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Failure Oft-Cell Homeostasis Preceding AIDS in HIV-1 Infection

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Failure Oft-Cell Homeostasis Preceding AIDS in HIV-1 Infection © 1995 Nature Publishing Group http://www.nature.com/naturemedicine • ····ARTICLES Failure ofT-cell homeostasis preceding AIDS in HIV-1 infection 2 2 joSEPH B. MARGOLICK\ ALVARO Ml1Noz , ALBERT D. DoNNENBERd, LAWRENCE P. PARK , 5 5 NOYA GALA!', jANIS V. GIORGI , MAURICE R.G. O'GORMAN", jOHN FERBAS , FOR THE MULTICENTER AIDS COHORT STUDY* 'Department ofMolecular Biology and Immunology, Johns Hopkins University School ofHygiene and Public Health, Room 7032, 615 North Wolfe Street, Baltimore, Maryland 21205-2179, USA 'Department ofEpidemiology, Johns Hopkins University School ofHygiene and Public Health, Room 795, 624 North Broadway, Baltimore, Maryland 21205, USA 'Montefiore University Hospital, 3459 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA 'The Hebrew Universtiy, Department ofEcological Medicine, Hadassah Medical School Jerusalem, P.O.B. 12272, Code 91120. Jerusalem, Israel 'Department ofMedicine, UCLA School ofMedicine,l2-939 FActor Building, 10833 LeConte Avenue, Los Angeles, California 90024-1745, USA •Department ofPediatrics, Northwestern University, 2300 Children's Plaza, Chicago, Illinois 60614, USA Co"espondence should be addressed to J.B.M. We and others have postulated that a constant number of T lymphocytes is normally maintained without regard to CD4• or cos• phenotype ('blind' T-cell homeostasis). Here we confirm essentially constant T-celllevels (despite marked decline in CD4• T cells and Increase in cos• T cells) in homosexual men with incident human Immunodeficiency virus, type 1 (HIV-1), infection who remained free of acquired immunodeficiency syndrome (AIDS) for up to eight years after seroconversion. In contrast, seroconverters who developed AIDS exhibited rapidly declining T cells (both CD4• and cos•) for approximately two years before AIDS, independent of the time between seroconversion and AIDS, suggesting that homeostasis failure is an important landmark in HIV disease progression. Given the high rate of T-cell turnover in HIV-1 infection, blind T-cell homeostasis may contribute to HIV pathogenesis through a cos• T lymphocytosis that interferes with regeneration of lost CD4• T cells. Consistent features of HIV-1 infection are progressive loss of and Wofsy', who reviewed evidence that it operates in HIV-nega­ C04• T lymphocytes and increase in cos· T lymphocytes. In a tive populations such as bone marrow transplant recipients and three-year follow-up of incident cases of HIV infection in the experimental animals and termed the mechanism 'blind home­ Multicenter AIDS Cohort Study (MACS), we observed that these ostasis' (ref. 3). two processes tended to balance each other, beginning 1.5 years Recently, high rates of co4• T-cell turnover in HIV-1 infection after seroconversion'. This led us to postulate a homeostatic have been demonstrated'·', highlighting the dynamic nature of mechanism that maintains a constant level of circulating T cells the immune response to HIV infection and the need to under­ without regard to the phenotype (C04• or cos•) of the T cells'. stand how this response is regulated. Blind T-cell homeostasis, if The same mechanism was independently proposed by Adleman it exists, could have important implications for the pathogenesis of HIV-1 infection. First, it would explain the stimulus to replace *The Multicenter AIDS Cohort Study (MACS) Includes the following: Baltimore: lost CD4· cells. Second, it would account for the gradual shift in The Johns Hopkins University School of Hygiene and Public Health: Alfred J. Saah, the balance between CD4' and Cos· T cells, since only the for­ Principal Investigator; Haroutune Armenian, Homayoon Farzadegan, Neil Graham, Nancy Kass, Joseph Margollck, Justin McArthur, Ellen Taylor. Chicago: Howard mer would be lost from HIV-related mechanisms. Third, it pre­ Brown Memorial Clinic-Northwestern University Medical School: John P. Phair, dicts that the net preferential replacement of co4• T cells by Principal Investigator; Joan S. Chmiel, Bruce Cohen, Maurice O'Gorrnan, Daina Variakojls, jerry Wesch, Steven M. Wolinsky. Los Angeles: University of California, CDS• T cells would eventuate in critically low levels of Co4• lym­ UCLA Schools of Public Health and Medicine: Roger Detels, Principal Investigator; phocytes leading to immune failure. Importantly, only a very Barbara R. Visscher, Irvin S.Y. Chen, Janice Dudley, John L. Fahey, John Ferbas, small net loss of co4• T cells per unit time would be sufficient to Janis V. Giorgi, Moon Lee, Oto Martinez-Maza, Eric N. Miller, Parunag Nishanian, Jeremy Taylor, Jerome Zack. Pittsburgh: University of Pittsburgh Graduate School of drive this process to a very low level of CD4• T cells over the long 2 Public Health: Charles R. Rinaldo, Principal Investigator; Lawrence Kingsley, James incubation period of AIDS • T. Becker, Albert D. Donnenberg, Phalgunl Gupta, Manto Ho, Sharon Zucconi. The follow-up described in our earlier report' extended only to Data Coordinating Center: The Johns Hopkins School of Hygiene and Public Health: Alvaro Munoz, Principal Investigator; Leonardo Epstein, Noya Gala!, Stephen three years after seroconversion, a length of time when no more Gange, Donald R. Hoover, Lisa P. jacobson, Lawrence P. Park, Kenrad Nelson, than 5% of subjects developed AIDS. In the present study, the Steven Piantadosi, Sol Su. National Institutes ofHealth : National Institute of Allergy and Infectious Diseases: Lewis Schrager, Project Officer; National Cancer Institute: follow-up extends to S years after seroconversion with substan­ Daniela Seminara. tially higher rates of AIDS cases. Patients with AIDS are well 674 NAlURE MEDICINE, VOLUME 1, NUMBER 7, JULY 1995 © 1995 Nature Publishing Group http://www.nature.com/naturemedicine • ARTICLES Fig. 1 Geometric means of absolute numbers of cir­ culating T-cell subsets (CD3', CD4', and CD8' lymphocytes) as a function of months since seroconver­ sion in MACS seroconvert­ ers for whom the time of seroconversion was known to within ±4.5 months (n = 372). Error bars indicate 95% confidence intervals, and the vertical dotted line the estimated time of sere­ conversion. Numbers of ob­ servations at each data point, beginning at <24 months before seroconver­ sion (the leftmost points on the graph), are 776, 162, 209, 256, 372, 368, 335, 0- All Observations 301, 286, 265, 248, 227, I I I I I I I I I I 203, 195, 162, 155, 138, <-24 -12 0 12 24 36 48 60 72 84 96 121, 107, 90, 65, 86. Months from Seroconversion 6 known to have depressed levels of total T cells • Therefore, we phocytes were not precisely matched to the change in CD3' lym­ could test not only whether blind T-cell homeostasis held true phocytes at all time points; for example, between 45 and 81 but how long before AIDS it fails. The longitudinal data provided months the CDS' cell count changed only slightly while the by cohorts with precise dates of seroconversion and onset of CD4' cell count declined at a variable rate. These discrepancies, AIDS allow forward (from seroconversion) and backward (from as well as the decline in T cells after 63 months, could be due to AIDS) analysis to present a comprehensive description of total T imprecision in the compensatory mechanism, or to the fact that cells as well as the principal T-cell subsets (CD4' and CDS') dur­ many AIDS-free seroconverters had limited follow-up (see legend ing the time between seroconversion and the onset of clinically to Fig. 2) and, therefore, could have been close to developing defined AIDS. The results show that blind T-cell homeostasis is AIDS, as discussed below. Taken together, these data extend our maintained for long periods after HIV-1 infection is established, previous observations on blind T-cell homeostasis for an addi­ but is lost in the last two years preceding AIDS. tional 5 years after seroconversion, and thus provide compelling support for the postulated blind T-cell homeostatic mechanism. Preservation of blind T-cell homeostasis Circulating T-lymphocyte levels in the full sample of 372 MACS Loss of blind T-cell homeostasis 1.5-2 years before AIDS seroconverters with well-defined times of seroconversion are Given that in AIDS-free HIV' individuals the T-cell levels were shown in Fig. 1. The sum of CD4' and CDS' lymphocytes essen­ relatively constant and that they are low at the onset of AIDS, we tially equalled the number of T cells and is not shown in subse­ next investigated the trajectories of T-celllevels among the 92 se­ quent figures. As previously reported, there was a progressive roconverters who had well-defined dates of onset of AIDS (Fig. decline in C04' lymphocytes after seroconversion, more rapid 3). Very little change in T-cell levels was seen until approxi­ for the first 6 to 12 months and then more gradual. COB' lym­ mately 1.5 years before AIDS. After this time, however, numbers phocytes rose similarly beginning at seroconversion. Total T (in­ of circulating T cells declined sharply. By regression analysis, the cluding C03') lymphocytes declined slightly for the first 12 mean rate of change during the last 1.5 years before AIDS was months after seroconversion and exhibited a gradual decline -14.2% per 6 months (95% confidence interval = -17.7% to thereafter. Because T -cell levels are lower in AIDS than in earlier -10.6%), that is, the mean value for a given 6-month period was stages of HIV infection•, we hypothesized that this gradual de­ equal to approximately S6o/o of the mean value for the preceding cline ofT lymphocytes was specifically due to lower T-celllevels 6-month period. Over the 1.5-year period of decline, this corre­ in subjects who developed AIDS. As shown in Fig. 2, removal of sponded to a decline from about 1,400 to about 900 T cells per observations from the 107 individuals who developed AIDS dur­ microlitre at the onset of AIDS. In contrast, the estimate for the ing the study period essentially abolished the decline in T-cell interval-1.5 to -3.5 years before AIDS was -2.5%, which was not levels shown in Fig.
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