Biological and molecular characterization of a rare case of cutaneous Richter syndrome

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia in a high‐grade lymphoma usually presenting nodal and bone marrow involvement. Richter syndrome can be localized at extranodal sites including the gastrointestinal tract, lungs, and skin. Cutaneous RS is an extremely rare disease apparently showing a less aggressive course than common presentations. While nodal RS has been extensively investigated in literature, pathogenesis and prognosis of cutaneous RS are still partially unknown, even if a role of Epstein‐Barr virus infection and p53 disruption has been suggested. Herein, we characterized the histopathological, immunohistochemical features and cytogenetics and molecular alterations of a case of cutaneous RS developed after 8 years chronic lymphocytic leukemia history. Moreover, we reviewed the literature reports concerning cutaneous RS and made a focus on biological patterns and prognostic implications.     

Reversibility of Central Nervous System Adverse Events in Course of Art

The purpose of this study is to evaluate the frequency of central nervous system adverse events (CNS-AE) on dolutegravir (DTG) and non-DTG containing ART, and their reversibility, in the observational prospective SCOLTA cohort. Factors associated with CNS-AE were estimated using a Cox proportional-hazards model. 4939 people living with HIV (PLWH) were enrolled in DTG (n = 1179) and non-DTG (n = 3760) cohorts. Sixty-six SNC-AE leading to ART discontinuation were reported, 39/1179 (3.3%) in DTG and 27/3760 (0.7%) in non-DTG cohort. PLWH naïve to ART, with higher CD4 + T count and with psychiatric disorders were more likely to develop a CNS-AE. The risk was lower in non-DTG than DTG-cohort (aHR 0.33, 95% CI 0.19–0.55, p < 0.0001). One-year follow-up was available for 63/66 PLWH with CNS-AE. AE resolution was reported in 35/39 and 23/24 cases in DTG and non-DTG cohorts, respectively. The probability of AE reversibility was not different based on ART class, sex, ethnicity, CDC stage, or baseline psychiatric disorder. At the same time, a lower rate of event resolution was found in PLWH older than 50 years (p = 0.017). In conclusion, CNS-AE leading to ART discontinuation was more frequent in DTG than non-DTG treated PLWH. Most CNS-AE resolved after ART switch, similarly in both DTG and non-DTG cohorts.     

Trajectories of CD4+/CD8+ T-Cells Ratio 96 Weeks after Switching to Dolutegravir-Based Two-Drug Regimens: Results from a Multicenter Prospective Cohort Study

The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with HIV-RNA < 50 copies/mL were included if they were on the DTG-2DR, the DTG + tenofovir/emtricitabine (TDF/FTC) regimen, the DTG + tenofovir alafenamide (TAF)/FTC regimen, or the DTG + abacavir/lamivudine (ABC/3TC) regimen; they were followed-up for at least one year. A total of 533 PWH were enrolled, 120 in the DTG + 3TC group, 38 in the DTG + protease inhibitors (PI) group, 67 in the DTG + rilpivirine (RPV) group, 49 in the DTG + TDF/FTC group, 27 in the DTG + TAF/FTC group, and 232 in the DTG + ABC/3TC group. After one year, the CD4/CD8 ratio significantly increased in the PWH treated with DTG + 3TC (+0.08 ± 0.26), DTG + TDF/FTC (+0.1 ± 0.19), and DTG + ABC/3TC (+0.08 ± 0.25). At two years, the CD4/CD8 increase was confirmed for PWH on DTG + TDF/FTC (+0.16 ± 0.28) and DTG + ABC/3TC (+0.1 ± 0.3). In the SCOLTA cohort, PWH on 2DRs experienced a CD4/CD8 increase only in the DTG + 3TC group. Controlled studies with longer follow-up will clarify the long-term immunological and clinical impacts of DTG-2DR.     

Safety and durability in a cohort of HIV-1 positive patients treated with once and twice daily darunavir-based therapy (SCOLTA Project)

Objective

To evaluate safety and durability of once-daily and twice-daily darunavir/ritonavir (DRV/r)-based treatment in HIV patients in clinical practice.

Methods

The Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) project is a prospective, observational, multicenter cohort created to assess the incidence of adverse events in patients receiving new antiretroviral drugs. Twenty-five Italian infectious diseases centers enroll patients and collect their data through this on-line system. Periodical evaluations of these patients, including physical examination and laboratory tests, were performed at baseline and every 6 months.

Results

Four hundred and twenty-nine patients were enrolled since May 2006. Eighty-five patients (19.8%) were prescribed once-daily DRV/r; 31 of them were treatment-naïve (36.5%). Among 54 (63.5%) treatment-experienced patients, 21 (38.9%) had undetectable viral load and started once-daily DRV/r as a simplification regimen. Patients on twice-daily regimen were older, more frequently lipodystrophic, HCV-coinfected, and in CDC stage C. In the following 24 months of follow-up, the viral load steadily decreased as well as the CD4 cell count rose. The reason for discontinuation did not significantly differ between groups. Mean blood glucose (BG) change from baseline did not show significant difference between groups, as well as high density lipoprotein cholesterol (HDL-C), triglycerides (TGL) and alanine transaminase (ALT). The survival curve shows that patients in the once-daily regimen withdrew treatment more frequently than those on twice-daily regimen (Log Rank Chi²P = 0.009).

Conclusion

Our study showed that DRV/r administrated both once daily or twice daily was safe and well tolerated with few discontinuations due to adverse events.     

Natural killer cells in HIV controller patients express an activated effector phenotype and do not up-regulate NKp44 on IL-2 stimulation

Control of HIV replication in elite controller (EC) and long-term nonprogressor (LTNP) patients has been associated with efficient CD8⁺cytotoxic T-lymphocyte function. However, innate immunity may play a role in HIV control. We studied the expression of natural cytotoxicity receptors (NKp46, NKp30, and NKp44) and their induction over a short time frame (2–4 d) on activation of natural killer (NK) cells in 31 HIV controller patients (15 ECs, 16 LTNPs). In EC/LTNP, induction of NKp46 expression was normal but short (2 d), and NKp30 was induced to lower levels vs. healthy donors. Notably, in antiretroviral-treated aviremic progressor patients (TAPPs), no induction of NKp46 or NKp30 expression occurred. More importantly, EC/LTNP failed to induce expression of NKp44, a receptor efficiently induced in activated NK cells in TAPPs. The specific lack of NKp44 expression resulted in sharply decreased capability of killing target cells by NKp44, whereas TAPPs had conserved NKp44-mediated lysis. Importantly, conserved NK cell responses, accompanied by a selective defect in the NKp44-activating pathway, may result in lack of killing of uninfected CD4⁺NKp44Ligand⁺ cells when induced by HIVgp41 peptide-S3, representing a relevant mechanism of CD4⁺ depletion. In addition, peripheral NK cells from EC/LTNP had increased NKG2D expression, significant HLA-DR up-regulation, and a mature (NKG2A−CD57⁺killer cell Ig-like receptor⁺CD85j⁺) phenotype, with cytolytic function also against immature dendritic cells. Thus, NK cells in EC/LTNP can maintain substantially unchanged functional capabilities, whereas the lack of NKp44 induction may be related to CD4 maintenance, representing a hallmark of these patients.A benign disease course with long-term nonprogressing disease (LTNP) up and beyond 20 y is observed in a minority (<1–2%) of HIV-1–infected patients who maintain high CD4⁺ T-cell counts (>500 µL) with low-level viremia (<1,000 cp/mL) without progression to AIDS in the absence of antiretroviral treatment (ART). A subset of LTNPs is aviremic virus-controlling (<50–75 cp/mL) patients who are considered to represent a distinct clinical entity defined as elite controllers (ECs) because of their efficient and extensive spontaneous control of viral replication (1, 2). Understanding of the mechanisms that underlie the lack of disease progression in EC and LTNP patients has attracted relevant scientific focus over the years, with the ultimate goal to exploit this understanding for therapeutic or vaccination purposes.Viral replication may be decreased in LTNP/EC because of virus mutations or host genetic background conferring reduced CD4⁺ T-cell susceptibility. However, both an intact viral replication capacity and a conserved CD4⁺ T-cell susceptibility to HIV infection in vitro have recently been proven in most HIV controller patients (3–5). Among cytotoxic effector cells, an acknowledged role in the control of viremia and disease has been attributed to CD8⁺ cytotoxic T lymphocytes (CTLs), which in these patients, display an exceptionally high avidity and breadth against HIV epitopes (1, 2, 6, 7). Vigorous and effective CTL responses associated to HLA class I haplotype (e.g., B*57 and B*27 alleles) represent an example of genetic background positively affecting HIV control (1, 2, 6, 7). Also, HLA-C polymorphisms have been implicated in the control of HIV (8). Unique allele carriage is, however, not a feature uniquely characterizing LTNPs/ECs. HIV controllers may lack this genetic background, but they have CTL responses with high avidity and breadth against HIV_gag. Conversely, this immunogenetic background may be present in progressors who display poorer CTL response quality (5, 9–11). Also, HLA B*5701 LTNPs/ECs and HLA-matched progressors cannot be distinguished by the clonal composition of HIV-specific CD8⁺ T cells (12).The relevance of natural killer (NK) cell function in the setting of HIV controller status has been suggested by genetic studies showing the association between HLA-Bw4_80I DNA carriage and specific killer cell Ig-like receptors (KIRs; i.e., KIR3DL1/S1) (13, 14). NK cell-associated control of HIV replication in vitro occurs with KIR3DS1⁺ NK cells in a HLA-Bw4_80I⁺ target cell genetic background (15); however, this result has not been subsequently reproduced in vivo in EC/LTNP cohorts (16). Various combinations of these mechanisms seem to be involved in the successful control of HIV replication in some LTNP and EC patients; however, none of them taken alone can fully explain this condition, and it has not been shown to identify all of these patients.Involvement of the activating NK receptors in disease progression was suggested by the demonstration that HIV-1 infection was associated to profoundly decreased expression of natural cytotoxicity receptors (NCRs; i.e., NKp46, NKp30, and NKp44) (17). This decrease, in turn, leads to an impaired cross-talk between NK cells and dendritic cells (DCs), resulting in an altered DC editing (18). Moreover, rates of CD4⁺ T-cell loss after ART interruption are inversely associated with NCR expression on NK cells before ART discontinuation (19).Interestingly, in the AIDS-free HIV infection model of chimpanzees, peripheral NK cells have absent/low baseline expression of NKp30, which was, however, inducible on cytokine-mediated in vitro NK cell activation (20). In addition, activating NK cell receptor induction/modulation has been reported in vivo and in vitro during treatment of human HCV infection involving NKp30 (21) and DNAX-accessory molecule 1 (DNAM-1,CD226) (22), which are both involved in DC–NK cell cross-talk (23, 24). In addition, activating NK cell receptor ligands are lost in CD4⁺ T cells of infected patients, with the exception of NKG2D-Ligands (e.g., MHC class I polypeptide-related sequence A/B,MICA/B) (25). Furthermore, HIV_nef and HIV_vpu have been shown to directly target NKG2D and DNAM-1 ligands (i.e., MICA/B and poliovirus receptor, PVR) (26, 27). These immune evasion mechanisms are in line with the idea that NK cells may exert a critical control of HIV-1 infection. In this context, an as yet uncharacterized NKp44-L is reported to be induced in uninfected CD4⁺ T cells by an HIV_gp41 peptide inducing innocent CD4⁺ T-cell bystander lysis (28, 29). These observations, thus, raise the question of whether differences in NCR surface expression may help to explain the different disease course observed in HIV controllers—LTNPs, ECs, or both.Here, we report a study addressing the activating NK cell receptors expression, their modulation, and the consequences on NK cell function in a cohort of HIV controller (LTNP and EC) patients. The data provide evidence that differences in inducibility/modulation of NCR may offer clues on how successful disease-free HIV-1 control may be achieved in these patients.     

Serum citrate levels,haptoglobin haplotypes and transferrin receptor (CD71) in patients with HIV-1 infection

Background: The progression of HIV-1 infection towards its more advanced stages is accompanied by changes in iron metabolism and increased body iron stores. Patients and Methods: Given the ability of HIV to alter iron metabolism, we studied the principal (transferrin system) and alternative (citrate system) iron pathways in a group of 65 HIV-infected patients (symptomatic stage B1–B3) and in a group of 36 healthy seronegative individuals. We determined serum citrate levels, haptoglobin (Hp) haplotypes, expression of transferrin receptor (CD71) on cell lines infected with HIV-1 as well as iron markers including blood iron, transferrin and ferritin. Results: Our data showed decreased serum citrate levels in the HIV-infected patients compared to controls (92.9 ± 22.4 μM/l vs 126.2 ± 29.2 μM/l; p < 0.01). In particular, the serum citrate levels negatively correlated with HIV-1 RNA copy number (mean: 2.53 ± 1.88 × 10⁵/ml, r_s = 0.70, p < 0.01) and positively correlated with CD4+ T-lymphocyte count (mean: 241 ± 168/ml, r_s = 0.64, p > 0.05). Accordingly, blood iron, transferrin and red cell concentrations were lower in HIV-infected patients compared to the controls, whereas serum ferritin levels were higher in HIV-infected patients. Moreover, the Hp haplotype distribution showed significant differences only in the group of HIV-infected patients (p = 0.02; χ² test). Conclusion: Our results show that iron metabolism is altered in patients with HIV-1 infection. The alternative pathway (citrate system) is particularly affected, since when citrate levels are low, both aconitase activity and HIV-1 replication need iron. Received: May 20, 2001 · Revision accepted: December 27, 2001     

Dipyridamole thallium-201 perfusion imaging for the study of ischemic heart disease in hemodialysis patients

To assess the usefulness of dipyridamole thallium perfusion imaging in the evaluation of myocardial perfusion in hemodialysis (HD), we studied 29 HD patients divided into three groups: A) 13 patients with clinical angina, B) 8 patients without angina but similar in age, sex, time on HD and hematocrit and C) 8 young asymptomatic patients (mean age 33 +/- 9.7 years). Dipyridamole thallium-201 (Tl-201) perfusion imaging revealed myocardial perfusion defects in 8 patients (61%) from group A, 4 (50%) from group B and 1 (12.5%) from group C. These defects were localized in the inferior, posterior and septal segments of the left ventricle. Abnormal myocardial perfusion was associated with age over 50 years and aortic calcifications (p less than 0.05). Eight patients died within the following four years. All had aortic calcifications (p less than 0.001). Our results show that myocardial perfusion defects are frequent even in non-symptomatic HD patients. This suggests that ischemic heart disease could be more frequent than estimated by clinical symptoms alone. Tl-201 scintigraphy may be a useful non-invasive procedure in cardiological evaluation of HD patients.