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Objective: The aim of this study was to characterize T-cell activation, exhaustion, maturation and Treg frequencies in individuals who acquire perinatal HIV (PHIV), in individuals who acquired HIV as adult (AHIV), and in healthy controls., Design: This cross-sectional study included people with HIV at least 14 and younger than 40 years, HIV-RNA less than 50 copies/ml on antiretroviral therapy for at least 6 months, and HC., Methods: We assessed the expression of PD-1, TIM-3, EOMES, CD38 + DR+, maturation status by CD4 + and CD8 + T cells and the frequency of CD4 + and CD8 + Treg cells. Principal component analysis (PCA) and k-means cluster analysis investigated which combination of immunological parameters better associated with each group., Results: Twenty-six PHIV and 18 AHIV with median ages of 26 (8.0) and 28 (6.8) years were consecutively enrolled. PHIV showed significant higher frequency of naive and lower frequency of terminal effector memory CD4 + and CD8 + T cells than AHIV. AHIV exhibited higher expression of exhaustion and activation markers. The statistical analysis returned two clusters with 94% of specificity and 88% of sensitivity identifying PHIV vs. AHIV. The nine healthy controls had a lower expression of exhaustion markers on both CD4 + and CD8 + T lymphocytes than PHIV and AHIV., Conclusion: These data may exclude major alterations of lymphopoiesis in PHIV, with even lower state of immune-activation and exhaustion compared with AHIV. This suggests that recent lack of virological control, may affect immune activation and exhaustion of CD4 + and CD8 + T cells., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The pathogenesis of HIV immunodeficiency is mainly dependent on the cytopatic effects exerted by the virus against infected CD4+ T cells. However, CD4+ T cell loss cannot be the only pathogenic factor since severe opportunistic infections may develop in HIV infected patients with normal CD4+ T cell counts and since the recent START study indicated that absolute CD4+ T cell counts are not predictive for AIDS and non-AIDS events. Recently our group demonstrated that CD8+CD28-CD127lowCD39+ regulatory T lymphocytes, previously found highly concentrated within tumor microenvironment, circulate with elevated frequency in the peripheral blood of HIV infected patients. Here, we show that these cells, that at least in part are HIV specific, express the PD1 immune checkpoint. Based on these evidences and considerations, in this Perspective article we speculate on the opportunity to treat HIV infected patients with anti-PD1 immune checkpoint inhibitors as a way to counteract the T regulatory cell compartment and to unleash virus-specific immune responses. In order to potentiate the immune responses against HIV we also propose the potential utility to associate immune checkpoint inhibition with HIV-specific therapeutic vaccination, reminiscent of what currently applied in oncologic protocols. We suggest that such an innovative strategy could permit drug-sparing regimens and, perhaps, lead to eradication of the infection in some patients.

Background: Limited studies have compared the impact of different antiretroviral regimens on soluble markers of inflammation with discordant results., Methods: In this prospective study, treatment naïve HIV-1-infected patients were included if they started their current regimen with atazanavir/ritonavir (ATV/r) (N = 73, Group 1) or darunavir/ritonavir (DRV/r) (N = 85, Group 2) plus tenofovir/emtricitabine. The analysis of IL-6, MCP-1, sCD163, VCAM-1, ox-LDL, and adiponectine was performed on two stored plasma samples, the first prior to antiretroviral therapy initiation and the second one year after initiation., Results: The results of our analysis show a difference in ox-LDL between the two groups with higher mean (SD) values in ATV/r based group 608.5 ± 137.4 versus 519.1 ± 119.6 in DRV/r group, after controlling for baseline levels of ox-LDL as well as other potential confounding factors controlled by means of matching design or linear regression modelling., Conclusions: Our analysis provides further data examining the association between the modulation of vascular inflammatory and of activation markers with specific protease inhibitors-based treatments over one year of exposure to these drugs. The data show little evidence for an association, supporting the notion that antiretroviral regimens has generally poor efficiency in downregulating these soluble markers.

Background: HIV-associated immunodeficiency is related to loss of CD4 + T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4 + T cells/μL. CD8 + CD28 - CD127 lo CD39 + T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients., Objectives: We sought to analyze the frequency of CD8 + CD28 - CD127 lo CD39 + Treg cells in the circulation of HIV-infected patients., Methods: The frequency of circulating CD8 + CD28 - CD127 lo CD39 + Treg cells was analyzed and correlated with viral load and CD4 + T-cell counts/percentages in 93 HIV-1-infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus-infected patients (n = 17), and healthy donors (n = 173)., Results: HIV-infected patients had increased circulating levels of functional CD8 + CD28 - CD127 lo CD39 + Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4 + T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non-AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant., Conclusion: HIV infection induces remarkable expansion of CD8 + CD28 - CD127 lo CD39 + Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Cross-sectional analysis on 20 HIV-1 patients with neurological symptoms admitted to two infectious disease units. Cut-off of HIV-RNA (VL) was 20 copies/ml for plasma and cerebral spinal fluid (CSF). Flow cytometry was used to analyze the phenotype of circulating and CSF T lymphocytes. CD38 mean fluorescence intensity (MFI) was higher on circulating CD4+T lymphocytes from patients with VL>20 copies/ml in plasma (P=0.001) or CSF (P=0.001). The frequency of circulating CD8+CD38+T cells and CD38 MFI on these cells were higher in patients with VL>20 copies/ml than in those with undetectable plasma VL (P=0.030 and P=0.023). The frequency of CSF CD4+CD38+T, as well as their CD38 and CD95 MFI, were increased in patients with detectable than non-detectable plasma VL (P=0.01, P=0.03, and P=0.05). The % CD38+CD8+T in CSF correlated with time of virological suppression (ρ=-0.462, P=0.040) and the CNS penetration-effectiveness (CPE) score (ρ=-0.467, P=0.038). In conclusion, (a) the expression of CD38+ on both CD4+, CD8+T lymphocytes from peripheral blood and CSF discriminated between viremic and non-viremic patients and (b) T cell activation/apoptosis markers inversely correlated with CPE to remark the importance for therapy to restore immunological functions.

This is a cross-sectional, case-control study analyzing the effect of antiretroviral therapy (ART) including or not maraviroc, on circulating monocytes and natural killer cells. Sixty-eight HIV-positive patients virologically suppressed receiving ART at least 6 months were subdivided as receiving (group 1) or not (group 2) maraviroc in their ART. Frequency of monocytes and natural killer cells, as well as their activation markers, were studied. Modulation of innate immune cells may be differently affected by combined ART.

Besides being present in serum in association with beta2-mu, HLA class I heavy chains are also present in serum as beta2-micro-free moieties. The increase in serum levels of beta2-micro-associated HLA class I heavy chains in conditions associated with an activation of the immune system have prompted us to measure the serum levels of beta2-mu-free HLA class I heavy chains in the course of immune responses to viral antigens and to mismatched histocompatibility antigens. The serum level of beta2-mu-free HLA class I heavy chains, like that of beta2-mu-associated HLA class I heavy chains was significantly increased in patients affected by advanced HIV-1 infection or by chronic hepatitis C (CHC). In the latter group of patients an association was found between a reduction in the beta2-mu-free HLA class I heavy chain serum level and response to therapy with interferon alpha and ribavirin. Moreover, the beta2-mu-free HLA class I heavy chain serum level was increased more than that of beta2-mu-associated HLA class I heavy chains during episodes of liver ischemia following liver transplantation and in the course of acute graft rejection and of acute graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (BMT). These results suggest that the serum levels of beta2-mu-free and beta2-mu-associated HLA class I heavy chains are independently regulated. Furthermore, beta2-mu-free HLA class I heavy chain serum level may be a useful marker to monitor response to therapy in CHC patients and the clinical course of liver and bone marrow grafts.

HLA class I and class II antigens circulate in serum as soluble molecules. Increased concentrations of soluble HLA class I molecules have been demonstrated in viral diseases, in rejection episodes following organ transplantation and in graft versus host disease. To explore the possibility of a variation of the serum concentrations of soluble HLA class II molecules in the same pathologic conditions we developed a double determinant immune assay that detects whole soluble HLA-DR molecules (sHLA-DR). The mean level of sHLA-DR antigens in sera from 23 healthy individuals was 0.64 +/- 0.72 microgram/ml. Elevated serum concentrations of sHLA-DR molecules were detected in sera from HIV infected patients in CDC2/3 and in CDC4 C1 stages (2.0 +/- 1.7 micrograms/ml and 4.6 +/- 1.7 micrograms/ml, respectively), in sera from patients affected by acute rejection after liver transplantation (5.3 +/- 3.7 micrograms/ml) and in sera from patients affected by severe acute graft versus host disease following bone marrow transplantation (8.8 +/- 3.1 micrograms/ml). The increase of sHLA-DR molecules in these sera significantly correlated with the elevation of soluble HLA class I antigens (P = 0.0004). The reported data suggest that both soluble HLA class I and class II molecules serum levels increase during viral infections and strong immune reactions and could suggest the involvement of these molecules in immunoregulation.