Carrington, Mary

Gao, Xiaojiang

O\u27Brien, Stephen J.

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Nova Southeastern UniversityNSUWorksBiology Faculty Articles Department of Biological Sciences9-20-2001MHC Class I Molecules and Progression to AIDSMary CarringtonNational Cancer Institute at FrederickXiaojiang GaoNational Cancer Institute at FrederickStephen J. O'BrienNational Cancer Institute at Frederick, sobrien1@nova.eduFollow this and additional works at: http://nsuworks.nova.edu/cnso_bio_facarticlesPart of the Genetics and Genomics Commons, and the Medicine and Health Sciences CommonsThis Article is brought to you for free and open access by the Department of Biological Sciences at NSUWorks. It has been accepted for inclusion inBiology Faculty Articles by an authorized administrator of NSUWorks. For more information, please contact nsuworks@nova.edu.NSUWorks CitationCarrington, Mary; Xiaojiang Gao; and Stephen J. O'Brien. 2001. "MHC Class I Molecules and Progression to AIDS." New EnglandJournal of Medicine 345, (12): 924-925. http://nsuworks.nova.edu/cnso_bio_facarticles/792 924 · N Engl J Med, Vol. 345, No. 12 · September 20, 2001 · www.nejm.org The New England Journal  of  Medicinelimited to patients with tumors 5 cm or less in diameter,long-term survival approaches 75 percent at four years,whereas transplantation in those with tumors larger than5 cm has been associated with less than 30 percent surviv-al. 2,3  These data led to the exclusion of patients with largertumors from the waiting list for cadaveric organs. We sug-gest that if the supply of cadaveric organs were to exceed thecurrent demand, patients with the worst outcomes would beconsidered candidates. Can we now refuse to offer these pa-tients transplantation when a healthy living donor providesthe graft?A BRAHAM  S HAKED , M.D., P H .D. University of PennsylvaniaPhiladelphia, PA 19104abraham.shaked@uphs.upenn.edu M ICHAEL  R. L UCEY , M.D. University of Wisconsin School of MedicineMadison, WI 53792-5124 1. Lucey MR, Brown KA, Everson GT, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg 1997;3:628-37. 2. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. 3. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocel-lular carcinoma: expansion of the tumor size limits does not adversely im-pact survival. Hepatology 2001;33:1394-403. The authors reply: To the Editor:  We agree with most of the views of Millerand Delmonico, including their conclusions that the “trans-plantation community . . . does indeed monitor itself ” andthat it shows “concern for the well-being of living donors.” 1,2 In our article, we never question this commitment. Wealso agree that the surgical model of innovation based onprofessional self-regulation rather than administrative reg-ulation has proved to be an extremely effective way to ad-vance the field of surgery to benefit patients.Our disagreement with Miller and Delmonico focuseson whether the professional regulatory model involving con-ferences, colloquiums, and position papers will prove ade-quate for dealing with the transplantation of liver graftsfrom adult living donors and for protecting potential do-nors. We believe that the best way to optimize the use ofthis innovative technology is to define clearly the experimen-tal protocol, standardize the operation, ensure the “fieldstrength” of the surgical team, and record and share alldata on outcomes (including program-specific data) withthe professional community and with patients. If the pro-fessional community can accomplish these tasks quickly —and thus far they have not — there may not be a need forformal regulatory control.Shaked and Lucey highlight an unresolved issue with re-gard to recipients. Since the four-year survival among pa-tients who have hepatocellular carcinomas larger than 5 cmand undergo transplantation is so poor, 3  this group has beenexcluded from the waiting list for cadaveric organs. Shakedand Lucey suggest that living donors be subjected to com-plications and possibly death to provide grafts to recipientswith hepatocellular carcinomas, even though the transplan-tation community has declined to use cadaveric grafts in suchpatients. In our article, we refer to the need to balance theshort-term and long-term risks to the donor with the poten-tial benefits to the recipient. The proposal offered by Shakedand Lucey demonstrates the need for the transplantationcommunity to specify what outcomes in a recipient are ac-ceptable before a living donor is subjected to surgical risk.It also raises the question of whether individual programscan be required to comply with standards established by thesurgical transplantation community through professionalself-regulation.D AVID  C. C RONIN  II, M.D., P H .D.J. M ICHAEL  M ILLIS , M.D.M ARK  S IEGLER , M.D. University of ChicagoChicago, IL 60637dcronin@surgery.bsd.uchicago.edu 1. Abecassis M, Adams M, Adams P, et al. Consensus statement on the live organ donor. JAMA 2000;284:2919-26. 2. American Society of Transplant Surgeons’ position paper on adult-to-adult living donor liver transplantation. Liver Transpl 2000;6:815-7. 3. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. MHC Class I Molecules and Progression to AIDS To the Editor:  Gao et al. (May 31 issue) 1  report the iden-tification of specific HLA-B*35-Px subtypes as responsiblefor the association between HLA-B*35 and rapid progres-sion to AIDS, and they stress the importance of homozygos-ity for HLA-B*35 as a predictor of even more rapid progres-sion. Their extensive analysis confirms the known protectiveeffect of the HLA-B*27 and B*57 subtypes against pro-gression to AIDS, at least in whites. 2 Unlike Gao and colleagues, we think that there is an im-portant influence of numerous major-histocompatibility-complex (MHC) gene products. The A1,B8,DR3 haplotype,for instance, has repeatedly been shown to be associatedwith fast progression to human immunodeficiency virus(HIV) disease and rapid loss of CD4 T cells, 3,4  and severalother HLA haplotypes can predict disease progression.2Caution should be exercised before early, aggressive antiret-roviral therapy is recommended for HLA-B*35–positivepatients. We have been following an HIV-infected womanwithout symptoms since her seroconversion in 1991 (she isnow 37 years old). She has never received antiretroviral ther-apy and still has a high CD4 cell count (606 per cubic mil-limeter, 36.6 percent of total lymphocytes) and CD4:CD8ratio (0.91), despite being homozygous for HLA-B*35. Per-haps the presence of HLA A2,A26 alleles in her haplotypecounteracts the effects of HLA-B*35, since A2 is commonin frequently exposed HIV-seronegative persons5 and A26may confer resistance to the progression of HIV disease.2FRANCESCA CAINELLI, M.D.ERCOLE CONCIA, M.D.SANDRO VENTO, M.D.University of Verona37138 Verona, Italyfrancescacainelli@yahoo.itThe New England Journal of Medicine Downloaded from nejm.org at NOVA SOUTHEASTERN UNIV on February 15, 2016. For personal use only. No other uses without permission.  Copyright © 2001 Massachusetts Medical Society. All rights reserved. CORRESPONDENCEN Engl J Med, Vol. 345, No. 12 · September 20, 2001 · www.nejm.org · 9251. Gao X, Nelson GW, Karacki P, et al. Effect of a single amino acid change in MHC class I molecules on the rate of progression to AIDS. N Engl J Med 2001;344:1668-75.2. Kaslow RA, Carrington M, Apple R, et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 1996;2:405-11.3. Kaslow RA, Duquesnoy R, VanRaden M, et al. A1, Cw7, B8, DR3 HLA antigen combination associated with rapid decline of T-helper lym-phocytes in HIV-1 infection: a report from the Multicenter AIDS Cohort Study. Lancet 1990;335:927-30.4. McNeil AJ, Yap PL, Gore SM, et al. Association of HLA types A1-B8-DR3 and B27 with rapid and slow progression of HIV disease. QJM 1996;89:177-85.5. Malkovsky M. HLA and natural history of HIV infection. Lancet 1996;348:142-3.The authors reply:To the Editor: To date, over 50 papers have been pub-lished that attempt to associate HLA haplotypes with therate of progression to AIDS. Because of low statistical pow-er and small samples, the results of many cannot be con-sidered rigorously validated. Among the strongest associ-ations are the influence of HLA class I homozygosity andthe codominant influence of HLA-B*35. The goal of ourrecent report was to demonstrate that the previously report-ed effect of B*351 could be connected directly to the pep-tide-binding specificity of certain HLA-B*35 subtypes. Weare, of course, aware of several other genetic factors thatmitigate progression to AIDS, including the genes encod-ing CC chemokine receptors 5 and 2, interleukin-10, andstromal-cell–derived factor 1 as well as other HLA alleles,and we described them in our cohorts.1,2 These factors maycounteract each other, which could be the case for theHLA-B*35–homozygous woman described by Cainelli et al.This patient’s AIDS-free survival for 10 years is remark-able. In our experience with six patients homozygous forHLA-B*35 in five cohorts, five progressed to an AIDS-defining condition in less than 6 years and the other onein less than 10 years.We agree that multiple genetic and viral influences shouldbe considered when a therapeutic regimen for an HIV-infected patient is chosen. We believe that B*35-Px is oneof the more influential factors.MARY CARRINGTON, PH.D.XIAOJIANG GAO, PH.D.STEPHEN O’BRIEN, PH.D.National Cancer InstituteFrederick, MD 21702carringt@mail.ncifcrf.gov1. Carrington M, Nelson GW, Martin MP, et al. HLA and HIV-1: hetero-zygote advantage and B*35-Cw*04 disadvantage. Science 1999;283:1748-52.2. O’Brien SJ, Nelson GW, Winkler CA, Smith MW. Polygenic and mul-tifactorial disease gene association in man: lessons from AIDS. Annu Rev Genet 2000;34:563-91.Spironolactone in Addition to ACE Inhibition to Reduce Proteinuria in Patients with Chronic Renal DiseaseTo the Editor: Angiotensin-converting–enzyme (ACE)inhibitors have been shown to reduce proteinuria and slowthe progression of renal disease.1 Although to date angio-tensin II has been the focus of attention as the primary me-diator of the renin–angiotensin–aldosterone system, severalstudies have raised the possibility that aldosterone itself hasa role in mediating progressive renal disease.2,3 Pitt et al.4showed that blockade of aldosterone receptors by spirono-lactone significantly reduced the risk of morbidity and deathamong patients with heart failure who were already receivingACE inhibitors. The authors hypothesized that the benefitswere not due to the hemodynamic effects of spironolac-tone but, instead, may have been due to an adverse effectof aldosterone on myocardial and vascular smooth-musclecells. We tested the hypothesis that spironolactone may actalong with ACE inhibitors in the kidney to reduce pro-teinuria.*P<0.02 for the comparison between pretreatment and post-treatment urinary protein, by the paired t-test. There were no other significant differencesbetween pretreatment and post-treatment values.TABLE 1. CLINICAL CHARACTERISTICS AND FINDINGS BEFORE AND AFTER TREATMENT WITH SPIRONOLACTONE IN EIGHT PATIENTS.SEX AGE URINARY PROTEIN CREATININE CLEARANCE SYSTOLIC PRESSURE DIASTOLIC PRESSURE DIAGNOSISBEFORE TREATMENTAFTER TREATMENTBEFORE TREATMENTAFTER TREATMENTBEFORE TREATMENTAFTER TREATMENTBEFORE TREATMENTAFTER TREATMENTyr g/day ml/sec mm/HgMale 62 2.87 0.94 1.30 0.66 120 120 80 70 Type 2 diabetesMale 60 8.90 3.30 0.58 0.59 120 110 80 70 Type 2 diabetesFemale 43 2.83 2.94 2.50 2.02 120 110 90 70 Systemic lupus erythematosusMale 71 3.00 1.80 0.62 0.45 200 170 100 90 Type 2 diabetesMale 55 2.21 0.86 2.40 3.90 170 130 90 80 Type 2 diabetesMale 74 6.17 2.02 1.24 1.30 120 130 90 80 Focal sclerosis with segmen-tal hyalinosisMale 61 1.17 0.36 1.71 1.51 140 160 90 70 Type 2 diabetesFemale 31 3.30 1.75 0.48 0.53 120 115 90 80 VasculitisMean ±SD* 3.81±2.50 1.75±1.02 1.35±0.80 1.37±1.17 138.8±30.4 130.6±22.7 88.8±6.4 76.3±7.4The New England Journal of Medicine Downloaded from nejm.org at NOVA SOUTHEASTERN UNIV on February 15, 2016. For personal use only. No other uses without permission.  Copyright © 2001 Massachusetts Medical Society. All rights reserved. 

MHC Class I Molecules and Progression to AIDS

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MHC Class I Molecules and Progression to AIDS

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