr 1551. 8. Helson L, Deb G, Donfrancesco A. Complete remission of stage III-IV neuroectodermal tumors after desferal, cytoxan, etoposide, carboplatin, thiotepa (D-CECaT). Proc Am Soc Clin Oncol 1992; abstr 1275. 9. Donfrancesco A, Deb G, Dominici C, Pileggi D, Castello MA, Helson L. Effects of a single course of deferoxamine in neuroblastoma patients. Cancer Res 1990; 50: 4929-30.

Institute for Medical Chemistry and Biochemistry, University of Innsbruck, and Ludwig Boltzmann Institute

for AIDS-Research, A-6020 Innsbruck, Austria

LOTHAR C. FUITH MARYAN CZARNECKI

HELMUT WACHTER DIETMAR FUCHS

Duliege AM, Amos CI, et al. High risk of HIV-1 infection for first-born twins. Lancet 1991; 338: 1471-75. 2. Lindgren S, Anzen B, Bohlin A, Lidman K. HIV and child-beating: clinical outcome and aspects of mother-to-infant transmission. AIDS 1991, 5: 1111-16. 3. Mayr P, Fuchs D, Fuith LC, et al. Pregnancy increases urinary neopterin levels in human immunodeficiency virus type 1 infection. Pteridines 1990; 2: 161-64. 4. Tonnensen E, Wahlgreen C. Influence of extradural and general anaesthesia on natural killer cell activity and lymphocyte subpopulations in patients undergoing hysterectomy. Br J Anaesth 1988; 60: 500-07. 5. Slade MS, Simmons RL, Yunis E, et al. Immunodepression after major surgery in normal patients. Surgery 1975; 78: 363-72. 6. Barbui T, Cortelazzo S, Minetti B, Galli M, Buelli M. Does splenectomy enhance risk of AIDS in HIV positive patients with chronic thrombocytopenia? Lancet 1987; ii: 1. Goedert JJ,

342-43.

Glutathione deficiency and HIV infection SIR,-Mr Staal and colleagues (April 11, p 909) review evidence indicating that HIV infection is associated with depletion of leucocyte glutathione (GSH) and that such deficiency might promote replication of the virus. They suggest that administration of N-acetylcysteine to HIV-infected patients may enhance intracellular GSH stores. Although there are sound reasons to support a trial of N-acetylcysteine therapy in HIV-infected patients, we feel that additional factors should be considered before such therapy is routinely used. First, it is well known that protein intake substantially affects

plasma GSH concentrations.1,2 Treatment strategies use of aminoacids or closely related compounds should be implemented after evaluation of the overall nutritional status of the patient and correction of any evident nutrient deficiencies. Simple measures such as maintaining adequate intake of protein with high biological value might help in the preservation of GSH stores in HIV-infected patients. Such protein would necessarily include methionine and cysteine, and this approach could reduce the potential need for or quantity of GSH precursors such as N-acetylcysteine. Staal et al state that GSH deficiency has been noted in symptom-free HIV-infected patients and therefore is not the consequence of a wasting syndrome. However, nutritional deficiencies are known to exist in patients with diarrhoea and non-traditional dietary habits, as well as in individuals receiving tissue and

involving

the

1604

prescription drugs. These deficiencies may occur before wasting is seen. Thus, the HIV-infected patient should be thoroughly evaluated, counselled, and undergo appropriate nutritional therapy before receiving a procysteine agent. Second, it has been suggested that N-acetylcysteine administration will reverse the plasma thiol deficiency associated with HIV infection and thereby provide the rate-limiting constituent necessary for adequate GSH synthesis. However, various

overt

leucocyte GSH remains unchanged and is substantially depressed in HIV-infected patients receiving therapy with zidovudine, which triples the plasma acid-soluble thiol concentration.3 Hence, Nacetylcysteine therapy alone may be inadequate for enhancing intracellular GSH concentration. We have found that the aminoacid glutamine is important for the preservation of GSH stores in animals subjected to oxidative injury. These experiments were done in the presence of methionine, the biological precursor of cysteine, and other nutrients.4 Early investigations with radiolabelled aminoacids have shown that extracellular glutamine is preferentially used over glutamate for the synthesis of GSH in several tissues and cell types. Under some circumstances, the availability of glutamine may be rate-limiting for GSH synthesis.s In addition, in-vitro studies showing that N-acetylcysteine can inhibit HIV replication were done with culture medium (RPMI 1640) containing high, supraphysiological concentrations of glutamine.6 Thus, the administration of glutamine could be an important adjunct to treatments aimed at enhancing tissue GSH stores. We have reported that the administration of glutamineenriched total parenteral nutrition (TPN) to bone-marrow transplant patients who received extensive chemotherapy and radiation therapy decreased their rate of infection by two-thirds compared with those receiving standard, glutamine-free TPN.7 The mechanisms responsible for this observation may involve immune modulation related in part to the maintenance of

glutathione stores. nutritional Appropriate supplementation with various

evaluation and support, GSH precursors, and concomitant administration of other antiviral agents may prove to be most beneficial for those infected with HIV. Laboratory for Surgical Metabolism and Nutrition, Department of Surgery, MALCOLM K. ROBINSON Brigham and Women’s Hospital ROY W. HONG and Harvard Medical School, DOUGLAS W. WILMORE Boston, Massachusetts 02115, USA

1. Shi

ECP, Fisher R, McEvoy M, Vantol R, Rose M, Ham JM. Factors influencing hepatic glutathione concentrations: a study in surgical patients. Clin Sci 1982; 62: 279-83.

2. Martensson J. The effect of fasting on leukocyte and plasma glutathione and sulfur amino acid concentrations. Metabolism 1986; 35: 118-21. 3. Eck HP, Gmunder H, Hartmann M, Petzoldt D, Daniel V. Droge W. Low concentrations of add-soluble thiol (cysteine) m the blood of HIV-1-infected patients. Biol Chem Hoppe-Seyler 1989; 370: 101-08. 4. Hong RW, Rounds JD, Helton WS, Robinson MK, Wilmore DW. Glutamine preserves liver glutathione after lethal hepatic injury. Ann Surg 1992; 215: 114-19. 5. Welboume TC. Ammonia production and glutamine incorporation into GSH in the functioning rat kidney. Can J Biochem 1979; 57: 233-37. 6. Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, Fauci AS. Suppression of HIV expression in chronically infected monocyte cells by glutathione, glutathione ester, and N-acetylcysteine. Proc Natl Acad Sci USA 1991; 88: 986-90. 7. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition following bone marrow transplantation: a randomized, double-blind controlled study. Ann Intern Med 1992; 116: 821-28.

T cells, V genes, and HIV SIR,-Professor Dalgleish and colleagues (April 14, p 824) describe an increase in CD3-positive T cells bearing the V (35 3 gene product in HIV-seropositive individuals with "normal" CD4 counts. During the past few months, and for identical reasons, we have undertaken a similar analysis of 13 symptom-free HIVseropositive patients. T cells were analysed for V region epitopes with a whole blood method and the Q Prep red cell lysis system (Coulter) in conjunction with the Diversi-T ab TCR kit (T Cell Sciences). At least 10 000 cells were counted for each analysis and the results expressed as a percentage of otp T cell receptor (TCR) positive cells. This was designed to eliminate the effects of the

variable increase in yò T cells recorded in the CD3-positive T cell population in HIV-infected patients.’ By contrast with Dalgleish et al, we observed highly significant reductions in the Vp5 1, Vpl2, and Vr:J2 subfamilies but no difference in the Vp5subfamily in the HIV group: %T cells expressing V-gene product HIV positive Controls Ab (designated specificity) (n= 13) (n = 13) 1-03 (1-58) 4-02 (1-18)* aV2a (Va2 subfamily) 2-72 (0-50) 2.74 (0-99) PV5a (Vp5’3 subfamily) 1 ’02 (0-28) 0-88 (0-36) PV5b (Vp5subfamily) 336 (0-55)* RV5c (VP5-1) 199 (127) 1-82 (1-12) 2-84 (1-84) pV6a(Vp6 subfamily) 3-45 (214) 3-97 (0-66) f)V8a (Vp8 subfamily) 0-91 (0-60) 1-78 (0-39)* pV12a (Vpl2 subfamily) Data

as mean

(SD). *p<0001

(Mann-Whitney U test).

Differences in the methods used by Dalgleish et al and ourselves unlikely to explain this disparity between the two studies. In the Dalgleish data the percentage of CD3 T cells expressing specific V gene products (Vgp) was consistently higher in the HIV group than in controls. Although this may be the result of reductions in CD3 T cells expressing Vgp other than those assessed, it suggests that their control group is flawed in some way. Imberti et al2 using a polymerase chain reaction method, have shown reductions in Vpl4toVp20 and Vo 12 in patients with AIDSS and generally lower values for these Vps in symptomless HIVseropositive patients with normal lymphocyte counts. Their data also suggest that the Vp6 and the Vp8 subfamilies are lower in symptomless HIV-infected individuals than in the controls. Our results are similar in showing several Vgp to be reduced in symptomless HIV infection. Furthermore, this group also found no evidence of a selective increase in T cells bearing specific Vgp in any HIV group. Grunewald et al3 have reported a biased expression of TCR V gene segments in CD4 and CD8 T cells. Although this may have contributed to the low Vp5-lsubfamily result in our HIV group, the degree of depression of the V r:J2 and V(i12 subfamilies and the preservation of the other subfamilies suggests that our results are real. Any investigation of TCR V gene use in HIV patients with low CD4 counts will clearly need to pay particular attention to this biased expression. The increase in V (353 gene product observed by Dalgleish et al is probably the result of their having an unusual control group. Since the progression of HIV infection may be affected by several cofactors, both studies would benefit by the proper comparison of TCR V gene expression in HIV-seropositive patients with a seronegative group exposed to similar cofactors. The explanation for the selective reduction in several Vgp in symptomless HIVinfected individuals is unclear. Further work is required to assess the presence of an HIV superantigen or the induction of are

alloreactivity by gpl20/41. NW Regional Immunology St Mary’s Hospital, Manchester M13 0JH, UK

Department,

Regional Department of Infectious Disease and Tropical Medicine, Monsall Hospital, Manchester

A. S. BANSAL L. M. GREEN R. S. H. PUMPHREY

B. MANDAL

1. de Paoli P, Gennari D, Martielli P, et al. A subset of &Ugr;&dgr; lymphocytes is increased during HIV-1 infection. Clin Exp Immunol 1991; 83: 187-91. 2. Imberti L, Sottini A, Bettinardi A. Selective depletion in HIV infection of T cells that bear specific T cell receptor V&bgr; sequences. Science 1991; 254: 860-62. 3. Grunewald J, Janson CH, Wigzell H. Biased expression of individual T cell receptor V gene segments in CD4 + and CD8 + human peripheral blood T lymphocytes. Eur J Immunol 1991; 21: 819-22.

Failure to detect human

papillomavirus in Kaposi’s sarcoma

S:R,—Two Lancet reports (Feb 29, pp 515 and 548) suggest the presence of human papillomavirus (HPV) in Kaposi’s sarcoma (KS) of both the AIDS-related and endemic (non-HIV-positive) types: HPV16 sequences were found in 20% of KS samples and "papilloma-related antigens" in 70% of samples, with localisation directly to KS lesions by immunohistochemical techniques. These