Strong HIV-1-Specific T Cell Responses in HIV-1-Exposed Uninfected Infants and Neonates Revealed after Regulatory T Cell Removal

BACKGROUND: In utero transmission of HIV-1 occurs on average in only 3%–15% of HIV-1-exposed neonates born to mothers not on antiretroviral drug therapy. Thus, despite potential exposure, the majority of infants remain uninfected. Weak HIV-1-specific T-cell responses have been detected in children exposed to HIV-1, and potentially contribute to protection against infection. We, and others, have recently shown that the removal of CD4(+)CD25(+) T-regulatory (Treg) cells can reveal strong HIV-1 specific T-cell responses in some HIV-1 infected adults. Here, we hypothesized that Treg cells could suppress HIV-1-specific immune responses in young children. METHODOLOGY/PRINCIPAL FINDINGS: We studied two cohorts of children. The first group included HIV-1-exposed-uninfected (EU) as well as unexposed (UNEX) neonates. The second group comprised HIV-1-infected and HIV-1-EU children. We quantified the frequency of Treg cells, T-cell activation, and cell-mediated immune responses. We detected high levels of CD4(+)CD25(+)CD127(−) Treg cells and low levels of CD4(+) and CD8(+) T cell activation in the cord blood of the EU neonates. We observed HIV-1-specific T cell immune responses in all of the children exposed to the virus. These T-cell responses were not seen in the cord blood of control HIV-1 unexposed neonates. Moreover, the depletion of CD4(+)CD25(+) Treg cells from the cord blood of EU newborns strikingly augmented both CD4(+) and CD8(+) HIV-1-specific immune responses. CONCLUSIONS/SIGNIFICANCE: This study provides new evidence that EU infants can mount strong HIV-1-specific T cell responses, and that in utero CD4(+)CD25(+) T-regulatory cells may be contributing to the lack of vertical transmission by reducing T cell activation

Predicting frequency distribution and influence of sociodemographic and behavioral risk factors of Schistosoma mansoni infection and analysis of co-infection with intestinal parasites

Geospatial analysis was used to study the epidemiology of Schistosoma mansoni, intestinal parasites and co-infections in an area (Ilha das Flores) in Sergipe, Brazil. We collected individually georeferenced sociodemographic, behavioral and parasitological data from 500 subjects, analyzed them by conventional statistics, and produced risk maps by Kernel estimation. The prevalence rates found were: S. mansoni (24.0%), Trichuris trichiura (54.8%), Ascaris lumbricoides (49.2%), Hookworm (17.6%) and Entamoeba histolytica (7.0%). Only 59/500 (11.8%) individuals did not present any of these infections, whereas 279/500 (55.8%) were simultaneously infected by three or more parasites. We observed associations between S. mansoni infection and various variables such as male gender, being rice farmer or fisherman, low educational level, low income, water contact and drinking untreated water. The Kernel estimator indicated that high-risk areas coincide with the poorest regions of the villages as well as with the part of the villages without an adequate sewage system. We also noted associations between both A. lumbricoides and hookworm infections with low education and low income. A. lumbricoides infection and T. trichiura infection were both associated with drinking untreated water and residential open-air sewage. These findings call for an integrated approach to effectively control multiple parasitic infections

Figure 5

<p>Augmented CD4⁺ HIV-1 immune responses to Gag peptide pools in exposed uninfected neonatal cord blood upon the removal of CD4⁺CD25⁺ Treg cells. A) IL-2 production by undepleted whole cord blood and peripheral blood mononuclear cells (MNCs) derived CD4⁺ T-cells (open white symbols) and CD25-depleted MNCs derived CD4⁺ T-cells (closed black symbols) is depicted. B) Flow cytometry plots from an exposed uninfected neonate (Patient 63) representing HIV-1 Gag induced IL-2 production in undepleted whole CBMC derived CD4⁺ T-cells and CD25-depleted CBMC derived CD4⁺ T-cells.</p

Figure 1

<p>CD4⁺ and CD8⁺ T cell immune responses were measured by cytokine flow cytometry. A) Gating strategy for the identification of polyfunctional IFN-gamma/TNF-alpha CD8⁺ T cell responses. B) Shown are representative data for the unstimulated and HIV-gag-specific response from subject PB-INF-4 after an 18 h <i>in vitro</i> stimulation.</p

Augmented CD8⁺ HIV-1 immune responses to Gag peptide pools in exposed uninfected neonatal cord blood upon the removal of CD4⁺CD25⁺ Treg cells. A) IFN-gamma production by undepleted whole cord blood and peripheral blood mononuclear cells (MNCs) derived CD8⁺ T-cells (open white symbols) and CD25-depleted MNCs derived CD8⁺ T-cells (closed black symbols) is depicted. B) Flow cytometry plots from an exposed uninfected neonate (Patient 30) representing HIV-1-Gag-induced IFN- gamma production in non-CD25-depleted CBMC derived CD8⁺ T-cells and CD25-depleted CBMC derived CD8⁺ T-cells.

<p>Augmented CD8⁺ HIV-1 immune responses to Gag peptide pools in exposed uninfected neonatal cord blood upon the removal of CD4⁺CD25⁺ Treg cells. A) IFN-gamma production by undepleted whole cord blood and peripheral blood mononuclear cells (MNCs) derived CD8⁺ T-cells (open white symbols) and CD25-depleted MNCs derived CD8⁺ T-cells (closed black symbols) is depicted. B) Flow cytometry plots from an exposed uninfected neonate (Patient 30) representing HIV-1-Gag-induced IFN- gamma production in non-CD25-depleted CBMC derived CD8⁺ T-cells and CD25-depleted CBMC derived CD8⁺ T-cells.</p

Figure 3

<p>Polyfunctional CD8⁺ T cell immune responses to the HIV-1 Gag peptide pool were detected by cytokine flow cytometry. Responses were measured in the cord blood of unexposed neonates (CB-UNEX; n = 4), HIV-1-exposed uninfected neonates (CB-EU; n = 6), and in the peripheral blood of HIV-1-exposed-uninfected infants (PB-EU 7 mo; n = 9) and young children (PB-EU 20 mo; n = 7), and in HIV-1-infected infants (PB-INF 7 mo; n = 5) and young children (PB-INF 25 mo; n = 5). Each group is represented by a different symbol.</p

CD8⁺ IFN-gamma T-cell immune responses to HIV-1 Gag <i>(A)</i> and Nef <i>(B)</i> peptide pools as well as SEB <i>(C)</i> in the cord blood of unexposed neonates (CB-UNEX; n = 4), HIV-1-exposed uninfected neonates (CB-EU; n = 6), and in the peripheral blood of HIV-1-exposed-uninfected infants (PB-EU 7 mo; n = 9) and young children (PB-EU 20 mo; n = 7), and in HIV-1-infected infants (PB-INF 7 mo; n = 5) and young children (PB-INF 25 mo; n = 5). Each group is represented by a different symbol.

<p>CD8⁺ IFN-gamma T-cell immune responses to HIV-1 Gag <i>(A)</i> and Nef <i>(B)</i> peptide pools as well as SEB <i>(C)</i> in the cord blood of unexposed neonates (CB-UNEX; n = 4), HIV-1-exposed uninfected neonates (CB-EU; n = 6), and in the peripheral blood of HIV-1-exposed-uninfected infants (PB-EU 7 mo; n = 9) and young children (PB-EU 20 mo; n = 7), and in HIV-1-infected infants (PB-INF 7 mo; n = 5) and young children (PB-INF 25 mo; n = 5). Each group is represented by a different symbol.</p