The ligation of programmed death-ligand 1 (B7-H1) to T cells results in the preferential production of interleukin 10 (IL-10). We investigated if B7-H1 would be upregulated in HIV infection, a disease characterized by increased IL-10 production, by measuring B7-H1, B7-1 (CD80), and B7-2 (CD86) expression and mRNA in 36 HIV-infected patients and in 22 healthy controls (HCs). Results showed that (1) B7-H1 expression and mRNA are augmented in cells of HIV patients; (2) increased IL-10 production in these patients is largely induced by B7-H1-expressing CD14 ؉ cells; (3) an inverse correlation is detected between B7-H1 expression and CD4 counts, whereas the up-regulation of B7-H1 is directly associated with HIV plasma viremia; (4) antiviral therapy results in the parallel down modulation of IL-10 production and B7-H1 expression/ synthesis; and ( IntroductionThe activation of T lymphocytes is dependent on the presentation of processed antigenic peptides in association with major histocompatibility (MHC) molecules to lymphocytes that express a T-cell receptor specific for that binary complex. 1,2 However, optimal lymphocyte activation requires a second signal that is delivered by the interaction between costimulatory, accessory molecules. 3,4 The cross-linking of CD28 on the surface of T lymphocytes allows for the activation of these cells. CD28 binds to a family of ligands on the surface of non-T cells that are collectively known as B7 molecules. 5,6 Beside B7.1 (CD80) and B7.2 (CD86), a number of other B7-like ligands have been described. 7-9 Among these ligands, B7-H1 is particularly interesting. B7-H1, also called PD-L1, is constitutively present on monocytes and could be induced on activated T cells. 7 B7-H1 does not interact with CD28, cytotoxic T-lymphocyte antigen 4 (CTLA-4), or inducible costimulator (ICOS) but was shown to bind to programmed death 1 (PD-1) 10,11 a CTLA-4-like molecule belonging to the immunoglobulin superfamily. Studies, however, suggested that receptors other than PD-1 can also ligate B7-H1. 7 Ligation of B7-H1 to T cells results in the preferential production of interleukin-10 (IL-10) 7 and in increased T-helper-dependent synthesis of trinitrophenyl (TNP)-specific immunoglobulin G2a (IgG2a) 12 in mice. These results suggest that ligation of B7-H1 may be responsible for promoting type 2 cytokine-biased responses.Interleukin-10 production by peripheral blood mononuclear cells (PBMCs) is augmented in infectious and noninfectious pathologies, including HIV disease. [13][14][15][16] In particular, cell-mediated immunity (CMI) is characteristically impaired in HIV infection. [17][18][19][20] The progression of this infection is associated with increased HIV replication, reduction of circulating CD4 ϩ T lymphocytes, functional defects of CMI, and augmented apoptosis of T lymphocytes. 21,22 An impairment in the production of type 1 cytokines accompanied by increased secretion of type 2 cytokines has also repeatedly been suggested to accompany progression of HIV disease. 14,16,23,24 Because IL-10, ...

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Evidences have recently suggested that the preservation of vaccine-induced memory rather than effector T cells is essential for better outcome and survival following pathogenic SIV challenge in macaques. However, an equivalent demonstration in humans is missing, and the immune correlates of HIV-1 control have been only partially characterized. We focused on the quantification of Ag-specific T cell precursors with high proliferative capacity (PHPC) using a peptide-based cultured IFN-γ ELISPOT assay (PHPC assay), which has been shown to identify expandable memory T cells. To determine which responses correlate with viral suppression and positive immunologic outcome, PBMC from 32 chronically untreated HIV-1-infected individuals were evaluated in response to peptide pools, representing the complete HIV-1 Gag, Nef, and Rev proteins, by PHPC and IFN-γ ELISPOT assay, which instead identifies effector T cells with low proliferative capacity. High magnitude of Gag-specific PHPC, but not ELISPOT, responses significantly correlated with low plasma viremia, due to responses directed toward p17 and p15 subunits. Only Gag p17-specific PHPC response significantly correlated with high CD4 counts. Analysis of 20 additional PBMC samples from an independent cohort of chronically untreated HIV-1-infected individuals confirmed the correlation between Gag p17-specific PHPC response and either plasma viremia (inverse correlation) or CD4 counts (direct correlation). Our results indicate that the PHPC assay is quantitatively and qualitatively different from the ELISPOT assay, supporting that different T cell populations are being evaluated. The PHPC assay might be an attractive option for individual patient management and for the design and testing of therapeutic and prophylactic vaccines.

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2–45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4–19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1–4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

BackgroundDual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection.MethodsWe retrospectively analyzed patients with HIV-RNA ≤50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA ≥200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis.ResultsFour hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6–97.2) without M184V and 87.8% (95% CI, 78.4–97.2) with M184V (P = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51–199 copies/mL) was 79.8% (95% CI, 67.8%–91.8%) with M184V vs 90.1% (95% CI, 84.0%–96.2%) without M184V (P = .016).ConclusionsPrevious selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips.

Sustained virologic response rates have increased dramatically following direct acting antiviral (DAA) therapy in chronic HCV infection. However, resistance-associated substitutions (RASs) may occur either prior to DAA or following drug exposure. The aim of this study was to determine RASs in DAA treatment-failing patients and the role of RASs in failure treatment. Six hundred and twenty HCV patients were evaluated. Direct sequencing of HCV genes was performed at breakthrough in all 31 patients failing DAAs, and in 19 baseline patients. Deep sequencing analysis was performed in 15/19 baseline patients. RASs were detected at breakthrough in 17/31 patients and at baseline in 11/19 patients, although, only 8/19 patients carried RASs associated with the prescribed regimen. Deep sequencing analysis showed RASs at baseline in 10/15 treatment-failing patients. No significant difference was observed with the Sanger sequencing. Treatment failure in the 14/31 patients without RASs was associated with suboptimal treatment. In 54.8% of treatment-failing patients one of the causes of failure might be the presence of RASs. In the majority of patients with RASs, mutations were present at baseline. Direct resistance test is advocated before treatment and at breakthrough in order to optimize retreatment regimens.

A defect of CTL function that selectively affects the granule-dependent mechanisms of lysis is observed in ART-treated individuals. Because interferon-gamma production is higher in these patients, this could be a defect primarily involving CTL. These data suggest an independence of CD8 T-cell numbers and their lytic ability in HIV-infected, ART-receiving patients. Immunomodulants are needed to successfully treat HIV infection.

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