A new, striking morphological alteration of P-glycoprotein expression in NK cells from AIDS patients

Natural killer cells from healthy donors express P-glycoprotein on their surface. This molecule is rearranged during the process of cell-mediated cytotoxicity and it appears to be clustered in the cell-to-cell contact regions. By contrast, in HIV-infected subjects this rearrangement is hindered. These results seem to be associated with cytoskeleton network alterations of the cell-mediated killing process occurring in AIDS patients and can contribute to the comprehension of the mechanisms of the natural killer cell deficiency found in these patients

The role of oxidative imbalance in progression to AIDS: effect of the thiolsupplier N-acetylcysteine

In this study we investigate the redox profile of HIV+ patients at different stages of disease with regard to immunological parameters, i.e., the number of circulating CD4+ and CD8+ lymphocytes. For this purpose, peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, HIV+ patients in the asymptomatic phase, long-term nonProgressors (LTNPs), and AIDS patients have been considered. Cells have been exposed in vitro to the prooxidizing agent menadione, which is able to induce superoxide anion formation, and the susceptibility of the cells to the induced oxidative stress was estimated. Moreover, the possibility that the susceptibility of the cells to oxidative stress might be reduced by preexposing them to the antioxidizing agent N-acetylcysteine (NAC) has also been analyzed. The results obtained can be summarized as follows: (1) treatment with the prooxidant agent is capable of inducing massive morphological alterations in PBMCs. In particular, a significant correlation was found between the decrease in number of CD4+ lymphocytes in patients at different stages of disease and the susceptibility of their PBMCs to oxidative stress; (2) preincubation with NAC was able to preserve partially the ultrastructural characteristics of PBMCs isolated from HIV+ patients. In particular, a direct relationship was found between the efficacy of NAC protection and CD4 counts; (3) evaluation of the plasma index of peroxidation and the number of circulating CD4 lymphocytes indicates the existence of a positive correlation between "systemic" oxidative imbalance and stage of the disease; and (4) cells from LTNPs display either oxidative susceptibility or oxidative markers similar to those of healthy donor cells. Our study suggests that the redox profile of patients may be considered a predictive marker of AIDS progression and that the acute infection and the asymptomatic phase of the disease may represent a useful period in which the combined use of antiretroviral and antioxidant drugs may be beneficial

Serum of healthy donors receiving granulocyte colony-stimulating factor induces T cell unresponsiveness

The effects of serum from healthy donors receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF) (G-serum) on blast transformation, expression of activation-related antigens, secretion of interleukin (IL)-2, and proliferation were evaluated in allogeneic lymphocytes stimulated with phytohemagglutinin. Escalating concentrations of G-serum induced 27%, 47%, and 70% suppression of lymphocyte proliferation; interestingly, CD4+ and CD8+ cells underwent blast transformation and up regulated early (CD69) and late (CD25, HLA-DR, and CD71) activation-related antigens. Negligible fractions of apoptotic cells were found after mitogenic challenge, suggesting that the strongly diminished proliferation was not attributable to extensive activation-induced programmed cell death of responding T cells. The levels of IL-2 in cultures containing G-serum were comparable to those in cultures performed without G-serum; however, high concentrations of exogenous IL-2 restored lymphocyte mitogenesis regardless of G-serum concentration. These findings--cell enlargement, upregulation of activation-related antigens, inability to proliferate after mitogenic stimulus, and restoration of cell division by exogenous IL-2--resembled those associated with "partial activation" of lymphocytes, a fundamental control mechanism of tolerance induction in T cell clones. Soluble immunoregulatory mediators infused with allogeneic hematopoietic progenitor products collected after rhG-CSF administration could induce T cell unresponsiveness in vivo, thus preventing clonal expansion and amplification of immune responses, and could account for the unexpectedly reduced incidence and severity of graft vs. host disease compared with allogeneic marrow infusion

Decreased function of Fas in patients displaying delayed progression of HIV-induced immune deficiency

INTRODUCTION: In acquired immune deficiency syndrome patients, apoptosis of uninfected lymphocytes may contribute to development of immune deficiency. This process may involve recruitment of Fas by human immunodeficiency virus products. In line with this possibility, the viral envelope glycoprotein gp120 does not induce death of T cells from subjects with the autoimmune/lymphoproliferative syndrome displaying defective Fas function. This study evaluates the possibility that Fas function defects delay progression of HIV-induced immune deficiency. MATERIALS AND METHODS: The susceptibility to Fas-induced cell death was assessed on T cells from 18 'long-term non-progressor', four 'non-progressor', four 'progressor' asymptomatic HIV-1-infected, and nine AIDS patients using anti-Fas monoclonal antibodies. RESULTS: Fas-induced cell death was significantly lower in long-term non-progressors and non-progressors than in normal controls, progressors, and AIDS. The single-patient data showed that 9/18 long-term non-progressors and 3/4 non-progressors, but no progressors or AIDS were resistant to Fas. Analysis of the uninfected parents of two long-term non-progressors displaying decreased Fas-function showed that the mother of one of them and the father of the other displayed the same Fas function defect as their children. Fusion of T cells from Fas-resistant individuals with a Fas-sensitive cell line gave rise to Fas-resistant hybrid lines not carrying HIV, which suggests that the resistant phenotype is due to molecules exerting a dominant negative effect on a normal Fas system. CONCLUSION: These data suggest that Fas-resistance in long-term non-progressors may be due to inherited alterations of the Fas signaling pathway and may be a novel factor in delayed progression

Effects of antiretroviral therapy on tube-like network formation of human endothelial cells.

New guidelines suggest that HIV-infected pregnant women should be offered combination antiretroviral therapy (zidovudine and protease inhibitors) to prevent fetal HIV infection but concerns remain about potential adverse effects for the infant. Prior small case series have suggested an increased risk for hemangioma. In this study we used zidovudine and indinavir, alone or in combination, to assess the effect on an in vitro angiogenesis system for endothelial cells. The increase in capillary tube formation, was associated with a significant increase in vascular endothelial growth factor (VEGF) production. Zidovudine and indinavir used in combination do not further strengthen both endothelial cell tubes formation and VEGF secretion. We conclude that zidovudine and indinavir may induce angiogenesis in an in vitro mode

RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

Objective: The hypothesis that been set forward that use of Renin Angiotensin Aldosterone System (RAAS) inhibitors is associated with COVID-19 severity. We set-up a multicenter Italian collaboration (CORIST Project, ClinicalTrials.gov ID: NCT04318418) to retrospectively investigate the relationship between RAAS inhibitors and COVID-19 in-hospital mortality. We also carried out an updated meta-analysis on the relevant studies.Methods: We analyzed 4069 unselected patients with laboratory-confirmed SARS-CoV-2 infection and hospitalized in 34 clinical centers in Italy from February 19, 2020 to May 23, 2020. The primary end-point in a time-to event analysis was in-hospital death, comparing patients who received angiotensin-converting-enzyme inhibitors (ACEeI) or angiotensin-receptor blockers (ARB) with patients who did not. Articles for the meta-analysis were retrieved until July 13th, 2020 by searching in web-based libraries, and data were combined using the general variance-based method.Results: Out of 4069 COVID-19 patients, 13.5% and 13.3% received ACE-I or ARB, respectively. Use of neither ACE-I nor ARB was associated with mortality (multivariable hazard ratio (HR) adjusted also for COVID-19 treatments: 0.96, 95% confidence interval 0.77-1.20 and HR = 0.89, 0.67-1.19 for ACE-I and ARB, respectively). Findings were similar restricting the analysis to hypertensive (N = 2057) patients (HR = 1.00, 0.78-1.26 and HR = 0.88, 0.65-1.20) or when ACE-I or ARB were considered as a single group. Results from the meta-analysis (19 studies, 29,057 COVID-19 adult patients, 9700 with hypertension) confirmed the absence of association.Conclusions: In this observational study and meta-analysis of the literature, ACE-I or ARB use was not associated with severity or in-hospital mortality in COVID-19 patients