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IMMUNOBIOLOGY
From the Cattedra di Immunologia, Università di
Milano, DISP LITA Vialba, Milano; Laboratorio di Biologia, Fondazione
Don C. Gnocchi, IRCCS, Via Capecelatro, Milano; Cattedra di Pediatria
IV, Università di Milano, Ospedale Luigi Sacco, Milano; and
Laboratorio di Virologia, Istituto Superiore di Sanità, Roma,
Italy.
Cell-mediated immunity and T-lymphocyte maturation are impaired in
HIV-infected children. These abnormalities would be detected in
HIV-uninfected offspring of HIV women (seroreverters [SR]) if HIV or
its soluble proteins could cross the placental barrier. Immunophenotypic analyses were performed in 20 healthy HIV-uninfected newborns of HIV-infected mothers (SR), and in 14 healthy newborns of
HIV-negative women (UC). The same analyses were performed in 3 groups
of older children: SR (n = 41); UC (n = 15); and HIV-infected children (n = 25). Antigen-specific cells were evaluated with ELISpot
and fluorimetric analyses; IL-7 serum concentration was measured by
enzyme-linked immunosorbent assay (ELISA). Results showed that in SR
newborns: (1) the CD4/CD8 ratio was reduced, (2) CD4+ and
CD8+ naive T-cell percentages were decreased, (3)
percentage of activated CD8+ T cells was increased, and (4)
percentages of CD3+/4 Mother-to-child transmission of HIV is the primary
route of infection in infants.1-3 Vertical HIV infection
occurs in 25% to 30% of pregnancies. Prepartum and intrapartum
prophylaxis with antiretroviral agents, along with elective cesarean
section and avoidance of breastfeeding, have nevertheless reduced
appreciably the incidence of this modality of
infection.4-7
Vertical HIV transmission can be the result of in utero or intrapartum
infection.1-3 That at least part of these infections occurs in utero confirms that the placental barrier is not impermeable to maternal pathogens. Transplacental passage of pathogens is a
well-known phenomenon, hence the observation that maternal infection with Toxoplasma gondii or cytomegalovirus can
result in fetal pathologies. Vertical transmission of pathogens is
facilitated by: (1) lack of HLA Class I expression by the
syncytiotrophoblast, (2) multiple vesicular and immunoglobulin
transport pathways; and (3) the presence of physical defects in the
trophoblast layers throughout gestation.8 T-placental
barrier can thus be permeable to microorganisms and proteins.
In the case of HIV infection, in utero exposure to the virus can
be associated with 2 possible outcomes: overt HIV infection and lack
thereof.9-16 Pediatric HIV infection results in a complex pattern of quantitative and qualitative defects involving the immune
system that has been described in depth.17 In utero
exposure not resulting in infection, and the possibility that HIV
and/or viral particles penetrate across the placental barrier even in the absence of fetal infection, is supported by experimental results. Thus, exposure to HIV in HIV-uninfected newborns of HIV-seropositive mothers is shown by the observation that HIV-specific T
helper9,10 and cytotoxic T cells11-15 can be
detected in these newborns. Additionally, a recent report showed that
susceptibility to apoptosis is augmented in cord blood T lymphocytes
from infants of HIV-infected mothers.16 Because in
HIV-infected women the fetus would develop in a microenvironment enriched with viral particles and/or whole virus, immune abnormalities could be observed even in HIV-uninfected newborns of HIV-seropositive mothers. In particular, because HIV recognizes CD4 as its main receptor,18,19 if immune abnormalities occur in these
newborns, an impairment of T- but not of B-lymphocyte function and/or
development, would be expected even in HIV-uninfected newborns of
HIV-infected mothers.
To verify this hypothesis, we performed in-depth immunologic
analyses in healthy HIV-uninfected newborns of HIV-infected mothers and
in healthy newborns of HIV-negative women. The same analyses were also
performed in older HIV-exposed and -unexposed healthy children as well
as in a group of HIV-infected children.
Results confirm the hypothesis that abnormalities in cell-mediated
immunity and T-cell development are present in HIV-uninfected newborns
of HIV-infected mothers. Surprisingly, some of these immune
abnormalities persist during childhood.
Patients and controls
Blood drawing and processing
Immunophenotypic analyses Lymphocyte subsets were evaluated using an Epics XL flow-cytometer (Coulter Electronics, Miami Lakes, FL) using 100 µL of EDTA peripheral blood incubated 30 minutes at 4°C with fluorochrome-labeled monoclonal antibodies. Erytrocyte lysis was obtained, after incubation with the Immuno-Prep Epics Kit (Coulter Electronics) and Q-prep Work Station (Coulter Electronics). Lymphocytes were analyzed using forward- and side- scatter properties. For each sample, multiparametric data were acquired for 5000 events.Determination of intracellular cytokine in antigen- and mitogen-stimulated T lymphocytes PBMCs were resuspended in 200 µL of RPMI1640 media (Sigma, St Louis, MO) supplemented with 2% AB+ serum (Sigma). PBMCs were incubated for 18 hours with: (1) a pool of previously described 5 synthetic peptides from the glycoprotein (gp)160 envelope of HIV-120 (2.5 µmol/L final concentration) (env); (2) influenza virus vaccine (A/Taiwan, A/Shanghai, and B/Victoria), 24 µg/L (final dilution 1:1000)(negative control); and (3) PMA (50 ng/mL)+ ionomycin (1 µmol/L)(positive control). Antibody to CD28 (R&D Systems, Minneapolis, MN) was added during incubation at a dose of 1 µg per well to facilitate costimulation.Interferon gamma ELISpot assays The 96-well nitrocellulose plates were precoated with a first layer IFN monoclonal antibodies (Mabtech, Nacka, Sweden).
2 × 105 cells per well PBMCs were then added in
duplicate wells either with env (20 µmol/L final concentration) in
the presence or the absence of neutralizing anti-CD4 monoclonal
antibody (see below), with no peptide (negative control), or in 1:100
PHA (M form; Sigma, St Louis, MO) (positive control). The 5 peptides used in the stimulation are promiscuous as they are
recognized by multiple HLA Class I molecules (including HLA A1, A2, A3,
A9, A25, A26, A29).21 Because these epitopes can also be
recognized by HLA Class II molecules,26 IFN production
by CD4+ was blocked by preincubating PBMCs with 100 ng/mL
of neutralizing recombinant human CD4 monoclonal antibody (R&D). Plates
were incubated overnight at 37°C in 7% CO2, then the
cells were discarded and the plates incubated at room temperature for 3 hours. A second biotinylated anti-IFN monoclonal antibody (7-B6-1
biotin; Mabtech), followed by streptavidin-conjugated alkaline
phosphatase (Mabtech) for 2 hours were subsequently used.
IFN-producing cells were detected using an alkaline
phosphatase-conjugate substrate kit (Bio-Rad laboratories, Hercules,
CA). The spots were counted by eye, and the numbers were confirmed
using a dissecting microscope (× 40). HIV-specific responses were
reported as number of spot-forming units (SFU) per 106
mononuclear cells after subtraction of background IFN secretion. Only responses observed in the wells in which IFN production by
CD4+ was blocked by preincubation of PBMCs with the
anti-CD4 antibody are reported. A positive response was defined as
follows: (1) more than 20 HIV-specific SFU/106 cells and
(2) HIV-stimulated SFU exceed background by a factor of at
least 2.
Measurement of serum IL-7 IL-7 was measured in serum samples using an enzyme-linking immunosorbent assay (ELISA) kit (Quantikine HS human IL-7; R&D) according to the instructions of the manufacturer.Statistical analysis The differences between the mean values of different groups were calculated for each variable (possibly transformed to approximate normality or square root transformation) by using multiple linear regression with dummy variables adjusted for CD4 and CD8 numbers.
Immune abnormalities in healthy newborns of HIV-infected and HIV-uninfected mothers Twenty healthy newborns of HIV-infected mothers (SRs) and 14 healthy newborns of HIV-uninfected women (unexposed controls, UCs) were included in the study. The mean age was comparable between the 2 groups (SR = 30 days; UC = 30.5 days) (Table 1). A panel of immunophenotypic markers was evaluated both in SRs and UCs. No differences were observed between the 2 groups in the absolute number or the percentages of natural killer (CD16+) and B lymphocytes (CD19+) (data not shown). A complex pattern of alteration was nevertheless detected when T-lymphocyte subsets were analyzed. Thus, in SRs compared with UCs, the percentage and absolute number of: (1) CD4+ T cells was reduced (P = .069), CD8+ T cells augmented (P < .0001), and consequently the CD4/CD8 ratio was diminished (P = .00015); (2) CD4+/45RA/62+ (naive) lymphocytes were reduced (P < .0001) and CD4+/45RO (memory) cells augmented (P < .001); (3) CD8+/RA+LFAlow (naive) lymphocytes were reduced (P = .0033) and CD8+/RA+LFAhigh ("revertant" CD8+ T cells suggested to be highly enriched in memory T lymphocytes) augmented (P = .0022); (4) CD8+/38dim lymphocytes were reduced (P < .001) and CD8+/CD38bright (activated) cells augmented (P < .0001); and finally, (5) CD3+/4 /8 (double negative
[DN]) and DN/25/44+ T lymphocytes were
augmented (P < .0001 in both cases)(Table 3).
CD4+/
Quantitation of IFN -secreting cells
was compared in SRs (n = 8) and UCs (n = 7). The mean number of
IFN-secreting cells was similar in SRs (11 ± 4 per
106 cells) and in UCs (7 ± 5 per 106 cells).
Nevertheless, an augmented number of HIV-specific IFN-secreting cells (greater than 2-fold the background) was detected in 3 of 8 SRs (39, 64, 72 per 106 cells)(the same newborns in whom
the highest frequencies of HIV-specific, IL-2-secreting
CD4+ T cells was detected) but in none of the UCs (data
not shown).
Immune abnormalities in older seroreverters, unexposed controls, and HIV-infected children The results obtained in newborns were verified in older children, who were divided in 3 categories: SR (n = 41), UC (n = 15), and HIV-infected children (n = 25), a group that, because of the success of pharmacologic prophylaxis in reducing mother-to-infant transmission of HIV was thankfully not available in the newborn population. None of the SRs underwent zidovudine prophylaxis at the time of delivery (Table 2). CD4 counts of HIV-infected children were reduced compared with both groups of uninfected individuals; this variable was thus included in the statistical analyses. Results confirmed that, even in older SRs compared with UCs, the percentage of: (1) CD4+/45RA/62+ (naive) lymphocytes was reduced (P = .03) and that of CD4+/45RO (memory) cells augmented (P = .001), (2) CD8+/CD38dim cells was reduced (P = .004) and that of CD8/38 bright cells augmented (P = .01), and (3) DN and DN/CD25/CD44+ cells was augmented
(P = .02 and .001, respectively). In all these cases, the
immunophenotype of SR was similar to the one observed in HIV-infected
children (Table 4).
CD4+/
Quantitation of CD8+/ -secreting cells were analyzed
in SRs (n = 8), UCs (n = 8), and HIV-infected children (n = 6)
and were detected in HIV-infected children (3 of 6 children were
positive) but not in SRs or UCs (data not shown).
Serum IL-7 in newborns and older children Serum IL-7 concentration was measured in newborns as well as in older SRs and UCs, and in HIV-infected children. Results showed serum IL-7 concentration to be significantly increased both in newborns and older SRs compared with newborn and older UCs (P = .02 and .01, respectively), with the highest levels present in HIV+ children (Figure 2). A trend, which, nevertheless, did not reach statistical significance, was noticed between higher serum IL-7 concentrations and lower CD4+ and CD4+/45RA/62+ T-lymphocyte counts in SR newborns as well as in SR and HIV+ children.
Vertical HIV infection occurs in 30% of cases in the absence of effective interventions.1-3 It is known that exposure to HIV or its soluble products can be detected in healthy, uninfected newborns of HIV-infected mothers.9-16 Thus, different studies have shown the presence of HIV-specific T helper9,10 and cytotoxic11-15 T cells in these uninfected newborns and have suggested that the activation of HIV-specific cell-mediated immunity could be associated with protection from infection.10 The results of this study show that intrauterine exposure to HIV or its soluble factors may occur during the pregnancies of HIV-infected mothers and appears to affect fetal immune maturation. Because the immune system develops during intrauterine life, and intrathymic maturation and selection of T lymphocytes are known to occur in this period,22-24 we investigated whether these processes could be influenced by the presence of HIV and/or its soluble proteins. This working hypothesis was further reinforced by the observation that thymic abnormalities are described in fetuses aborted from HIV-seropositive women, even in the absence of thymic HIV infection.25 In particular, because HIV infection disrupts cell-mediated immunity,26-28 and the envelope glycoproteins of HIV bind to CD4,18,19 we would have expected immune abnormalities to be prevalent in the T-lymphocyte compartment. Results showed that, whereas no alterations are detected in either B lymphocytes or natural killer cells, a complex pattern of defects in CD4+ and CD8+ T-lymphocyte subpopulations and a peripheral increase in immature T lymphocytes are detected in HIV-uninfected newborns of HIV-infected mothers; these abnormalities tend to persist over time and are still present in older healthy children of HIV-infected mothers. Thus, we report that the physiologic development of the immune system is impaired in HIV-uninfected newborns of HIV-infected mothers. All the pregnant mothers and newborns included in the study received zidovudine (according to PACTG 076), a protocol that, together with cesarean section,29-31 reduces the incidence of vertical infection.4-7 The immune abnormalities detected in uninfected newborns of HIV-seropositive mothers are not likely to be secondary to drug-related effects because the same abnormalities were observed in older children of HIV-infected mothers who did not undergo prophylaxis with zidovudine or any other antiviral drug. Memory T cells were augmented and naive T lymphocytes were diminished in HIV-uninfected newborns of HIV-infected mothers suggesting that massive antigenic exposure is occurring in these individuals. Analysis of antigen-stimulated IL-2 production showed the presence of a significant number of HIV-specific CD4+ T helper cells in HIV-uninfected newborns. The observation that the frequency of influenza-specific T helper cells was negligible in the same individuals strongly suggests that the alterations in the memory or naive cells detected in these newborns are associated with exposure to HIV and/or its soluble products. Detection of recall antigen-specific CD4+ T cells at birth is indeed a rare event and, in particular, influenza-specific T-helper responses are not present at birth in either HIV-infected or healthy children.32-35 The immune abnormalities observed in HIV-uninfected newborns of HIV-infected mothers could therefore be secondary to exposure to HIV and/or viral soluble products. That immune abnormalities are present in HIV-uninfected newborns of HIV-infected mothers was recently suggested by the observation that IL-12 production is impaired in cord blood lymphocytes of these newborns36; cord blood T lymphocytes of HIV-exposed but uninfected newborns were also shown to be more susceptible to apoptosis.16 Although high frequencies of HIV-specific CD4+ T
helper cells were detected in most HIV-uninfected newborns of
HIV-infected mothers, HIV-specific, IFN An elevated number of DN/CD25 In this context, it is important to underline that serum IL-7 concentrations were found to be elevated in newborn and older healthy children of HIV-infected mothers. IL-7 is required for thymopoiesis, enhances the survival of developing thymocytes and mature T cells by up-regulating bcl-2, and functions as a maturation factor for postthymic naive T cells. Additionally, the IL-7 receptor is crucial in thymic development, as its expression is down-regulated in thymocytes that fail the positive selection process and up-regulated in positively selected thymocytes.43,44 IL-7 is augmented during T-cell reconstitution43 and in HIV-infected individuals. In particular, recent results showed the presence of an inverse correlation between serum IL-7 concentrations and CD4 as well as CD4+/45RA+/62L+ T cells in HIV-infected children.45 The augmented levels of serum IL-7 observed in newborn and older healthy children of HIV-infected mothers thus are consistent with the observation that T-cell homeostasis is impaired in these individuals. As suggested by previously published data,10 the frequency of HIV-specific CD4+ T cells diminishes after birth and is comparable in older children of HIV-infected and uninfected mothers. These results show that antigen-specific immune activation is decreased once exposure to the antigen ceases and, in this case, suggest that exposure to HIV is indeed an intrauterine event and is interrupted after birth. It is nevertheless interesting that, even years after the exposure to HIV is ended, impairments in CD4+ and CD8+ T lymphocytes persist. These results strongly suggest that the maturation/developmental abnormalities associated with intrauterine exposure to HIV are long-lasting and persist after the exposure to the virus has ceased. These observations raise the concern that these children might be more susceptible to diseases such as autoimmune conditions and certain infections. Longitudinal studies on multiple cohorts of HIV-exposed and uninfected children will be needed to clarify this issue.
We are grateful to Drs Gene Shearer, Cristal Mackall, and Claire Cougnet, EIB, NCI, NIH, Bethesda, MD, for critically reading this manuscript and offering useful suggestions. We are also grateful to Drs Daria Trabattoni, Mara Biasin, Marta Cogliati, and Maria Luisa Fusi.
Submitted February 25, 2000; accepted August 3, 2000.
Supported by grants from Istituto Superiore di Sanita I and II Progetto AIDS 1998-99.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Mario Clerici, Chair of Immunology, DISP LITA Vialba, Via GB Grassi, 74, 20157 Milano, Italy; e-mail: mago{at}mailserver.unimi.it.
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© 2000 by The American Society of Hematology.
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  S. Arpadi, A. Fawzy, G. M Aldrovandi, C. Kankasa, M. Sinkala, M. Mwiya, D. M Thea, and L. Kuhn Growth faltering due to breastfeeding cessation in uninfected children born to HIV-infected mothers in Zambia Am. J. Clinical Nutrition, August 1, 2009; 90(2): 344 - 353. [Abstract] [Full Text] [PDF]
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 A. L. Slogrove, M. F. Cotton, and M. M. Esser Severe Infections in HIV-Exposed Uninfected Infants: Clinical Evidence of Immunodeficiency J Trop Pediatr, July 14, 2009; (2009) fmp057v1. [Abstract] [Full Text] [PDF]
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A. L. Webb, K. Manji, W. W. Fawzi, and E. Villamor Time-independent Maternal and Infant Factors and Time-dependent Infant Morbidities including HIV Infection, Contribute to Infant Growth Faltering during the First 2 Years of Life J Trop Pediatr, April 1, 2009; 55(2): 83 - 90. [Abstract] [Full Text] [PDF]
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 D. B. Schramm, S. Meddows-Taylor, G. E. Gray, L. Kuhn, and C. T. Tiemessen Low Maternal Viral Loads and Reduced Granulocyte-Macrophage Colony-Stimulating Factor Levels Characterize Exposed, Uninfected Infants Who Develop Protective Human Immunodeficiency Virus Type 1-Specific Responses Clin. Vaccine Immunol., April 1, 2007; 14(4): 348 - 354. [Abstract] [Full Text] [PDF]
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F. Rouet, A. Inwoley, D. K. Ekouevi, I. Viho, R. Becquet, C. Sakarovitch, L. Bequet, B. Tonwe-Gold, M.-L. Chaix, V. Leroy, et al. CD4 Percentages and Total Lymphocyte Counts as Early Surrogate Markers for Pediatric HIV-1 Infection in Resource-Limited Settings J Trop Pediatr, October 1, 2006; 52(5): 346 - 354. [Abstract] [Full Text] [PDF]
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S. Shalekoff, G. E. Gray, and C. T. Tiemessen Age-Related Changes in Expression of CXCR4 and CCR5 on Peripheral Blood Leukocytes from Uninfected Infants Born to Human Immunodeficiency Virus Type 1-Infected Mothers Clin. Vaccine Immunol., January 1, 2004; 11(1): 229 - 234. [Abstract] [Full Text] [PDF]
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 C. M. Steffens, E. Z. Managlia, A. Landay, and L. Al-Harthi Interleukin-7-treated naive T cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1 Blood, May 1, 2002; 99(9): 3310 - 3318. [Abstract] [Full Text] [PDF]
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S. D. Nielsen, D. L. Jeppesen, L. Kolte, D. R. Clark, T. U. Sorensen, A.-M. Dreves, A. K. Ersboll, L. P. Ryder, N. H. Valerius, and J. O. Nielsen Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts Blood, July 15, 2001; 98(2): 398 - 404. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
) or HIV-uninfected (newborn UC, 
) mothers. The
horizontal bar indicates mean values.
) or HIV-uninfected (newborn UC, 
)
mothers. (B) IL-7 serum concentration in older healthy children of
HIV-uninfected (UC children, 
) is shown as well. Mean and SD are shown.
families are perturbed in CD4 and CD8+ T lymphocytes
of HIV-uninfected newborns of HIV-infected mothers.