Original Article
Early Progression of Disease in HIV-Infected Infants with Thymus Dysfunction
N Engl J Med 1996; 335:1431-1436November 7, 1996
- Abstract
Background
Infants with congenital thymic deficiency (the DiGeorge syndrome) have immunodeficiency and a characteristic pattern of low CD4+ and CD8+ T-lymphocyte counts and low CD5+ B-lymphocyte counts. Because the thymus is essential for the generation of CD4+ cells, we sought evidence of thymus dysfunction in infants infected perinatally with the human immunodeficiency virus (HIV).
Methods
We studied the immunophenotypes of 59 infants with maternally transmitted HIV, 5 infants with the DiGeorge syndrome, and 168 infants exposed to HIV but not infected. The criteria for a presumed thymic defect were reductions in both the CD4+ and CD8+ T-cell subgroups during the first six months of life that were confirmed in a subgroup of infants by low counts of CD4+CD45RA+ and CD4+CD45RO+ T cells and CD5+ B cells.
Results
Of the 59 HIV-infected infants, 17 had immunophenotypes similar to those of infants with the DiGeorge syndrome. The risks of the acquired immunodeficiency syndrome (AIDS) by the ages of 12 and 24 months were, respectively, 75 percent and 92 percent in these 17 infants, as compared with 14 and 34 percent in the other 42 infants (P<0.001). Nine of the HIV-infected infants with the DiGeorge-like immunophenotype (53 percent) died within six months of the progression to AIDS, as compared with only three of the other infants (7 percent, P = 0.006).
Conclusions
In some infants infected perinatally with HIV, a pattern of lymphocyte depletion develops that resembles the pattern in congenital thymic deficiency. Since HIV disease progresses rapidly in such infants, they may be candidates for early antiviral therapy and attempts at immune reconstitution.
Media in This Article
Figure 1
T-Lymphocyte Counts during the First Year of Life in HIV-Infected Patients with and without the Thymic-Defect Profile and Controls.Figure 2
Kaplan–Meier Plots of Clinical Outcomes in HIV-Infected Infants in the First Three Years of Life, According to Whether the Thymic-Defect Profile Was Present in the First Six Months.Article Activity
- Article
Perinatal human immunodeficiency virus (HIV) infection generally has a more rapid course than HIV infection in adults.1,2 The pattern of progression is bimodal, with the acquired immunodeficiency syndrome (AIDS) developing in a subgroup of infants very early in life and progressing much more slowly in others.3-6 These distinct patterns imply differences in pathogenesis. The hallmark of disease progression is the depletion of CD4+ T cells, which has generally been attributed to HIV-induced destruction of lymphocytes by various mechanisms.2 However, defective generation of CD4+ cells by the thymus, caused by HIV, could also contribute to such depletion, particularly in young children in whom the thymus is more active.7 HIV-infected children have low counts of CD4+CD45RA+ cells,8 which are believed to originate in the thymus.7 Several other reports have suggested thymic involvement in HIV infection. These include histopathological examinations of the thymus of HIV-infected fetuses and children9-12 and virologic studies in patients,13,14 thymic cultures,15-17 and SCID-hu mice.18-20
Infants with severe congenital thymic anomalies (the DiGeorge syndrome) have immunophenotypic profiles characterized by low counts, not only of CD4+ and CD8+ T cells, but also of CD5+ B cells (unpublished data). We have also found low CD5+ B-cell counts in some HIV-infected infants less than one year old.21 To examine further a possible relation between the congenital and acquired immune defects, we studied immunophenotypes and assessed thymic involvement in infants with maternally acquired HIV infection and infants exposed to HIV but not infected with it. We also examined the relation of the immunophenotypes associated with a “thymic defect” to the progression of HIV disease.
Methods
Study Population
We selected 59 children with perinatal HIV infection and a control group of 168 HIV-exposed but uninfected infants, born after 1985, in whom immunophenotypic studies had been performed at least once during the first six months of life. Forty of the infected infants were identified by prenatal screening of their mothers and were followed prospectively from birth, and the other 19 were referred to our center before the age of six months either because the mother was known to be seropositive for HIV (8 infants) or because the infant had an illness compatible with a diagnosis of HIV infection (11 infants). Five infants with severe cases of the DiGeorge syndrome (two boys and three girls; mean age at the start of the study, 3.1 months) were included for comparison. The diagnosis of the DiGeorge syndrome was made on the basis of previously described criteria.22,23
Follow-up data on the HIV-infected and the HIV-exposed infants were collected at regular intervals in our pediatric clinics. The diagnosis of HIV infection was based on the criteria of the Centers for Disease Control and Prevention (CDC) for pediatric HIV infection,24 with an age of 18 months used as the cutoff age for persistently positive serologic tests. Seropositive infants below that age were considered to be infected with HIV if they had at least two positive tests for HIV by the polymerase chain reaction, the immune-complex–dissociated p24 antigen assay, or both, or if they had an AIDS-defining condition. The clinical status of infected children was determined according to the criteria of the CDC.
Flow Cytometry
A whole-blood staining technique was used to quantitate subpopulations of mononuclear cells in peripheral blood by direct two-color immunofluorescence, as previously described.8 Specific cell-surface markers were identified by the following pairs of monoclonal antibodies (Becton Dickinson) conjugated with fluorescein isothiocyanate (FITC) or phycoerythrin (PE): Leucogate (CD45 and CD14); Simultest isotype control FITC–IgG1 and PE–IgG2a; Simultest FITC–CD3 and PE–CD4; FITC–CD3 and PE–CD8; FITC–CD5 and PE–CD19; FITC–CD4 and RD1–2H4 (for CD45RA+); and FITC–CD4 and RD1–4B4 (for CD45RO+). Because the last three of these markers were introduced in 1992, subgroups of CD5+ B cells, CD4+CD45RA+ (naive) T cells, and CD4+CD45RO+ (memory) T cells were studied in only about one third of the infants. A single-laser flow cytometer (FACScan, Becton Dickinson) that distinguishes between forward and right-angle scatter of light was used with an appropriate software package (Simulset, Becton Dickinson).
Immunospot Assays
Enzyme-linked immunospot (Elispot) and reverse enzyme-linked immunospot (Relispot) assays, described previously by our group,25,26 were used to quantitate the cells secreting specific antibodies to HIV glycoprotein 160 (gp160) and the total number of cells secreting IgG, respectively.
Statistical Analysis
Because patients with the DiGeorge syndrome have both low CD4+ counts and low CD8+ counts, these counts were studied jointly in the noninfected controls (when more than one lymphocyte-subgroup measurement was made in the first six months of life, the later value was used). Infants in whom both of these counts were below the 5th percentile of the joint distribution in the control group during the first six months of life were defined as having the thymic-defect immunotype. This approach was validated in the infants whose CD5+ B-cell counts we studied.
Lymphocyte subgroups were quantitated in the HIV-infected and the HIV-exposed (but uninfected) control populations at intervals of approximately three months and were characterized with standard descriptive statistics, including medians and ranges (from the 10th to the 90th percentile). Kruskal–Wallis tests and Wilcoxon rank-sum statistics were used to compare the distributions of lymphocyte counts in the study groups. Characteristics of the progression of disease were compared by the chi-square test or Fisher's exact test. Data on the time to an event were described with Kaplan–Meier estimates, and the corresponding comparisons between groups were made with generalized Wilcoxon test statistics. All P values are two-sided and unadjusted for multiple comparisons.
Results
HIV-Infected Patients
AIDS developed during the first year of life in 19 of the 59 HIV-infected children studied (10 boys and 9 girls). In the remaining 40 infants (21 boys and 19 girls), either AIDS developed after the first year of life (17 infants) or it had not developed by the time of the last follow-up after the age of one year (23 infants). AIDS was diagnosed at a median age of 4.0 months among the infants in whom it developed during the first year and (by Kaplan–Meier estimate) at an age of 40.5 months among the other infants. When the infants referred to the center were included in the analysis, the proportion of infants with AIDS in the first year of life was overestimated (19 of 59, or 32 percent); among the HIV-infected infants followed prospectively from birth, this proportion was 16.6 percent.
Studies of Lymphocyte Subgroups
In the control group, the 5th percentile of the values measured during the first six months of life was 1900 per cubic millimeter in the case of CD4+ cells and 850 per cubic millimeter in the case of CD8+ cells. Infants in whom both the CD4+ and CD8+ counts were below these values were considered likely to have a thymic defect. Seventeen such infants were identified (the “thymic defect” group); they were compared with the remaining 42 HIV-infected infants (the “no thymic defect” group). The differentiation between the groups was validated on the basis of the markedly low CD5+ B-lymphocyte counts noted among 10 infants in the thymic-defect group whose CD5+ B-cell counts were obtained, as compared with the counts in 9 infants tested in the no-thymic-defect group and 42 infants in the control group (Table 1Table 1
Absolute Lymphocyte Counts during the First Six Months of Life in HIV-Infected Patients with the Thymic-Defect Profile, HIV-Infected Patients without the Profile, and Controls Exposed to, but Not Infected with, HIV.).The proportion of all HIV-infected children studied who had the thymic-defect profile was thus 29 percent (17 of 59). However, among HIV-infected infants followed prospectively from birth, the proportion was 15 percent (6 of 40).
Table 1 shows the median CD3+, CD4+, and CD8+ T-lymphocyte counts in the groups with and without the thymic-defect profile and in the HIV-exposed but uninfected controls. Although the CD4+ counts were significantly lower in the no-thymic-defect group than in the controls, the distributions of CD8+ counts in these two groups were similar. The absolute CD4+CD45RA+ and CD4+CD45RO+ counts were lower in the infants with the thymic-defect profile than in the infants without that profile or the controls (Table 1). The percentage of CD4+CD45RA+ cells was slightly lower in the thymic-defect group (83 percent) than in either the no-thymic-defect group (88 percent, P = 0.04) or the controls (89 percent, P = 0.02) (data not shown). The percentage of CD4+CD45RO+ cells did not differ significantly among the three groups (thymic-defect group, 23 percent; no-thymic-defect group, 20 percent; controls, 20 percent).
When we studied only the 10 patients with the thymic-defect profile whose CD5+ B-cell counts had been obtained, we found that their CD3+ counts (median, 1300 per cubic millimeter), CD4+ counts (median, 640 per cubic millimeter), and CD8+ counts (median, 475 per cubic millimeter) were similar to those in the thymic-defect group as a whole.
Changes in the counts of CD4+ and CD8+ T cells during the first year of life in the two groups of HIV-infected infants and the controls are shown in Figure 1AFigure 1
T-Lymphocyte Counts during the First Year of Life in HIV-Infected Patients with and without the Thymic-Defect Profile and Controls. and Figure 1B, along with corresponding values in the infants with the DiGeorge syndrome. The differences between the groups in CD4+ cell counts during the first six months of life were maintained during the second six months. The median CD4+ counts in the thymic-defect group were significantly lower than those in the no-thymic-defect group and were close to the values in patients with the DiGeorge syndrome. The similarity between the patients in the thymic-defect group and the patients with the DiGeorge syndrome was also evident with regard to CD8+ cell counts. In contrast, the CD8+ counts in the patients without the thymic-defect profile rose above those of the uninfected controls after the first three months and remained slightly higher thereafter.Correlation of Immunophenotypes with the Progression to AIDS
Among the 17 infants with the thymic-defect profile, AIDS developed in 14 during the first year of life, in 1 at 13 months, and in 1 at 20 months; the remaining infant did not yet have AIDS at the age of 36 months. In comparison, AIDS developed during the first year of life in 5 of the 42 infants in the no-thymic-defect group, and the remaining 37 infants in that group had a slower progression to AIDS or no such progression. Figure 2AFigure 2
Kaplan–Meier Plots of Clinical Outcomes in HIV-Infected Infants in the First Three Years of Life, According to Whether the Thymic-Defect Profile Was Present in the First Six Months. and Figure 2Bshows Kaplan–Meier plots of the risk of AIDS and of survival for the two HIV-infected groups. The risk of the development of AIDS was 75 percent within 12 months and 92 percent within 24 months in the thymic-defect group, as compared with 14 percent and 34 percent, respectively, in the no-thymic-defect group (P<0.001) (Figure 2A). The risk of dying of AIDS was 38 percent within 12 months and 64 percent within 24 months in the thymic-defect group, as compared with 0 and 3 percent, respectively, in the group without the thymic-defect profile (P<0.001) (Figure 2B). The difference in survival is not entirely due to the fact that the AIDS diagnoses occurred earlier in the thymic-defect group. Even after the AIDS diagnosis, there was a difference in survival between the two groups; 9 of 17 infants in the thymic-defect group (53 percent) died within six months after their AIDS diagnosis, as compared with only 3 of 42 infants in the no-thymic-defect group (7 percent, P = 0.006) (data not shown).We further analyzed the specific clinical findings in the HIV-infected infants. Pneumocystis carinii pneumonia occurred more frequently in the thymic-defect group (8 of 17, or 47 percent) than in the no-thymic-defect group (6 of 42, or 14 percent; P = 0.015) and was the principal cause of AIDS and death in the patients with the thymic-defect profile. The median survival after the diagnosis of P. carinii pneumonia was one month for the patients in the thymic-defect group. Among the six patients in the no-thymic-defect group in whom P. carinii pneumonia developed, two died, 8 and 27 months after diagnosis; the other four remained alive 24 to 49 months after the diagnosis.
Among the 5 infants of the 42 in the no-thymic-defect group in whom AIDS was diagnosed during the first year of life, the diagnosis was due to P. carinii pneumonia in 4 and to encephalopathy and esophageal candidiasis in 1. Only one of these five patients died, at the age of 31 months; the other four were still alive after the age of 2 years. These five infants had slower and less marked decreases in the CD4+ count, and higher CD8+ counts, than the infants with the thymic-defect profile.
Other opportunistic infections, recurrent bacterial infections, and encephalopathy were more common than P. carinii pneumonia among the infants in the no-thymic-defect group. However, these conditions did not differ significantly in frequency between the two groups, which probably reflects the fact that the infants in the thymic-defect group died at earlier ages. Hypogammaglobulinemia early in life, as evidenced by low serum immunoglobulin levels, low counts of immunoglobulin-secreting cells as detected by the Relispot assay,26 or both, was noted in 3 of 8 infants with thymic-defect profiles but none of 28 infants without this profile who were tested (P = 0.007). The measurement of cells secreting specific antibodies against gp160 with the Elispot assay25 showed that by six months of age none of 8 patients tested in the thymic-defect group had B cells that secreted such antibodies, as compared with 17 of 21 tested in the no-thymic-defect group (P<0.001).
Discussion
The acquired immunodeficiency associated with HIV is characterized by a depletion of CD4+ T cells that results from the direct or indirect effects of the virus.2 In adults and many pediatric patients, CD8+ T-lymphocyte counts are often elevated until the end stage of AIDS, possibly because of “blind homeostasis”27 (the theory that as the CD4+ counts decrease in HIV infection the CD8+ counts increase so that the total number of CD3+ T cells remains constant). In contrast, the severe congenital immunodeficiency due to thymic aplasia is associated with marked decreases in both CD4+ and CD8+ lymphocytes, since both T-cell subgroups require a functional thymus in order to develop. We have recently detected decreases in CD5+ B cells in infants with the DiGeorge syndrome (unpublished data). Such cells (or B-1a cells) normally constitute more than 60 percent of the total number of B cells in the first year of life, decreasing to adult levels (10 to 30 percent) by the age of three years.21 These cells make up a substantial proportion of the small number of B lymphocytes found in the thymus of mice28 and humans29; in the latter, they have been postulated to play a part in the negative selection of autoreactive T-cell clones.30
In this study, we have identified a subpopulation of HIV-infected infants with an immunophenotype resembling that of patients with the DiGeorge syndrome. Our findings suggest that the pathogenesis of disease in this group of infants may involve HIV-induced dysfunction of the thymus. The prominent role of the thymus in the development of T-cell immunity in the fetus and young child7,31 makes it reasonable to assume that damage to this organ induced by HIV would have far greater consequences in young children. Thymic lesions were seen in the fetuses of HIV-seropositive mothers who underwent either spontaneous11 or intentional12 abortion. Almost all the HIV-infected infants we studied who had the thymic-defect profile had a rapid progression to AIDS during their first year and subsequently survived a significantly shorter time than HIV-infected children without this profile. We postulate that in children with such a defect, early disruption of the thymic microenvironment by HIV results in a reduced post-thymic reservoir of lymphocytes in peripheral lymphoid sites. The heavy demand for CD4+ cells to regenerate in order to compensate for the HIV-induced post-thymic destruction2 would be expected to exhaust this smaller reservoir rapidly and cause early progression of disease. Thus, the bimodal pattern of progression in pediatric AIDS3-6 may be explained largely by differences in the potential of HIV strains to cause early thymic disruption.
There have been variable histopathological findings on examination of the thymus in specimens obtained at autopsy from patients who died of AIDS at various ages9-12 and in macaques infected with simian immunodeficiency virus who have severe immunodeficiency.32 These findings include combinations of thymitis, disruption of the stromal architecture, loss of Hassall's corpuscles, and thymocyte depletion. These features were all observed at autopsy in the thymus of one of our patients with the thymic-defect profile, who died at the age of nine months.
Strains of HIV differ in their effects on thymic epithelium and thymopoiesis in culture15-17 and in SCID-hu mice.18-20 Particularly relevant is a recent observation indicating that viral strains from one child with rapid progression of HIV disease and another with slow progression have different effects on thymopoiesis in culture.17 In a young adult with HIV infection, thymus-derived viral clones had more affinity for thymocytes than did viral clones in peripheral blood,14 and their genotypic and phenotypic characteristics differed.
Other investigators have noted an increased risk of rapid disease progression in infants with virus detected soon after birth, lower CD4+ counts at an early age, and higher degrees of viral replication as measured by the quantitative polymerase chain reaction or the p24 antigen assay.6,33,34 We do not yet have sufficient data on the early detection of virus or on the viral load in enough infants with and without the thymic-defect profile. However, the very early depletion of T lymphocytes in the affected infants in the thymic-defect group reinforces the likelihood that the virus was transmitted in utero. If this is indeed the case, it may be expected that the proportion of infants found to have the thymic-defect profile will be larger among HIV-infected infants whose mothers received zidovudine35 late in gestation or only at delivery than among those whose mothers received zidovudine earlier.
The proportion of infants with the thymic-defect profile was 15 percent among the HIV-infected infants we followed prospectively, but a larger sample is required for this proportion to be assessed more accurately. All our patients with the thymic-defect profile continued to have marked lymphopenia after the first six months of life, except for one patient, who had a slight and transient increase in the CD8+ count to about 1100 cells per cubic millimeter.
In addition to their pathogenetic importance, our findings have clinical implications that include the need for prompt identification of patients in whom AIDS progresses early and who have the thymic-defect profile. The recent recommendations for early prophylaxis against P. carinii pneumonia in all HIV-exposed children36 may prove particularly beneficial in children under the age of six months, and thereafter if HIV infection is demonstrated. Therapeutic approaches will need to be more aggressive among these infants, with earlier use of antiviral agents and perhaps even immune reconstitution with thymic transplantation.37
Supported in part by a grant (U64-CCU404456-06) from the CDC and by grants (R01-AI32456 and R01-AI39081) from the National Institute of Allergy and Infectious Diseases.
We are indebted to Ms. Ashley Carter, B.S., for her expert technical assistance, and to the staff members of our pediatric HIV clinics for their support and dedication.
Source Information
From the Division of Infectious Diseases, Epidemiology and Immunology, Department of Pediatrics, Emory University, 69 Butler St. SE, Atlanta, GA 30303, where reprint requests should be directed to Dr. Nahmias.
- References
References
1
Oxtoby MJ. Vertically acquired HIV infection in the United States. In: Pizzo PA, Wilfert CM, eds. Pediatric AIDS: the challenge of HIV infection in infants, children, and adolescents. 2nd ed. Baltimore: Williams & Wilkins, 1994:3-20.
2
Levy JA . Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 1993;57:183-289
Medline3
Tovo PA ,de Martino M ,Gabiano C , et al. Prognostic factors and survival in children with perinatal HIV-1 infection: the Italian Register for HIV Infections in Children. Lancet 1992;339:1249-1253
CrossRef | Web of Science | Medline4
Frederick T ,Mascola L ,Eller A ,O'Neil L ,Byers B . Progression of human immunodeficiency virus disease among infants and children infected perinatally with human immunodeficiency virus or through neonatal blood transfusion. Pediatr Infect Dis J 1994;13:1091-1097
CrossRef | Web of Science | Medline5
The European Collaborative Study
Web of Science | Medline6
Mayaux MJ ,Burgard M ,Teglas JP , et al. Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease. JAMA 1996;275:606-610
CrossRef | Web of Science | Medline7
Mackall CL ,Fleisher TA ,Brown MR , et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995;332:143-149
Full Text | Web of Science | Medline8
Ibegbu C ,Spira TJ ,Nesheim S , et al. Subpopulations of T and B cells in perinatally HIV-infected and noninfected age-matched children compared with those in adults. Clin Immunol Immunopathol 1994;71:27-32
CrossRef | Medline9
Rosenzweig M ,Clark DP ,Gaulton GN . Selective thymocyte depletion in neonatal HIV-1 thymic infection. AIDS 1993;7:1601-1605
CrossRef | Web of Science | Medline10
Joshi VV ,Oleske JM . Pathologic appraisal of the thymus gland in acquired immunodeficiency syndrome in children: a study of four cases and a review of the literature. Arch Pathol Lab Med 1985;109:142-146
Web of Science | Medline11
Langston C ,Lewis DE ,Hammill HA , et al. Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection. J Infect Dis 1995;172:1451-1460
CrossRef | Web of Science | Medline12
Papiernik M ,Brossard Y ,Mulliez N , et al. Thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. Pediatrics 1992;89:297-301
Web of Science | Medline13
Brossard Y ,Aubin JT ,Mandelbrot L , et al. Frequency of early in utero HIV-1 infection: a blind DNA polymerase chain reaction study on 100 fetal thymuses. AIDS 1995;9:359-366
Web of Science | Medline14
Calabro ML ,Zanotto C ,Calderazzo F , et al. HIV-1 infection of the thymus: evidence for a cytopathic and thymotropic viral variant in vivo. AIDS Res Hum Retroviruses 1995;11:11-19
CrossRef | Web of Science | Medline15
Schnittman SM ,Denning SM ,Greenhouse JJ , et al. Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCRαβ+ and TCRγδ+ to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion. Proc Natl Acad Sci U S A 1990;87:7727-7731
CrossRef | Web of Science | Medline16
Valentin H ,Nugeyre MT ,Vuillier F , et al. Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro. J Virol 1994;68:3041-3050
Web of Science | Medline17
Uittenbogaart C, Anisman D, Jamieson B, et al. Immature thymocytes are depleted by viral isolates from children with a rapid disease progression. In: Program and abstracts of the International Conference of the Immunological Societies, San Francisco, July 20–23, 1995. New York: Clinical Immunology Society, 1995. abstract.
18
Stanley SK ,McCune JM ,Kaneshima H , et al. Human immunodeficiency virus infection of the human thymus and disruption of the thy-mic microenvironment in the SCID-hu mouse. J Exp Med 1993;178:1151-1163
CrossRef | Web of Science | Medline19
Su L ,Kaneshima H ,Bonyhadi M , et al. HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity 1995;2:25-36
CrossRef | Web of Science | Medline20
Kollman TR ,Kim A ,Pettoello-Mantovani M , et al. Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice. J Immunol 1995;154:907-921
Web of Science | Medline21
Ibegbu CC ,Nahmias AJ ,Spira TJ , et al. CD5+ B cells in normal newborns and infants, and in those with HIV and intrauterine infections. Ann N Y Acad Sci 1992;651:572-575
CrossRef | Web of Science | Medline22
Greenberg F . What defines DiGeorge anomaly? J Pediatr 1984;115:412-41323
Bastian J ,Law S ,Vogler L , et al. Prediction of persistent immunodeficiency in the DiGeorge anomaly. J Pediatr 1989;115:391-396
CrossRef | Web of Science | Medline24
1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of ageMMWR Morb Mortal Wkly Rep 1994;43:1-10
Medline25
Nesheim S ,Lee FK ,Sawyer M , et al. Diagnosis of human immunodeficiency virus infection by enzyme-linked immunospot assays in a prospectively followed cohort of infants of human immunodeficiency virus-seropositive women. Pediatr Infect Dis J 1992;11:635-639
Web of Science | Medline26
Lee FK ,Nahmias AJ ,Spira T , et al. Enumeration of human peripheral blood lymphocytes secreting immunoglobulins of major classes and subclasses in healthy children and adults. J Clin Immunol 1991;11:213-218
CrossRef | Web of Science | Medline27
Margolick JB ,Munoz A ,Donnenberg AD , et al. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection: the Multicenter AIDS Cohort Study. Nat Med 1995;1:674-680
CrossRef | Web of Science | Medline28
Nango K ,Inaba M ,Inaba K , et al. Ontogeny of thymic B cells in normal mice. Cell Immunol 1991;133:109-115
CrossRef | Web of Science | Medline29
Isaacson PG ,Norton AJ ,Addis BJ . The human thymus contains a novel population of B lymphocytes. Lancet 1987;2:1488-1491
CrossRef | Web of Science | Medline30
Inaba M ,Inaba K ,Fukuba Y , et al. Activation of thymic B cells by signals of CD40 molecules plus interleukin-10. Eur J Immunol 1995;25:1244-1248
CrossRef | Web of Science | Medline31
Spits H ,Lanier LL ,Phillips JH . Development of human T and natural killer cells. Blood 1995;85:2654-2670
Web of Science | Medline32
Li SL ,Kaaya EE ,Ordonez C , et al. Thymic immunopathology and progression of SIVsm infection in cynomolgus monkeys. J Acquir Immune Defic Syndr Hum Retrovirol 1995;9:1-10
Medline33
Papaevangelou V ,Pollack H ,Rigaud M , et al. The amount of early p24 antigenemia and not the time of first detection of virus predicts the clinical outcome of infants vertically infected with human immunodeficiency virus. J Infect Dis 1996;173:574-578
CrossRef | Web of Science | Medline34
De Rossi A ,Masiero S ,Giaquinto C , et al. Dynamics of viral replication in infants with vertically acquired human immunodeficiency virus type 1 infection. J Clin Invest 1996;97:323-330
CrossRef | Web of Science | Medline35
Recommendations of the U . S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1994;43:1-2036
1995 Revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeficiency virusMMWR Morb Mortal Wkly Rep 1995;44:1-11
Medline37
Nahmias AJ, Hong R, Nesheim S, et al. Thymic transplantation in pediatric AIDS. In: Program and abstracts of the 1995 International Symposium on Clinical Immunology, San Francisco, July 20–23, 1995. New York: Clinical Immunology Society, 1995. abstract.
- Citing Articles (55)
Citing Articles
1
B. G. Kapogiannis, M. M. Soe, S. R. Nesheim, E. J. Abrams, R. J. Carter, J. Farley, P. Palumbo, L. J. Koenig, M. Bulterys. (2011) Mortality Trends in the US Perinatal AIDS Collaborative Transmission Study (1986-2004). Clinical Infectious Diseases 53:10, 1024-1034
CrossRef2
Charlene D Young, Jonathan B Angel. (2011) HIV infection of thymocytes inhibits IL-7 activity without altering CD127 expression. Retrovirology 8:1, 72
CrossRef3
Andres F. Camacho-Gonzalez, Allison C. Ross, Rana Chakraborty. (2010) The Clinical Care of the HIV-1–Infected Infant. Clinics in Perinatology 37:4, 873-885
CrossRef4
Kosuke Kawai, Gernard Msamanga, Karim Manji, Eduardo Villamor, Ronald J. Bosch, Ellen Hertzmark, Wafaie W. Fawzi. (2010) Sex differences in the effects of maternal vitamin supplements on mortality and morbidity among children born to HIV-infected women in Tanzania. British Journal of Nutrition 103:12, 1784-1791
CrossRef5
M. A. A. Kusters, R. H. J. Verstegen, E. F. A. Gemen, E. de Vries. (2009) Intrinsic defect of the immune system in children with Down syndrome: a review. Clinical & Experimental Immunology 156:2, 189-193
CrossRef6
Nazma Mansoor, Brian Abel, Thomas J. Scriba, Jane Hughes, Marwou de Kock, Michele Tameris, Sylvia Mlenjeni, Lea Denation, Francesca Little, Sebastian Gelderbloem, Anthony Hawkridge, W. Henry Boom, Gilla Kaplan, Gregory D. Hussey, Willem A. Hanekom. (2009) Significantly skewed memory CD8+ T cell subsets in HIV-1 infected infants during the first year of life. Clinical Immunology 130:3, 280-289
CrossRef7
Carina A. Rodriguez, Sarah Koch, Maureen Goodenow, John W. Sleasman. (2008) Clinical implications of discordant viral and immune outcomes following protease inhibitor containing antiretroviral therapy for HIV-infected children. Immunologic Research 40:3, 271-286
CrossRef8
Isaac Ssewanyana, Mohamed Elrefaei, Grant Dorsey, Theodore Ruel, Norman G. Jones, Anne Gasasira, Moses Kamya, Justine Nakiwala, Jane Achan, Edwin Charlebois, Diane Havlir, Huyen Cao. (2007) Profile of T Cell Immune Responses in HIV‐Infected Children from Uganda. The Journal of Infectious Diseases 196:11, 1667-1670
CrossRef9
Salvador Resino, Elena Seoane, Maria Dolores Gurbindo Guti??rrez, Juan Antonio Le??n, Maria ??ngeles Mu??oz-Fern??ndez. (2006) CD4+ T-Cell Immunodeficiency Is More Dependent on Immune Activation Than Viral Load in HIV-Infected Children on Highly Active Antiretroviral Therapy. JAIDS Journal of Acquired Immune Deficiency Syndromes 42:3, 269-276
CrossRef10
Jason C Lee, Maria Ines Boechat, Marvin Belzer, Joseph A Church, Jaime De Ville, Karin Nielsen, Stephanie Weston, Yongzhi Geng, Theresa Dunaway, Christina Kitchen, Paul A Krogstad. (2006) Thymic volume, T-cell populations, and parameters of thymopoiesis in adolescent and adult survivors of HIV infection acquired in infancy. AIDS 20:5, 667-674
CrossRef11
W. L. Lin, J. E. Fincke, L. R. Sharer, D. S. Monos, S. Lu, J. Gaughan, C. D. Platsoucas, E. L. Oleszak. (2005) Oligoclonal T cells are infiltrating the brains of children with AIDS: sequence analysis reveals high proportions of identical beta-chain T-cell receptor transcripts. Clinical and Experimental Immunology 141:2, 338-356
CrossRef12
Raphaël Ho Tsong Fang, Emmanuel Khatissian, Valérie Monceaux, Marie-Christine Cumont, Stéphanie Beq, Jean-Claude Ameisen, Anne-Marie Aubertin, Nicole Israël, Jérôme Estaquier, Bruno Hurtrel. (2005) Disease progression in macaques with low SIV replication levels: on the relevance of TREC counts. AIDS 19:7, 663-673
CrossRef13
Michael Neely, Andrea Kovacs. (2004) Management of antiretroviral therapy in neonates, children, and adolescents. Current HIV/AIDS Reports 1:2, 97-104
CrossRef14
Daniel L. Tuttle, Carter R. Coberley, Xiaoming Xie, Zhong C. Kou, John W. Sleasman, Maureen M. Goodenow. (2004) Effects of Human Immunodeficiency Virus Type 1 Infection on CCR5 and CXCR4 Coreceptor Expression on CD4 T Lymphocyte Subsets in Infants and Adolescents. AIDS Research and Human Retroviruses 20:3, 305-313
CrossRef15
Michael Neely, Andrea Kovacs. (2003) Management of antiretroviral therapy in neonates, children, and adolescents. Current Infectious Disease Reports 5:6, 521-530
CrossRef16
William T. Shearer, Howard M. Rosenblatt, Rebecca S. Gelman, Rebecca Oyomopito, Susan Plaeger, E.Richard Stiehm, Diane W. Wara, Steven D. Douglas, Katherine Luzuriaga, Elizabeth J. McFarland, Ram Yogev, Mobeen H. Rathore, Wende Levy, Bobbie L. Graham, Stephen A. Spector. (2003) Lymphocyte subsets in healthy children from birth through 18 years of age. Journal of Allergy and Clinical Immunology 112:5, 973-980
CrossRef17
Eric D Miller, Jonathan A Smith, Monika Lichtinger, Liping Wang, Lishan Su. (2003) Activation of the signal transducer and activator of transcription 1 signaling pathway in thymocytes from HIV-1-infected human thymus. AIDS 17:9, 1269-1277
CrossRef18
Daniel C. Douek, Louis J. Picker, Richard A. Koup. (2003) T C
ELL DYNAMICS IN HIV-1I NFECTION *. Annual Review of Immunology 21:1, 265-304
CrossRef19
Elaine J Abrams, Jeffrey Wiener, Rosalind Carter, Louise Kuhn, Paul Palumbo, Stephen Nesheim, Francis Lee, Peter Vink, Marc Bulterys. (2003) Maternal health factors and early pediatric antiretroviral therapy influence the rate of perinatal HIV-1 disease progression in children. AIDS 17:6, 867-877
CrossRef20
Donald P Kotler. (2003) Human immunodeficiency virus and pregnancy. Gastroenterology Clinics of North America 32:1, 437-448
CrossRef21
Ping Ye, Athena P. Kourtis, Denise E. Kirschner. (2003) Reconstitution of thymic function in HIV-1 patients treated with highly active antiretroviral therapy. Clinical Immunology 106:2, 95-105
CrossRef22
Anita L. Belman. (2002) HIV-1 infection and AIDS. Neurologic Clinics 20:4, 983-1011
CrossRef23
Laura A. Napolitano, Joan C. Lo, Michael B. Gotway, Kathleen Mulligan, Jason D. Barbour, Diane Schmidt, Robert M. Grant, Robert A. Halvorsen, Morris Schambelan, Joseph M. McCune. (2002) Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 16:8, 1103-1111
CrossRef24
Gregory D. Sempowski, Barton F. Haynes. (2002) I
MMUNE RECONSTITUTION IN PATIENTS WITH HIV INFECTION . Annual Review of Medicine 53:1, 269-284
CrossRef25
ALAN MEYERS, AMRIK SHAH, ROBERT H. CLEVELAND, WILLIAM R. CRANLEY, BEVERLY WOOD, SUSAN SUNKLE, SCOTT HUSAK, ELLEN R. COOPER. (2001) Thymic size on chest radiograph and rapid disease progression in human immunodeficiency virus 1-infected children. The Pediatric Infectious Disease Journal 20:12, 1112-1118
CrossRef26
Joseph M. McCune. (2001) The dynamics of CD4+ T-cell depletion in HIV disease. Nature 410:6831, 974-979
CrossRef27
Marlene S. Orandle, P. Cynthia Crawford, Julie K. Levy, Robin Udoji, George P. Papadi, Tina Ciccarone, Ayalew Mergia, Calvin M. Johnson. (2000) CD8 + Thymic Lymphocytes Express Reduced Levels of CD8β and Increased Interferon γ in Cats Perinatally Infected with the JSY3 Molecular Clone of Feline Immunodeficiency Virus. AIDS Research and Human Retroviruses 16:15, 1559-1571
CrossRef28
Denise Kirschner, G. F. Webb, Miles Cloyd. (2000) Model of HIV-1 Disease Progression Based on Virus-Induced Lymph Node Homing and Homing-Induced Apoptosis of CD4+ Lymphocytes. Journal of Acquired Immune Deficiency Syndromes 24:4, 352-362
CrossRef29
Denise Kirschner, G. F. Webb, Miles Cloyd. (2000) Model of HIV-1 Disease Progression Based on Virus-Induced Lymph Node Homing and Homing-Induced Apoptosis of CD4+ Lymphocytes. JAIDS Journal of Acquired Immune Deficiency Syndromes 24:4, 352-362
CrossRef30
Barton F. Haynes, M. Louise Markert, Gregory D. Sempowski, Dhavalkumar D. Patel, Laura P. Hale. (2000) The Role of the Thymus in Immune Reconstitution in Aging, Bone Marrow Transplantation, and HIV-1 Infection. Annual Review of Immunology 18:1, 529-560
CrossRef31
Alessandra Vigano, Stefano Vella, Marina Saresella, Angelo Vanzulli, Dorella Bricalli, Simonetta Di Fabio, Pasquale Ferrante, Mauro Andreotti, Maria Pirillo, Leonard G. Dally, Mario Clerici, Nicola Principi. (2000) Early immune reconstitution after potent antiretroviral therapy in HIV-infected children correlates with the increase in thymus volume. AIDS 14:3, 251-261
CrossRef32
AM Prentice, AC Collinson. (2000) Does breastfeeding increase thymus size?. Acta Paediatrica 89:1, 8-12
CrossRef33
Jennifer C. Woo, Gregg A. Dean, Alora Lavoy, Ross Clark, Peter F. Moore. (1999) Investigation of Recombinant Human Insulin-Like Growth Factor Type I in Thymus Regeneration in the Acute Stage of Experimental FIV Infection in Juvenile Cats. AIDS Research and Human Retroviruses 15:15, 1377-1388
CrossRef34
Paul Krogstad, Christel H. Uittenbogaart, Ruth Dickover, Yvonne J. Bryson, Susan Plaeger, Alan Garfinkel. (1999) Primary HIV Infection of Infants: The Effects of Somatic Growth on Lymphocyte and Virus Dynamics. Clinical Immunology 92:1, 25-33
CrossRef35
Barton F. Haynes. (1999) HIV Infection and the Dynamic Interplay between the Thymus and the Peripheral T Cell Pool. Clinical Immunology 92:1, 3-5
CrossRef36
Marléne Moussa, Barbara Mognetti, Sylvie Dubanchet, Elisabeth Menu, Pierre Roques, Gabriel Gras, Dominique Dormont, Françoise Barre-Sinoussi, Gérard Chaouat. (1999) Review: Vertical Transmission of HIV: Parameters Which Might Affect Infection of Placental Trophoblasts by HIV-1: A Review. American Journal of Reproductive Immunology 41:5, 312-319
CrossRef37
John W. Sleasman, Robert P. Nelson, Maureen M. Goodenow, David Wilfret, Alan Hutson, Michael Baseler, Judy Zuckerman, Philip A. Pizzo, Brigitta U. Mueller. (1999) Immunoreconstitution after ritonavir therapy in children with human immunodeficiency virus infection involves multiple lymphocyte lineages. The Journal of Pediatrics 134:5, 597-606
CrossRef38
Thomas Böhler, Judith Walcher, Gabi Hölzl-Wenig, Magdalena Geiss, Bernd Buchholz, Richard Linde, Klaus-Michael Debatin. (1999) Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents. AIDS 13:7, 779-789
CrossRef39
Judy Lieberman, Linda A. Trimble, Rachel S. Friedman, Julianna Lisziewicz, Franco Lori, Premlata Shankar, Heiko Jessen. (1999) Expansion of CD57 and CD62L-CD45RA+ CD8 T lymphocytes correlates with reduced viral plasma RNA after primary HIV infection. AIDS 13:8, 891-899
CrossRef40
Alessandra Vigano, Stefano Vella, Nicola Principi, Dorella Bricalli, Natascia Sala, Antonino Salvaggio, Marina Saresella, Angelo Vanzulli, Mario Clerici. (1999) Thymus volume correlates with the progression of vertical HIV infection. AIDS 13:5, F29-F34
CrossRef41
Barton F. Haynes, Laura P. Hale, Kent J. Weinhold, Dhavalkumar D. Patel, Hua-Xin Liao, Peter B. Bressler, Dawn M. Jones, James F. Demarest, Kristin Gebhard-Mitchell, Ashley T. Haase, John A. Bartlett. (1999) Analysis of the adult thymus in reconstitution of T lymphocytes in HIV-1 infection. Journal of Clinical Investigation 103:4, 453-460
CrossRef42
Barton F. Haynes, Laura P. Hale. (1998) The human thymus. Immunologic Research 18:3, 175-192
CrossRef43
Randall G. Fisher, Gregory J. Wilson, Joyce E. Johnson, Margie A. Scott, William M. Mitchell. (1998) CHROMOSOMAL PROVIRAL SEQUENCES OF HUMAN IMMUNODEFICIENCY VIRUS IN MULTIPLE THYMIC CELL TYPES IN A PATIENT WITH ACQUIRED IMMUNODEFICIENCY SYNDROME AND MASSIVE THYMIC HYPERPLASIA. The Pediatric Infectious Disease Journal 17:11, 1050-1052
CrossRef44
F. BUSEYNE, M. BURGARD, J.P. TEGLAS, E. BUI, C. ROUZIOUX, M.-J. MAYAUX, S. BLANCHE, Y. RIVIÈRE. (1998) Early HIV-Specific Cytotoxic T Lymphocytes and Disease Progression in Children Born to HIV-Infected Mothers. AIDS Research and Human Retroviruses 14:16, 1435-1444
CrossRef45
Barton F. Haynes, Laura P. Hale. (1998) The human thymus. Immunologic Research 18:2, 61-78
CrossRef46
TIM NIEHUES, JENNIFER NDAGIJIMANA, GERD HORNEFF, VOLKER WAHN. (1998) CD28 Expression in Pediatric Human Immunodeficiency Virus Infection. Pediatric Research 44:2, 265-268
CrossRef47
Denise E. Kirschner, Ramit Mehr, Alan S. Perelson. (1998) Role of the Thymus in Pediatric HIV-1 Infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 18:2, 95-109
CrossRef48
Donald P. Kotler. (1998) HIV IN PREGNANCY. Gastroenterology Clinics of North America 27:1, 269-280
CrossRef49
Glen N. Gaulton. (1998) Viral pathogenesis and immunity within the thymus. Immunologic Research 17:1-2, 75-82
CrossRef50
André Nahmias, Carlos Abramowsky, Istvan Dobronyi, Chris Ibegbu, Sheryl Henderson. (1998) Infection and immunity at the maternal-placental-fetal interface: Focus on HIV-1. Placenta 19, 103-124
CrossRef51
M.K Hellerstein, J.M McCune. (1997) T Cell Turnover in HIV-1 Disease. Immunity 7:5, 583-589
CrossRef52
Thomas F. M??ller, Scott O. Grebe, M. Christine Neumann, Jochen Heymanns, Klaus Radsak, Hans Sprenger, Harald Lange. (1997) Persistent Long-Term Changes In Lymphocyte Subsets Induced By Polyclonal Antibodies1. Transplantation 64:10, 1432-1437
CrossRef53
Lishan Su. (1997) HIV-1 pathogenesis and therapeutic intervention in the SCID-hu Thy/Liv mouse: a model for primary HIV-1 infection in the human thymus. Reviews in Medical Virology 7:3, 157-166
CrossRef54
Barbara Moepps, Reinhard Frodl, Hans-Reimer Rodewald, Marco Baggiolini, Peter Gierschik. (1997) Two murine homologues of the human chemokine receptor CXCR4 mediating stromal cell-derived factor 1α activation of Gi2 are differentially expressedin vivo. European Journal of Immunology 27:8, 2102-2112
CrossRef55
Glen N. Gaulton, Janice V. Scobie, Michael Rosenzweig. (1997) HIV-1 and the thymus. AIDS 11:4, 403-414
CrossRef
