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Bone marrow transplantation is the treatment of choice for some patients with acute myeloid leukemia and myelodysplastic syndrome (MDS). Patients with high-risk disease, such as those with MDS, in second (or subsequent) complete remission or those with poor-risk cytogenetics will benefit the most from this approach. With current transplantation techniques, outcomes have improved over recent years. Although relapse and graft-versus-host disease still are important problems faced by these patients, novel approaches have been developed to decrease the risk of complications, with excellent results. [ABSTRACT FROM AUTHOR]

Up to one-third of patients with classical Hodgkin lymphoma (cHL) are not responsive to first-line therapy or eventually relapse. Immune checkpoint inhibitors (ICIs) have been successfully employed to treat relapsed/refractory cHL (r/r cHL) but place patients at risk of financial toxicity. Early-phase trials and observational data suggest that low doses of ICIs may achieve similar results to those obtained with high doses. In this study, we report a single-center experience using low-dose nivolumab (LD-Nivo) in different combinations for r/r cHL, including monotherapy, LD-Nivo plus brentuximab vedotin (BV), and LD-Nivo plus chemotherapy. The primary outcome was to assess the efficacy of LD-nivo in patients with r/r cHL. We included 23 consecutive patients (median age 27 years; 57% female). LD-Nivo was prescribed in 40, 100, and 140 mg fixed doses Q2W. Survival analysis was performed employing the Kaplan-Meier method. 73% of patients achieved an overall response, 43% complete response, and 30% partial response. One-year overall survival was 94.4% (95% CI, 0.84-1), and the 1-year progression-free survival was 89.4% (95% CI, 0.77-1). OS and PFS were similar accross combinations. The median dose of nivolumab was 0.78 mg/kg (range, 0.62-1.11), and the median number of cycles until a response was documented was 6 (range, 2-9). During follow-up, 18 patients received transplantation (11 autologous, 6 allogeneic). No statistically significant differences in survival or response were detected between nivolumab combinations or doses. Adverse events were observed in 61% of the patients, with none grade 3-4. LD-Nivo demonstrated promising results in relapsed/refractory HL, highlighting its potential as a cost-effective treatment option. Further research is needed to validate these findings and guide clinical practice., Competing Interests: Declarations. Ethics approval: This study was reviewed and approved by the Institutional Review Board from Facultad de Medicina y Hospital Universitario “Dr. José Eleuterio González” UANL with the number HE23-00012. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all participants in the study. Competing interests: AGL: Advisory Board: Pfizer, Janssen. Honoraria: Sanofi, AMGEN, Astellas, Janssen, Merck, Novartis. LV: speaker Sanofi, Janssen, Roche, Bristol; Advisory Board: Janssen, Abbvie. DGA: Honoraria for speaker and advisory: Amgen, Janssen, Abbie, Roche, Takeda, Novartis, BMS, MSD, Sanofi, Pfizer, Teva. Research involving human participants and animals: The Institutional Review Board from Facultad de Medicina y Hospital Universitario “Dr. José Eleuterio González” UANL, with the number HE23-00012, reviewed and approved this study. All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Original content: The authors declare that the current work's results were previously presented at the American Society of Hematology Meeting & Exposition 2023 in a poster abstract available at https://doi.org/10.1182/blood-2023-188171 ., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Human immunodeficiency virus (HIV)-1 infection can activate the expression of human endogenous retroviruses (HERVs), particularly HERV-K (HML-2). HIV controllers (HICs) are rare people living with HIV (PLWHs) who naturally control HIV-1 replication and overexpress some cellular restriction factors that negatively regulate the LTR-driven transcription of HIV-1 proviruses., Objectives: To understand the ability of HICs to control the expression of endogenous retroviruses., Methods: We measured endogenous retrovirus type K6 (ERVK-6) RNA expression in peripheral blood mononuclear cells (PBMCs) of HICs (n = 23), antiretroviral (ART)-suppressed subjects (n = 8), and HIV-1-negative (NEG) individuals (n = 10) and correlated the transcript expression of ERVK-6 with multiple HIV-1 cellular restriction factors., Findings: Our study revealed that ERVK-6 RNA expression in PBMCs from HICs was significantly downregulated compared with that in both the ART and NEG control groups. Moreover, we detected that ERVK-6 RNA levels in PBMCs across all groups were negatively correlated with the expression levels of p21 and MCPIP1, two cellular restriction factors that limit the activation of macrophages and T cells by downregulating the activity of NF-kB., Main Conclusions: These findings support the hypothesis that HICs activate innate antiviral mechanisms that may simultaneously downregulate the transcription of both exogenous (HIV-1) and endogenous (ERVK-6) retroviruses. Future studies with larger cohorts should be performed to confirm this hypothesis and to explore the role of p21 and MCPIP1 in regulating HERV-K expression in physiological and pathological conditions.

HIV-1 has an antisense gene overlapping env that encodes the ASP protein. ASP functions are still unknown, but it has been associated with gp120 in the viral envelope and membrane of infected cells, making it a potential target for immune response. Despite this, immune response patterns against ASP are poorly described and can be influenced by the high genetic variability of the env gene. To explore this, we analyzed 100k HIV-1 ASP sequences from the Los Alamos HIV sequence database using phylogenetic, Shannon entropy (Hs), and logo tools to study ASP variability in worldwide and Brazilian sequences from the most prevalent HIV-1 subtypes in Brazil (B, C, and F1). Data obtained in silico guided the design and synthesis of 15-mer overlapping peptides through spot synthesis on cellulose membranes. Peptide arrays were screened to assess IgG and IgM responses in pooled plasma samples from HIV controllers and individuals with acute or recent HIV infection. Excluding regions with low alignment accuracy, several sites with higher variability (Hs > 1.5) were identified among the datasets (25 for worldwide sequences, 20 for Brazilian sequences). Among sites with Hs < 1.5, sequence logos allowed the identification of 23 other sites with subtype-specific signatures. Altogether, amino acid variations with frequencies > 20% in the 48 variable sites identified were included in 92 peptides, divided into 15 sets, representing near full-length ASP. During the immune screening, the strongest responses were observed in three sets, one in the middle and one at the C-terminus of the protein. While some sets presented variations potentially associated with epitope displacement between IgG and IgM targets and subtype-specific signatures appeared to impact the level of response for some peptides, signals of cross-reactivity were observed for some sets despite the presence of B/C/F1 signatures. Our data provides a map of ASP regions preferentially targeted by IgG and IgM responses. Despite B/C/F1 subtype signatures in ASP, the amino acid variation in some areas preferentially targeted by IgM and IgG did not negatively impact the response against regions with higher immunogenicity.

Background: Elite controllers (EC) are human immunodeficiency virus (HIV)-positive individuals who can maintain low viral loads for extended periods without antiretroviral therapy due to multifactorial and individual characteristics. Most have a small HIV-1 reservoir composed of identical proviral sequences maintained by clonal expansion of infected CD4+ T cells. However, some have a more diverse peripheral blood mononuclear cell (PBMC)-associated HIV-1 reservoir with unique sequences., Objectives: To understand the turnover dynamics of the PBMC-associated viral quasispecies in ECs with relatively diverse circulating proviral reservoirs., Methods: We performed single genome amplification of the env gene at three time points during six years in two EC with high intra-host HIV DNA diversity., Findings: Both EC displayed quite diverse PBMCs-associated viral quasispecies (mean env diversity = 1.9-4.1%) across all time-points comprising both identical proviruses that are probably clonally expanded and unique proviruses with evidence of ongoing evolution. HIV-1 env glycosylation pattern suggests that ancestral and evolving proviruses may display different phenotypes of resistance to broadly neutralising antibodies consistent with persistent immune pressure. Evolving viruses may progressively replace the ancestral ones or may remain as minor variants in the circulating proviral population., Main Conclusions: These findings support that the high intra-host HIV-1 diversity of some EC resulted from long-term persistence of archival proviruses combined with the continuous reservoir's reseeding and low, but measurable, viral evolution despite undetectable viremia.

The analysis of the HIV-1 proviral dynamics after superinfection in the context of both natural and antiretroviral therapy (ART)-mediated suppression could yield unique insights into understanding the persistence of viral variants that seeded the infected cells at different times. In this study, we performed a longitudinal analysis of the env diversity of PBMC-associated HIV DNA quasispecies in two HIV controllers (EEC09 and VC32) that were superinfected with subtype F1 viruses several years after primoinfection with subtype B viruses. Patient EEC09 started ART soon after superinfection, while patient VC32 maintained a natural control of virus replication for at least six years following the superinfection. Our analysis revealed no significant temporal changes in the overall proportion of primo-infecting and superinfecting proviral variants over 2-3 years after superinfection in both HIV controllers. Upon the introduction of ART, individual EEC09 displayed no evidence of HIV-infected cell turnover or viral evolution, while subject VC32 displayed some level of HIV-infected cell reseeding and detectable evolution (divergence) of both viral variants. These results confirm that proviral variants that seeded the reservoir at different times throughout infection could persist for long periods under fully suppressive ART or natural viremic control, but the HIV-1 proviral dynamics could be different in both settings.

Background: The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs., Methods: From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered., Results: Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and "other." Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae., Conclusions: IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms., Competing Interests: S.R.W. has received clinical trial funding from Janssen Vaccines. The other authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pre-exposure prophylaxis (PrEP) prevents HIV infection among men who have sex with men (MSM) and transgender women (TGW) who are the groups that presents the high incidence risk in Brazil. This cross-sectional secondary analysis describes possible risk compensation, attitudes, and beliefs regarding the use of PrEP among 723 MSM and TGW evaluated in the PrEP Brazil study pre-screening phase. Possible risk compensation was reported by 31.6% individuals. In the multivariate model, factors that increased the likelihood of possible risk compensation were: self-referring as white vs. Black (AOR 2.05; CI 1.09, 3.85), perceiving high likelihood of getting HIV in next 12 months (AOR 1.78; CI 1.23, 2.56), being less afraid of HIV infection if using PrEP (AOR 1.93; CI 1.19, 3.14), feeling liberated to have more partners if using PrEP (AOR 2.93; CI 1.92, 4.49), and believing closest friends would use PrEP (AOR 2.51; CI 1.1, 5.71). We found that possible risk compensation was more common among individuals who presented high-risk perception for HIV infection, probably reflecting they feel at risk and could benefit from PrEP use.

HIV-1 infection is characterized by generalized deregulation of the immune system, resulting in increased chronic immune activation. However, some individuals called HIV controllers (HICs) present spontaneous control of viral replication and have a more preserved immune system. Among HICs, discordant results have been observed regarding immune activation and the frequency of different T cell subsets, including Treg and Th17 cells. We evaluated T cell immune activation, differentiation and regulatory profiles in two groups of HICs-elite controllers (ECs) and viremic controllers (VCs)-and compared them to those of cART-treated individuals (cART) and HIV-1-negative (HIV-neg) individuals. ECs demonstrated similar levels of activated CD4+ and CD8+ T cells in comparison to HIV-neg, while cART and VCs showed elevated T cell activation. CD4+ T cell subset analyses showed differences only for transitional memory T cell frequency between the EC and HIV-neg groups. However, VC individuals showed higher frequencies of terminally differentiated, naïve, and stem cell memory T cells and lower frequencies of transitional memory and central memory T cells compared to the HIV-neg group. Among CD8+ T cell subsets, ECs presented higher frequencies of stem cell memory T cells, while VCs presented higher frequencies of terminally differentiated T cells compared to the HIV-neg group. HICs showed lower frequencies of total Treg cells compared to the HIV-neg and cART groups. ECs also presented higher frequencies of activated and a lower frequency of resting Treg cells than the HIV-neg and cART groups. Furthermore, we observed a high frequency of Th17 cells in ECs and high Th17/Treg ratios in both HIC groups. Our data showed that ECs had low levels of activated T cells and a high frequency of activated Treg and Th17 cells, which could restrict chronic immune activation and be indicative of a preserved mucosal response in these individuals., Competing Interests: The authors have declared that no competing interests exist.

Background: HIV controllers (HICs) are a rare group of HIV-1-infected individuals able to naturally control viral replication. Several studies have identified the occurrence of HIV dual infections in seropositive individuals leading to disease progression. In HICs, however, dual infections with divergent outcomes in pathogenesis have been described., Case Presentation: Here, we present a case report of a HIC diagnosed in late 1999 who displayed stable CD4 + T cell levels and low plasmatic viral load across 12 years of follow-up. In early 2013, the patient started to present an increase in viral load, reaching a peak of 10,000 copies/ml in early 2014, followed by an oscillation of viremia at moderate levels in the following years. The genetic diversity of env proviral quasispecies from peripheral blood mononuclear cells (PBMCs) was studied by single genome amplification (SGA) at six timepoints across 2009-2017. Phylogenetic analyses of env sequences from 2009 and 2010 samples showed the presence of a single subtype B variant (called B 1 ). Analyses of sequences from 2011 and after revealed an additional subtype B variant (called B 2 ) and a subsequent dominance shift in the proviral quasispecies frequencies, with the B 2 variant becoming the most frequent from 2014 onwards. Latent syphilis related to unprotected sexual intercourse was diagnosed a year before the first detection of B 2, evidencing risk behavior and supporting the superinfection hypothesis. Immunologic analyses revealed an increase in CD8 + and CD4 + T cell immune activation following viremia increase and minor T cell subset alterations during follow-up. HIV-specific T cell responses remained low throughout the follow-up period., Conclusions: Altogether, these results show that loss of viremia control in the HIC was associated with superinfection. These data alert to the negative consequences of reinfection on HIV pathogenesis, even in patients with a long history of viremia control and an absence of disease progression, reinforcing the need for continued use of adequate prevention strategies.

Introduction: Nodular regenerative hyperplasia (NRH) is a rare condition is associated to immune, neoplastic, vascular disorders, and certain drugs and toxins. Portal hypertension is the main complication., Aim: To report the case of a woman with NRH and aplastic anemia, association not previously described., Case: A 31- year-old hispanic female presented with pancitopenia and cholestasis. Bone marrow biopsy: aplastic anemia. Abdominal ultrasound revealed multiple liver nodules, without hepato-splenomegaly. No abnormalities were noted in hepatic vessels. Antimitochondrial (AMAs) were positive. Coagulation tests were normal. Liver biopsy: hepatocite nodules with central atrophy and sinusoidal dilatation in the absence of significant fibrosis. No arteritis, thrombosis or bile duct damage was found., Discussion: Pathogenesis of NRH remains unclear. The most accepted theory was developed by Wanless 24 years ago, and reinforced in 1997. It states that alterations in hepatic blood flow (portal obliterative venopathy) originate a specific response, initially consisting of apoptosis secondary to acute ischemia, with ensuing parenchymal atrophy and surrounding areas of liver regeneration and chronic ischemia. The common pathologic mechanism of all the diseases associated with NRH involves liver blood-flow abnormalities secondary to microthromboses, vascular congestion, or vasculitis. In the current case we were unable to document evidence of liver flow abnormalities. Noteworthy, there are previous descriptions of the as- sociation of NRH with primary biliary cirrhosis, and this patient was AMA positive, but without bile duct damage in liver biopsy., Conclusions: We cannot sustain Wanless' theory, and this is the first description of the association of NRH with aplastic anemia.