IL-10-secreting T cells from HIV-infected pregnant women... : AIDS (original) (raw)
Introduction
Since the beginning of the acquired immunodeficiency syndrome (AIDS) epidemic, caused by human immunodeficiency virus (HIV), the number of infected young women has been increasing fast [1], mainly in developing countries, where the frequency of pregnancy among them is also elevated. This fact brings significant impact to the number of HIV-exposed children [2].
Concerning the HIV infection in fertile women, the risk of disease progression does not increase during pregnancy. This finding is very interesting because during pregnancy, different local and systemic immune events operate to support the survival of the fetus in the uterus by attenuating the maternal cellular immune response, which is exactly the phenotype involved in HIV control.
In this context, authors have suggested that during pregnancy, the secretion of high levels of both IL-10 and transforming growth factor β (TGF-β) by regulatory T-cells type 1 (Tr-1) and T helper 1 (Th3), respectively, takes place at the maternal–fetal interface in order to support normal growth and development of the fetus [3,4]. These pregnancy-related immunological changes depend on endocrine changes with progesterone and estrogen as powerful modulators of cytokine production [5]. Although estrogen and progesterone decrease the levels of tumor necrosis factor-α (TNF-α), IL-1, and interferon (IFN)-γ, they increase IL-10 production by maternal T cells [6–8].
In fact, the low levels of these regulatory T cells have been associated with maternal Th1-mediated spontaneous abortion [9,10]. In this regard, the pregnancy loss is associated with a dense influx of maternal CD4+ and CD8+ T cells to the decidua and a release of high quantities of TNF-α, IL-2, and IFN-γ in response to father-derived fetal HLA (human leukocyte antigen) antigens [11]. The embryotoxic potential of these cytokines is mainly due to their capacity to activate natural killer cells and macrophages, which are able to attack the placenta [11].
Therefore, it remains conceivable that beneficial T-cell responses to many different pathogens may be suppressed during pregnancy, as a side effect of the immunomodulatory mechanisms that favor maternal–fetal tolerance [12–14]. In this scenario, we can envisage that infectious diseases tend to become chronic, then elevating the risk of vertical transmission. On the contrary, the shift in the maternal immunological repertoire towards Th1 following infections can favor fetal growth restriction as well as fetal death [15]. In this context, until now, the characterization of maternal cytokine profile and its correlation with the dynamics of HIV replication was not studied. It is possible that this relationship might have an important impact on the risk of vertical HIV transmission. Therefore, we aimed to study the impact of maternal immune events on virus replication in groups of HIV-1-infected pregnant women who control or do not control the plasma viral load (PVL) and to analyze their relationship with the risk of vertical virus transmission.
Materials and methods
Patients
For our study, 62 HIV-1-infected pregnant women who controlled (G1, n = 32) or not controlled (G2, n = 30) the PVL were recruited from the Obstetrics Service of three public hospitals in Rio de Janeiro State. As controls for pregnancy-related immune events, healthy HIV-1-noninfected (G0, n = 15) pregnant women, matched by age and gestational time, were recruited from the same services.
Some characteristics of the HIV-infected pregnant women were obtained from medical records (Table 1). As it is accepted that the majority of HIV-1 vertical transmissions occur in late gestational times and during the delivery, peripheral blood samples were collected 24–48 h before the elective caesarean section.
Characteristics of pregnant women.
All patients studied were antiretroviral therapy (ART) naïve before pregnancy. Although the antiretroviral drugs were available at the site, some pregnant women were still without treatment at the time of blood collection (24–48 h before delivery), because they only looked for medical assistance just before delivery, and most of them were not aware of their seropositivity. All patients received continuous intravenous zidovudine (ZDV) infusion during the elective caesarian section. Pregnant women with any other infection besides HIV-1, who smoked or used illegal substances, were not included in the study, as these factors may cause adverse pregnancy outcomes.
The infected statuses of the neonates were confirmed or eliminated by nucleic acid technique (PCR) for env, nef, and vif HIV-1 provirus genes 2 weeks after prophylaxis with ZDV, that is, 6 weeks after birth.
A written informed consent was obtained from all mothers. This study was approved by the Ethical Committee for Research on Human Subjects of the Federal University of State of Rio de Janeiro (UNIRIO).
T-cell culture and stimulation
The peripheral blood (20 ml) from uninfected (G0) and from HIV-1-infected pregnant women who controlled (G1) or not controlled (G2) the PVL were drawn into tubes containing EDTA. Immediately after blood collection, an aliquot (2 ml) was separated for obtaining the total plasma for systemic cytokine quantification by enzyme-linked immunosorbent assay (ELISA). The remaining blood was used to obtain the peripheral blood mononuclear cells (PBMCs), by centrifugation on Ficoll-Hypaque density gradient using standard procedures [16].
In order to obtain the total T cells, PBMCs were first allowed to adhere in 24-well plates with 2 ml of RPMI supplemented with FBS (fetal bovine serum) (10% v/v) for 60 min at 37°C in a humidified 5% CO2 atmosphere, then submitted to B cells negative selection, using magnetic beads coated with anti-CD19 monoclonal antibody (mAb). The efficacy of this procedure was about 97% as evaluated by flow cytometry (data not shown). The viable T lymphocytes (1 × 106/ml) were cultured in a 96-well flat-bottomed microtiter plate with 200 μl of RPMI 1640 added with 2 mmol/l of L-glutamine (GIBCO, Carlsbad, California, USA), 10% of FCS, 20 U/ml of penicillin, 20 μg/ml of streptomycin, and 20 mmol/l of _N_-2-hydroxyethylpiperazine-_N_′-2-ethanesulfonic acid (HEPES) buffer. To induce polyclonal activation, these cultures were maintained with plate-bound anti-CD3 mAb (1 μg/ml; OKT3, mouse IgG1; Ortho Biotech, Bridgewater, New Jersey, USA) and anti-CD28 (1 μg/ml; clone CLB; Research Diagnostic, Flanders, New Jersey, USA). The cells were cultured at 37°C in a humidified 5% CO2 incubator for 3 days for proliferation and cytokine assays and for 7 days for in-vitro virus replication assessment.
Proliferation assay
The T cells (1 × 105/well) were activated or not activated with anti-CD3 and anti-CD28 for 3 days. The cellular proliferation was measured following addition of 0.5 μCi/well of [3H] thymidine during the last 8 h of incubation. After this period, the cells were harvested in glass fiber filters in an automatic cell harvester, and radioactive incorporation was measured using a liquid scintillation counter. In some experiments, saturating doses of anti-IL-10 mAb (22 μg/ml, B&D System, Minneapolis, Minnesota, USA) or its isotype-matching antibody control (IgG2a) were added. The results were shown as mean ± SD from each patient group.
The role of interleukin-10 produced by activated T cells on the in-vitro HIV-1 replication
The saturating doses of anti-IL-10 mAb (22 μg/ml, B&D System) were added in some wells at the time of stimulation of T-cell cultures with anti-CD3 and anti-CD28, and the supernatants were collected 7 days later. As controls, some wells were kept in the presence of the isotype-matching control antibody (IgG2a). The supernatants were stored at −70°C until use. The HIV RNA was measured by a commercial quantitative reverse transcriptase polymerase chain reaction (RT-PCR) kit (Amplicor HIV Monitor Test; Roche Molecular System, Branchburg, New Jersey, USA), with a detection threshold of 80 copies of HIV RNA/ml.
Cytokine determination
The plasma samples and the supernatants collected from polyclonally activated T-cell cultures after 3-day incubation were submitted to cytokine measurement by OptEIA ELISA kits (BD, Pharmingen, San Diego, California, USA), according to manufacturer's protocol. Briefly, each ELISA was performed using pairs of mAbs directed to human IL-1β, TGF-β, IL-10, IL-4, TNF-α, and IFN-γ. The reaction was revealed with streptavidin–horseradish peroxidase, using 3,3′,5,5′-tetramethylbenzidine (TMB) as substrate. Recombinant human IL-1β, TGF-β, IL-4, IFN-γ, TNF-α, and IL-10 ranging from 10 to 500 ρg/ml were used to construct standard curves.
Statistical analysis
The nonparametric Mann–Whitney U test was applied to determine whether the three groups were statistically different for each given variable. The impact of anti-IL-10 mAb on the in-vitro HIV-1 replication for the G1 group was analyzed using paired Student's t test. Pearson's correlation was used to analyze the correlation between the levels of in-vitro IL-10 production and HIV-1 replication and to determine whether it was statistically different. The significance in all experiments was defined as P value of less than 0.05.
Results
Virological and immunological characteristics of the patients
We worked with asymptomatic HIV-1-infected pregnant women who control (G1, <80 copies of HIV-1 RNA/ml) or do not control (G2, 450–27 000 copies of HIV-1 RNA/ml) their PVL (Table 1). As controls, healthy HIV-1-seronegative pregnant women (G0) were recruited.
All patients were asymptomatic and had CD4 cell counts above 400 cells/μl. Concerning the ART, of the 32 patients who controlled the PVL (G1), most (26 out of 32, 82%) were under ART introduced between 20 and 32 weeks of gestation, as soon as the HIV infection was confirmed. Among them, 20 out of 26 patients were receiving ZDV monotherapy, and six out of 26 patients were receiving ZDV and nevirapine (NVP) dual therapy. In these ART-treated G1 patients, the PVL at baseline (before ART) ranged from less than 80 (four out of 26) to 24 800 (22 out of 26) copies of RNA-HIV-1 per milliliter, and the baseline CD4 cell counts were above 400 cells/μl. The other six out of 32 women in G1 (18%) controlled spontaneously the PVL. Among the patients of G2, seven out of 30 (23%) were under ART with ZDV/NVP. When compared either with G0 or G1 groups, the mean values of CD4+ T-cell counts were significantly lower in the patients of G2 (P < 0.05), though no patient had levels of less than 400 CD4+ cells/μl (Table 1). Furthermore, all of them remained asymptomatic until delivery.
Concerning the quantification of peripheral CD8+ T cells, as expected, the mean values were significantly higher in HIV-1-infected patients, in comparison with control group (G0). Finally, though all infants were born at term, the G2 babies had a tendency to lower birth weight (P = 0.056) (Table 1).
Lower T-cell proliferation and higher interleukin-10 production were observed among the HIV-1-infected pregnant women with optimal viral suppression
As shown in Fig. 1, the extent of lymphoproliferative response of the T-cell cultures from both G0 and G1 groups was significantly lower than the detected in G2 cultures. As regards the systemic cytokine profile, the IL-4 and IL-10 were the dominant cytokines measured in the plasma obtained from both G0 and G1 groups (Fig. 2a). Although these cytokines were also detected in the G2 plasmas, the production of proinflammatory cytokines IL-1β, TNF-α was significantly higher in this latter group than in G0 and G1 (Fig. 2a). Concerning TGF-β, its levels were highly variable among the samples, and the differences did not reach any statistical significance. A similar cytokine profile was observed in the supernatants collected from the polyclonally activated T-cell cultures. As shown in Fig. 2c, the IL-10 production was significantly lower in the supernatants of polyclonally activated T-cell cultures from G2 group, when compared with G0 and G1 groups. Additionally, TNF-α and IFN-γ were significantly higher in G2 cultures. No statistical difference in IL-4 release was observed between the three groups. Concerning TGF-β, though its concentrations in the cultures did not reach statistical difference, higher level of this cytokine tended to be secreted by activated T-cell cultures from G1 group (P < 0.057), compared with G2 patients (Fig. 2c).
Proliferative response of T cells from HIV-1-infected pregnant women. T-cell cultures (1 × 105/well) purified from HIV-1-infected pregnant women who control (G1, n = 32) or do not control (G2, n = 30) the PVL were kept in culture with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml) mAbs for 3 days. As control, the proliferative response of T-cell cultures from HIV-1-seronegative pregnant women was also measured. Proliferation was determined by [3H] thymidine uptake. Of note, any spontaneous proliferation was detectable in wells containing medium alone (data not shown). G0, G1, G2 indicate groups. Horizontal bars within boxes correspond to the median, box limits correspond to 25th and 75th percentiles, and vertical lines indicate the range. cpm, counts per minute. The P values are indicated in the figure.
Cytokine profile obtained from HIV-1-infected pregnant women. The cytokines were evaluated in (a) plasma collected from HIV-1-seronegative pregnant women (G0, n = 15) or from HIV-1-infected pregnant women who control (G1, n = 32) or do not control (G2, n = 30) the PVL. The same cytokines were evaluated in (b) nonactivated (medium) or (c) activated T-cell cultures (1 × 105/well) with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml) mAbs during 3 days. The cytokines were evaluated by ELISA. In subpart a, the horizontal bars within boxes correspond to the median, box limits correspond to 25th and 75th percentiles, and vertical lines indicate the range. The mean values of G1 and G2 were compared in the figure. G0, G1, G2 indicate groups. ELISA, enzyme-linked immunosorbent assay; IFN, interferon; mAb, monoclonal antibody; PVL, plasma viral load; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor-α. * P < 0.05; ** P < 0.001; *** P < 0.0001, respectively.
Interleukin-10-secreting T cells from HIV-1-infected pregnant women downregulate in-vitro virus replication and T helper 1 cytokine secretion
As shown in Fig. 3a, a higher HIV-1 replication was observed in the activated T-cell cultures from patients with detectable PVL. Interestingly, when the cultures were sorted by their levels of in-vitro IL-10 secretion and HIV-1 replication, we observed that the highest IL-10 secretion clearly correlated with lower in-vitro virus replication (Fig. 3b).
Role of IL-10 produced by activated T cells from HIV-1-infected pregnant women on in-vitro viral replication. The T-cell cultures (1 × 105/well) from HIV-1-infected pregnant women who control (G1, n = 32) or do not control (G2, n = 30) the PVL were stimulated with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml). Supernatants were collected after 3 days for IL-10 measurement by ELISA and after 7 days to quantify the level of HIV-1 replication as determined by reverse transcriptase polymerase chain reaction. In (a), the mean of HIV-1 RNA copies per milliliter for each patient group is indicated; in (b), the inverse correlation between in-vitro HIV-1-RNA copies and IL-10 secretion is shown; in (c), we have the mean of HIV-1 replication for each patient group after addition of anti-IL-10 mAb (22 μg/ml) or isotype-matching IgG2a at the beginning of incubation. G0, G1, G2 indicate groups. ELISA, enzyme-linked immunosorbent assay; PVL, plasma viral load. The P values are indicated in the figure.
In order to understand the extent of this inverse correlation, we added saturating doses of anti-IL-10 mAb at the beginning of the incubation periods and evaluated the virus replication 7 days later. As demonstrated in Fig. 3c, the blockade of IL-10 activity clearly enhanced the ability of HIV-1 to replicate. In the T-cell cultures from G1 group, which were able to produce higher IL-10 levels, the anti-IL-10 mAb increased the in-vitro viral replication up to three times when compared withcontrol wells (isotype-matching control). In G2 cell cultures, though the effect was lower, the endogenous IL-10 neutralization also enhanced HIV-1 replication significantly. In these cell cultures, the IL-10 neutralization tends to attenuate the polyclonally activated T-lymphocyte proliferation from G1 patients, but the values were not significantly different (Fig. 4a). No evidence of changing in the proliferative response was observed in the G2 cell cultures (data not shown). Nevertheless, the blockade of IL-10 significantly augmented the IL-1β, TNF-α, and IFN-γ secretion in these G1 cell cultures (Fig. 4b). Considering G2 cell cultures, among the cytokines assayed, the IL-10 neutralization augmented significantly just the secretion of TNF-α, but in less extension (P = 0.042) (data not shown).
Effect of IL-10 blockade on in-vitro T-cell proliferation and cytokine production from HIV-1-infected pregnant women. T-cell cultures (1 × 105/well) from HIV-1-infected pregnant women who control (G1, n = 32) their PVL were stimulated with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml) in the presence of saturating doses of anti-IL-10 mAb (22 μg/ml) or isotype-matching IgG2a in the beginning of these cultures. After 3 days, we evaluated (a) the cellular proliferation, detected by [3H] thymidine uptake, and (b) the release of IL-1β, TNF-α, and IFN-γ by ELISA. In (a), the horizontal bars within boxes correspond to the median, box limits correspond to 25th and 75th percentiles, and vertical lines indicate range. ELISA, enzyme-linked immunosorbent assay; IFN, interferon; mAb, monoclonal antibody; PVL, plasma viral load; TNF-α, tumor necrosis factor-α; cpm, counts per minute. The P values are indicated in the figure.
Maternal antiretroviral treatment enhances the interleukin-10 production
In our system, IL-10 was the major cytokine produced by G1 group. Nevertheless, 18% of them were not under antiretroviral treatment. When we separated the patients from G1 by ART-treated (ART+) or not ART-treated (ART−), we observed that higher levels of IL-10 were detected in the plasma of treated pregnant women (Fig. 5a). Interestingly, in vitro, there was no significant difference between the IL-10 dosage in the supernatants of polyclonally activated T-cell cultures from ART+ or ART− G1 patients (Fig. 5b). Although the number of G2 patients submitted to ART was low (seven out of 30), five of them (out of seven) showed higher IL-10 production after in-vitro polyclonal activation, and, unlike G1, the T-cell cultures from ART-treated G2 patients released higher IL-10 levels as compared to ones that were not ART-treated (−) from the same group (Fig. 5b).
Impact of maternal antiretroviral treatment on IL-10 production. The figure shows the IL-10 production by HIV-1-infected pregnant women who control (G1, n = 32) or do not control (G2, n = 30) their PVL and were treated (ART +, n = 26/32 for G1 and 7/30 for G2) or not treated (ART −, n = 06/32 for G1 and 23/30 for G2) with antiretroviral drugs during pregnancy. IL-10 values derive from (a) plasma and (b) supernatants of T-cell cultures (1 × 105/well) activated with anti-CD3 (1 μg/ml) and anti-CD28 (1 μg/ml), collected 3 days after incubation. The values are presented as mean ± SD for each subgroup. G0, G1, G2 indicate groups. The P values are indicated in the figure. ART, antiretroviral therapy; PVL, plasma viral load.
Evaluation of vertical transmission
In our cohort, the results of proviral DNA-PCR from the blood of babies obtained 2 weeks after prophylaxis with ZDV revealed that nine out of 62 children were vertically infected with HIV-1 (Table 1). The majority of them were born from ART-naive mothers (eight out of 62). Importantly, no ART-treated mothers from G2 group infected their babies, though they had low, but detectable PVL (450–4200 copies of RNA-HIV-1/ml). Only one out of nine virus-infected babies was born from ART-treated mother who controlled her PVL (Table 1). In this case, her treatment was introduced lately (>30 weeks of gestation), when her PVL at baseline (before ART) was more than 15 000 copies of HIV RNA per milliliter.
Discussion
The present study was designed to investigate the impact of maternal immune events on HIV-1 replication and to correlate them with the risk of vertical virus transmission. We worked with two groups of HIV-1-infected pregnant women who controlled (G1) or not controlled (G2) their PVL. To minimize the differences concerning the clinical status of the infection, all of them were asymptomatic and had CD4+T-cell counts above 400 cells/μl.
In our study, we observed that the T-cell proliferation in response to polyclonal activators, either in PBMC cultures (data not shown) or in T-cell-enriched suspensions, was lower in G0 (HIV-1-seronegative) and G1 than in G2 group. This phenomenon could be related, at least in part, to a higher tendency of the cells to produce IL-10, which has been shown to reduce T-lymphocytes proliferation in several conditions [18]. In our system, after the blockade of IL-10 by anti-IL-10 mAb, we observed a clear tendency towards an attenuation of the T-cell proliferation in G1 group, though it did not reach statistical significance. Furthermore, other mechanisms, besides IL-10, could be involved in reducing T-cell proliferation, such as pregnancy-induced maternal regulatory CD4+ CD25+ FoxP3+ T cells [6,19].
Concerning the cytokine profile, we observed that IL-10 was the dominant cytokine measured in the plasma and supernatants collected from both polyclonally activated PBMC (data not shown) and T-cell-enriched cultures from HIV-1-uninfected pregnant women (G0), as well as from those virus-infected pregnant women with undetectable PVL (G1). Furthermore, in our study, this high IL-10 secretion was clearly related with low in-vitro HIV-1 replication, whereas the production of IL-1β, TNF-α, and IFN-γ correlated with intense virus replication.
Excessive production of IL-10 in HIV-infected patients has been suggested to cause deleterious effects by decreasing the production of Th1 cytokines [20]. On the contrary, there is a broad consensus among investigators that, during the pathogenesis of HIV infection, the disease progression is closely associated with the level of immune activation [21–23]. Some studies have found a significant direct correlation between PVL and systemic TNF-α and IL-1 production [24–26]. These inflammatory cytokines, produced by an array of immune cells, can favor intense HIV replication in CD4+ T cells as well as in trophoblast, revealing, thus, a potential impact of placental inflammation in enhancing the risk of vertical transmission [27–33]. Interestingly, in our system, the addition of anti-IL-10 mAb elevated, mainly in G1 cultures, the concentration of RNA copies of HIV-1. The mechanism by which IL-10 reduces the in-vitro HIV-1 replication did not primarily involve a diminution of target-cell proliferation, but it was related to an important downregulation of proinflammatory cytokines' release. In agreement with our results, some studies have demonstrated that IL-10 is able to inhibit in-vitro HIV replication [33–37]. Weissman _et al._[38] demonstrated that IL-10 blocks HIV-induced TNF-α and IL-6 release and inhibited the virus replication in monocyte-derived macrophage cultures. Another study performed by Goletti _et al._[39] suggested that the impairment of HIV-1 replication in PBMC cultures from purified protein derivative (PPD)-anergic donors is directly related to higher IL-10 and lower IL-2 and TNF-α secretion compared with cultures obtained from PPD-reactive donors. Furthermore, in HIV-infected patients who carry an allele linked to increased IL-10 production, survival was doubled and the CD4+ T-cell loss was attenuated compared with noncarriers of this allele [40]. Therefore, the high levels of IL-10 produced by pregnant women can attenuate HIV-1 replication by elevating the threshold of CD4+ T-cell activation, thus, reducing the production of new viral particles.
In fact, the pregnancy-related immune events can also modify the dynamics of other chronic viral infections. Pregnant women who are chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) may experience a normalization of hepatic aminotransferases levels [41,42]. In the case of HCV, a significant reduction was also observed in the HCV RNA blood levels in this period of woman's life, with the lowest viral load being observed in the third trimester of pregnancy [42]. An abrupt increase in HCV RNA blood levels, paralleling a hepatitis flare, and a 120-fold increase in alanine aminotransferase (ALT) level were documented 1 month after delivery [42].
In our study, among the pregnant women who control the PVL (G1), levels significantly higher of IL-10 were detected in the plasma from antiretroviral-treated patients. The same tendency was observed in women from G2 group, in a smaller extent. In the culture supernatants, however, this correlation between ART and enhanced IL-10 production was observed only in G2 group, which may indicate that endogenous IL-10 production was already saturated in G1 cultures. There is also a possibility of involvement of another IL-10 source that was not present in peripheral T cells. As demonstrated by Pornprosert _et al._[43], ZDV significantly downregulates TNF-α mRNA expression in chorionic villi from HIV-1-uninfected women placenta, which could favor, indirectly, the maternal IL-10 production. The ART-treated patients of our cohort had received either ZDV alone (20 out of 33, 60%) or combined with NVP (13/33, 40%). Therefore, a contribution of ZDV for the in-vivo production of IL-10 cannot be discarded.
According to the present recommendations, pregnant women should receive highly active antiretroviral therapy (HAART) schemes, whose components are two nucleoside analog reverse transcriptase inhibitors (NRTIs), associated with a protease inhibitor [44]. The introduction of the protease inhibitor in schemes to treat HIV-infected pregnant women, however, elevated the risk of premature delivery [45], and a recent study by Fiore _et al._[46] suggested that this phenomenon was related to high levels of maternal proinflammatory cytokines. The HAART is very efficient in inducing immunofunctional reconstitution in AIDS patients [47–49]. This powerful scheme can favor the breakdown of the maternal tolerance to fetal antigens and then elevate the risk of spontaneous abortions or premature delivery. Although these two-drug schemes are less potent in inducing immune reconstitution, they could be sufficient to control the HIV replication during the pregnancy and, thus, avoid vertical transmission, with the help of the antiviral effect of pregnancy-related IL-10 and with lower risk of maternal–fetal tolerance breakdown. Therefore, all these data together suggest that, at least in HIV-infected pregnant women with low AIDS progression rate, a revision in the therapeutic protocols for antiretroviral treatment should be made.
In conclusion, our results reveal that the high IL-10-secreting T cells from HIV-1-infected pregnant women help to subvert the viral replication by reducing the maternal proinflammatory cytokines. Furthermore, our results suggest that this phenomenon is upregulated by single or two-drug maternal antiretroviral treatment with NRTIs. At the moment, we are dedicating our efforts to perform a better phenotype characterization of these IL-10-secreting T cells, which can provide valuable information in order to help in the design of better therapeutic strategies for this immunological special group of HIV-1-infected patients.
Acknowledgements
Financial support: This work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
Contribution: C.A.M.B. and R.B. designed and performed research, and wrote the article; J.H., U.C.L., and R.G.S. performed and analyzed the data; A.A.L.S., C.S.M.S, and R.M.A collected the samples and contributed to analysis of the data; M.R. and D.K. contributed to analysis of the data and wrote the article; A.F.B.A and A.T. designed research and contributed vital reagents.
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Keywords:
antiretroviral therapy; cytokines; HIV; interleukin-10; pregnancy; tumor necrosis factor-α
© 2009 Lippincott Williams & Wilkins, Inc.