Histidine-Rich Glycoprotein Inhibits HIV-1 Infection in a pH-Dependent Manner.

Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure, allowing its interaction with many ligands, including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has been shown to regulate different biological responses, such as angiogenesis, coagulation, and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of Ghost cells, Jurkat cells, CD4+ T cells, and macrophages by HIV-1 at a low pH (range, 6.5 to 5.5) but not at a neutral pH. HRG was shown to interact with the heparan sulfate expressed by target cells, inhibiting an early postbinding step associated with HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect, which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defense mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of HEp-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus 2 (HSV-2), respectively, suggesting that HRG might display broad antiviral activity under acidic conditions.IMPORTANCE Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated to be 1 in every 1,000 episodes of sexual intercourse, reflecting the high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses, such as respiratory syncytial virus and herpes simplex virus 2, was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display broad antiviral activity.

Respiratory Syncytial Virus (RSV) Infects CD4+ T Cells: Frequency of Circulating CD4+ RSV+ T Cells as a Marker of Disease Severity in Young Children.

BACKGROUND: Although human airway epithelial cells are the main target of respiratory syncytial virus (RSV), it also infects immune cells, such as macrophages and B cells. Whether T cells are permissive to RSV infection is unknown. We sought to analyze the permissiveness of CD4+ T cells to RSV infection. METHODS: CD4+ and CD8+ T cells from cord blood, healthy young children, and adults were challenged by RSV or cocultured with infected HEp-2 cells. Infection, phenotype, and cytokine production by T cells were analyzed by flow cytometry or enzyme-linked immunosorbent assay. Expression of RSV antigens by circulating CD4+ T cells from infected children was analyzed by flow cytometry, and disease severity was defined by standard criteria. RESULTS: CD4+ and CD8+ T cells were productively infected by RSV. Infection decreased interleukin 2 and interferon γ production as well as the expression of CD25 and Ki-67 by activated CD4+ T cells. Respiratory syncytial virus antigens were detected in circulating CD4+ and CD8+ T cells during severe RSV infection of young children. Interestingly, the frequency of CD4+ RSV+ T cells positively correlated with disease severity. CONCLUSIONS: Respiratory syncytial virus infects CD4+ and CD8+ T cells and compromises T-cell function. The frequency of circulating CD4+ RSV+ T cells might represent a novel marker of severe infection.

ATP-Induced Inflammation Drives Tissue-Resident Th17 Cells in Metabolically Unhealthy Obesity.

Obesity-induced inflammation is conducted by a metabolic pathway, which eventually causes activation of specialized immune cells and leads to an unresolved inflammatory response within the tissue. For this reason, it is critically important to determine how hypertrophic fat tissue alters T cell balance to drive inflammation. In this study, we identify the purinergic signaling as a novel mechanism driving the adaptive Th17 response in human visceral adipose tissue (VAT) of metabolically unhealthy obese patients. We demonstrate that ATP acting via the P2X7 receptor pathway promotes a Th17 polarizing microenvironment with high levels of IL-1ß, IL-6, and IL-17 in VAT explants from lean donors. Moreover, in vitro blockade of the P2X7 receptor abrogates the levels of these cytokines. These findings are consistent with a greater frequency of Th17 cells in tissue from metabolically unhealthy obese donors, revealed not only by the presence of a baseline Th17-promoting milieu, but also by the higher expression of steadily recognized Th17 markers, such as RORC, IL-17 cytokine, and IL-23R, in comparison with metabolically healthy obese and lean donors. In addition, we demonstrate that CD39 expression on CD4(+)effector T cells represents a novel Th17 marker in the inflamed VAT, which also confers protection against ATP-induced cell death. The manipulation of the purinergic signaling might represent a new therapeutic target to shift the CD4(+)T cell balance under inflammatory conditions.

Identification and clinical relevance of naturally occurring human CD8+HLA-DR+ regulatory T cells.

The lack of responsiveness to self and non-self Ags is normally maintained by multiple mechanisms, including the suppressive activities of several T cell subsets. In this study, we show that CD8(+) T cells from both adult peripheral blood and umbilical cord blood mononuclear cells constitutively expressing HLA-DR represent a natural human CD8(+) regulatory T cell subset. Their suppressive effect appears to be cell-to-cell contact dependent and may involve CTLA-4 signaling between neighboring T cells. These regulatory T cells can be expanded in vitro and exhibit a suppressive capacity similar to that observed in ex vivo CD8(+)HLA-DR(+) T cells. The high frequency of CD8(+)HLA-DR(+) T cells that we detected in patients with non-small cell lung cancer deserves further work to confirm their putative suppressor effect within the tumor.

Regulatory and effector T-cells are differentially modulated by Dexamethasone.

It is assumed that the ratio between effector T cells (Teff) and regulatory T cells (Tregs) controls the immune reactivity within the T-cell compartment. The purpose of this study was to investigate if Dexamethasone (Dex) affects Teff and Tregs subsets. Dex induced on Tregs a dose and time-dependent apoptosis which resulted in a relative increase of Teff. After TCR activation, Dex induced a strong proliferative inhibition of Teff, but a weaker proliferative inhibition on Tregs. These effects were modulated by IL-2, which not only restored the proliferative response, but also prevented Dex-induced apoptosis. The highest dose of IL-2 prevented apoptosis on all FOXP3+CD4+ T cells. Meanwhile, the lowest dose only rescued activated Tregs (aTregs), probably related to their CD25 higher expression. Because Dex did not affect the suppressor capacity of aTregs either, our results support the notion that under Dex treatment, the regulatory T-cell compartment maintains its homeostasis.

Analysis of suppressor and non-suppressor FOXP3+ T cells in HIV-1-infected patients.

Recently, it was shown that peripheral blood FOXP3+CD4+ T cells are composed of three phenotypic and functionally distinct subpopulations. Two of them having in vitro suppressive effects were characterized as resting Treg cells (rTregs) and activated Treg cells (aTregs). A third subset, identified as FOXP3+ non-Tregs, does not display any suppressor activity and produce high levels of Th1 and Th17 cytokines upon stimulation. In the present study we focus on the characteristics of these three subsets of FOXP3+CD4+ T cells in untreated HIV-1-infected patients. We found that the absolute counts of rTregs, aTregs and FOXP3+ non-Tregs were reduced in HIV-1 patients compared with healthy donors. The relative frequency of rTregs and aTregs was similar in HIV-1 patients and healthy donors, while the frequency of FOXP3+ non-Tregs was significantly higher in HIV-1 patients, reaching a maximum in those patients with the lower values of CD4 counts. Contrasting with the observations made in FOXP3- CD4+ T cells, we did not find a negative correlation between the number of rTregs, aTregs or FOXP3+ non-Tregs and virus load. Studies performed with either whole PBMCs or sorted aTregs and FOXP3+ non-Tregs cells showed that these two populations of FOXP3+ T cells were highly permissive to HIV-1 infection. Upon infection, FOXP3+ non-Tregs markedly down-regulates its capacity to produce Th1 and Th17 cytokines, however, they retain the ability to produce substantial amounts of Th2 cytokines. This suggests that FOXP3+ non-Tregs might contribute to the polarization of CD4+ T cells into a Th2 profile, predictive of a poor outcome of HIV-1-infected patients.