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Adequate re-establishment of thymopoiesis is critical for long-term immune reconstitution after hematopoietic cell transplantation (HCT), potentially impacting patient survival rates. This study aimed to evaluate immune reconstitution in pediatric HCT recipients by quantifying recent thymic emigrants (RTEs), specifically CD3+CD31+CD45RA+ cells. We conducted a retrospective analysis of 186 pediatric patients transplanted between 2013 and 2020, undergoing their first allogeneic HCT, who were alive in the first 100 days after transplantation with immune recovery evaluation at three time points: day 100, day 180 and day 360 after HCT. We analyzed the distribution of peripheral blood subsets of T, B and natural killer lymphocytes and assessed the impact of underlying disease, HCT type, stem cell source, recipient age, conditioning regimen, graft-versus-host disease (GVHD) occurrence and cytomegalovirus (CMV) reactivation on immune recovery. At day 100, patients under 10 years exhibited higher RTE CD4+ and CD8+CD31+CD45RA+ counts compared with older patients (5.3 versus 2.2 cells/µL, P = 0.022 and 48 versus 72.8 cells/µL, P = 0.049, respectively). Patients with haploidentical HCT had lower RTE CD4+ counts compared with those with unrelated or related donors (2.4 versus 4.4 versus 7.9 cells/µL, P = 0.024). Administration of rabbit anti-thymocyte globulin negatively impacted RTE CD4+ production (median, 6.5 versus 2.4 cells/µL, P = 0.007). At day 180, the presence of GVHD had a negative influence on RTE production (11.7 versus 56.8 cells/µL, P < 0.001), particularly higher-grade acute GVHD (without, 56.8 cells/µL, grade 1–2, 28.1 cells/µL, grade 3–4, 6.0 cells/µL, P < 0.001). Patients with CMV reactivation had higher CD8+CD31+CD45RA+ compared with those without reactivation (median, 204.6 versus 100.2 cells/µL, P = 0.022). At day 360, no variables significantly affected RTE recovery. Overall survival at 5-year follow-up was 87.7%, with a median of 1170 days (range, 122–3316). Multivariate analysis showed that age >10 years (P = 0.038), negative CMV donor serology (P = 0.0029) and acute GVHD (P = 0.0026) had a negative impact on survival. This study highlights variations in RTE production based on patient age, donor type and immunosuppression regimen employed. [ABSTRACT FROM AUTHOR]

There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)–hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA− memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment. Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 106/kg CD45RA− memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2–specific response within the CD45RA− memory T cells and the most frequent human leukocyte antigen typing in the Spanish population. We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events. Adoptive cell therapy with off-the-shelf CD45RA− memory T cells containing SAR-CoV-2–specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia. NCT04578210 [ABSTRACT FROM AUTHOR]

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination. [ABSTRACT FROM AUTHOR]

It is widely acknowledged that HIV infection results in disruption of the gut’s mucosal integrity partly due a profound loss of gastrointestinal CD4+ T cells that are targets of the virus. In addition, systemic inflammation and immune activation that drive disease pathogenesis are reduced but not normalized by antiretroviral therapy (ART). It has long been postulated that through the process of microbial translocation, the gut microbiome acts as a key driver of systemic inflammation and immune recovery in HIV infection. As such, many studies have aimed at characterizing the gut microbiota in order to unravel its influence in people with HIV and have reported an association between various bacterial taxa and inflammation. This review assesses both contradictory and consistent findings among several studies in order to clarify the overall mechanisms by which the gut microbiota in adults may influence immune recovery in HIV infection. Independently of the gut microbiome, observations made from analysis of microbial products in the blood provide direct insight into how the translocated microbiome may drive immune recovery. To help better understand strengths and limitations of the findings reported, this review also highlights the numerous factors that can influence microbiome studies, be they experimental methodologies, and host-intrinsic or host-extrinsic factors. Altogether, a fuller understanding of the interplay between the gut microbiome and immunity in HIV infection may contribute to preventive and therapeutic approaches.

Objectives: Limited data are available on the long-term outcomes in recent years for late HIV diagnosis (LD). Methods: All subjects with HIV enrolled in the ICONA cohort in 2009-2022 who started antiretroviral treatment (ART) within 4 months from diagnosis were included and divided into: (i) pre-ART CD4 count ≥350/mm3 without AIDS (non-LD), (ii) pre-ART CD4 count

Recent studies demonstrated that myeloid-derived suppressor cells (MDSCs) are involved in the pathogenesis and progression of multiple myeloma (MM). Nevertheless, data on the quantitative and functional changes in MDSCs during standard MM treatment remain poorly understood. Here, we determined that monocytic MDSCs (M-MDSC; CD14+HLA-DRlow/–) and granulocytic MDSCs (PMN-MDSC; Lin–HLA-DR–CD33+CD66b+) in MM patients in remission following induction therapy (IT) were significantly increased, while early MDSCs (E-MDSCs; Lin–HLA-DR–CD33+CD66b–) were decreased compared to the donor group. In progression, MM patients had the most pronounced decrease in E-MDSCs and enhanced levels of PMN-MDSCs. IT was accompanied with a decrease in the expression of arginase-1 (Arg-1). In MM patients with relapse or resistance to IT, Arg-1+ cell frequency in M-MDSCs and E-MDSCs, as well as PD-L1+ M-MDSCs, was increased, which may facilitate tumor immunosuppression. G-CSF administration led to a significant increment in the MDSC subsets. At the engraftment, circulating M-MDSC and PMN-MDSCs were temporarily increased, with a gradual decline to the pre-transplant levels in 12 months. The percentage of E-MDSCs was decreased at the leukocyte recovery. Patients with a higher (>Me) M-MDSC count at the engraftment had a shorter post-transplant leukopenia duration (Me 11 vs. 13 days; pU = 0.0086). The advanced MM stage, depth of response, and lower relative count of circulating E-MDSCs at the engraftment were independent risk factors associated with a lower progression-free survival.The obtained data allow us to hypothesize that MDSCs may play a positive role at the stage of leukocyte recovery by ameliorating the long-term anti-tumor response in MM.

Objectives: We aimed to determine if starting antiretroviral therapy (ART) in the first 30 days after acquiring HIV infection has an impact on immunovirological response. Methods: Observational, ambispective study including 147 patients with confirmed acute HIV infection (January/1995-August/2022). ART was defined as very early (≤30 days after the estimated date of infection), early (31-180 days), and late (>180 days). We compared time to viral suppression (viral load [VL]

ObjectiveThis study aims to analyze the efficacy of anti-syphilis treatment and the impact of syphilis events on HIV virology and immunology in HIV/syphilis co-infected patients on long-term antiretroviral therapy (ART) and to investigate the incidence and factors of syphilis recurrence/re-infection/serofast state. The insights derived from this investigation can potentially guide strategies for preventing and managing syphilis and AIDS.MethodsA retrospective case–control study was conducted at the AIDS clinic of Peking Union Medical College Hospital from January 2003 to December 2022. The study involved 86 HIV/syphilis co-infected patients and 86 HIV mono-infected patients matched based on age, baseline CD4 + T cell counts, and viral load. We examined the clinical characteristics of HIV/syphilis co-infected patients, evaluated the efficacy of anti-syphilis treatment, and analyzed the dynamic changes in HIV virology and immunology. The Generalized Estimating Equations (GEE) model investigated the factors associated with HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state.ResultsSyphilis serofast state was observed in 11.6% (10/86) of HIV/syphilis co-infected patients after treatment, and 33.7% (29/86) had syphilis recurrence or re-infection. The overall effectiveness of syphilis treatment stood at 76.8% (63/82). Notably, the effectiveness of syphilis treatment displayed a significant correlation with baseline syphilis titers exceeding 1:128 (p = 0.003). Over the 10-year follow-up period on ART, the HLA-DR + CD8+/CD8 + % levels in the HIV/syphilis co-infected group were markedly higher than those in the HIV mono-infected group (p 0.05). GEE analysis model revealed that elevated HLA-DR + CD8+/CD8 + % levels were associated with HIV/syphilis co-infection (OR = 1.026, 95% CI = 1.007–1.046; p = 0.007) and syphilis recurrence/reinfection/serofast state (OR = 1.036, 95% CI = 1.008–1.065; p = 0.012).ConclusionWhile HIV/syphilis co-infected patients typically receive adequate treatment, the incidence of syphilis recurrence and reinfection remain notably elevated. A heightened HLA-DR + CD8+/CD8+ % is a notable risk factor for HIV/syphilis co-infection and syphilis recurrence/reinfection/serofast state. Therefore, it is advisable to reinforce health education efforts and ensure regular follow-ups for people living with HIV undergoing ART to monitor syphilis infection or increased risk of syphilis infection.

• The CD4+/CD8+ ratio pre-treatment is the strongest predictor of immune recovery. • The immune benefits of early antiretroviral therapy might derive from higher pre- antiretroviral therapy CD4+/CD8+ ratios. • Treatment with integrase inhibitors might be related to earlier immune recovery. We aimed to determine if starting antiretroviral therapy (ART) in the first 30 days after acquiring HIV infection has an impact on immunovirological response. Observational, ambispective study including 147 patients with confirmed acute HIV infection (January/1995-August/2022). ART was defined as very early (≤30 days after the estimated date of infection), early (31-180 days), and late (>180 days). We compared time to viral suppression (viral load [VL] <50 copies/ml) and immune recovery (IR) (CD4+/CD8+ ratio ≥1) according to the timing and type of ART using survival analysis. ART was started in 140 (95.2%) patients. ART was very early in 24 (17.1%), early in 77 (55.0%), and late in 39 (27.9%) cases. Integrase strand transfer inhibitor (INSTI)-based regimens were the most used in both the overall population (65%) and the very early ART group (23/24, 95.8%). Median HIV VL and CD4+/CD8+ ratio pre-ART were higher in the very early ART group (P <0.05). Patients in the very early and early ART groups and treated with INSTI-based regimens achieved IR earlier (P <0.05). Factors associated with faster IR were the CD4+/CD8+ ratio pre-ART (hazard ratio: 9.3, 95% CI: 3.1-27.8, P <0.001) and INSTI-based regimens (hazard ratio: 2.4, 95% CI: 1.3-4.2, P = 0.003). The strongest predictors of IR in patients who start ART during AHI are the CD4+/CD8+ ratio pre-ART and INSTI-based ART regimens. [ABSTRACT FROM AUTHOR]

ABSTRACT Although gut microbiota alteration and related blood microbe profiles in human immunodeficiency virus (HIV)-infected individuals are associated with the disease progression, how abnormal blood microbe profiles influence the inflammation and immune restoration are not fully understood. To address these issues, this study enrolled 24 healthy controls (HCs) and 91 HIV-infected individuals, including 30 treatment-naïve individuals (TNs), 31 immunological non-responders (INRs), and 30 immunological responders (IRs); subsequently, we analyzed blood microbe profiles using metagenomic sequencing and Olink proteomics technology, and identify inflammation-related proteins in peripheral blood samples of these individuals. The results showed increased translocation of microbes in the blood of TNs. This translocation did not return to normal level in either IRs or INRs who received antiretroviral therapy. In addition, Porphyromonas gingivalis significantly increased in TNs, IRs, and INRs compared to HCs. P. gingivalis was inversely associated with CD4+ T-cell counts, CD4/CD8 ratio, latency-associated peptide transforming growth factor-β1, and tumor necrosis factor-related activation-induced cytokine (TRANCE) and positively associated with HIV reservoirs. Burkholderia multivorans and Bacillus thuringiensis significantly decreased in TNs, IRs, and INRs compared to HCs and were positively associated with CD4+ T-cell counts and the CD4/CD8 ratio and negatively associated with HIV reservoir size and pro-inflammatory factors. We identified several species of microbes that were associated with CD4+ T-cell restoration on antiretroviral therapy, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius were positively associated with HIV reservoir size and pro-inflammatory proteins. Another group of bacteria, B. multivorans, B. thuringiensis, Vibrio vulnificus, and Acinetobacter baumannii, which were negatively associated and pro-inflammatory proteins. In conclusion, different microbes within blood of HIV-infected individuals were found to be closely associated with persistent inflammation and immune restoration, suggesting the blood microbe profiles of HIV-infected individuals also influence disease progression. IMPORTANCE The characteristics of blood microbiota in HIV-infected individuals and their relevance to disease progression are still unknown, despite alterations in gut microbiota diversity and composition in HIV-infected individuals. Here, we present evidence of increased blood microbiota diversity in HIV-infected individuals, which may result from gut microbiota translocation. Also, we identify a group of microbes, Porphyromonas gingivalis, Prevotella sp. CAG:5226, Eubacterium sp. CAG:251, Phascolarctobacterium succinatutens, Anaerobutyricum hallii, Prevotella sp. AM34-19LB, and Phocaeicola plebeius, which are linked to poor immunological recovery. This work provides a scientific foundation toward therapeutic strategies targeting blood microbiota for immune recovery of HIV infection.

Presentation to care with advanced HIV disease (AHD) is a significant problem in sub-Saharan Africa. We evaluated factors associated with immune recovery among individuals presenting to care with AHD in Zimbabwe. We conducted a retrospective evaluation of outcomes among adult (>18 years old) individuals with AHD (CD4 count ≤200 cells/mm3) receiving care at 18 outpatient primary care clinics in Harare, Zimbabwe. Baseline and 12-month CD4 count data were extracted from medical records. CD4 count recovery (defined as CD4 count >200 cells/mm3) after 12 months on non-nucleotide reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) regimen was determined and factors associated with CD4 count recovery were established using logistic regression. All statistical analysis was performed on SPSS v23. A total of 1,338 participant records were included in the analysis. The median interquartile range (IQR) age was 37 (30-43) years and 52% were females. The baseline median (IQR) CD4 count was 50 (28–75) cells/mm3 and was significantly lower among patients with history of cryptococcal meningitis compared to those without [25 (10–52) vs. 52 (32–77), respectively; p = .0009]. The median (IQR) CD4 count at 12 months after ART initiation increased from 50 (28–75) at baseline to 180 (92–290) cells/mm3. Immune recovery with a CD4 count >200 cells/mm3 was observed in 181/417 (43%). Male gender and low baseline CD4 count were strong predictors of poor immunological recovery on ART. Immunological recovery following ART initiation was 43% among individuals with AHD. Male patients are most vulnerable to persistent immunological failure. Clinical Trial Registration number: NCT02434172. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) patients can benefit from allogeneic hematopoietic cell transplantation (alloHCT) and achieve long-term remission. Recovery of T cell quantity and quality is critical to reduce the incidences of life-threatening complications after alloHCT. Although the general recovery level of γδ T cells is recognized to be associated with outcomes of patients who suffered from various hematological diseases and received alloHCT, the correlation between γδ T cell subsets and the prognosis in AML patients following transplantation remains to be investigated. In the current study, the recoveries of T cell subpopulations in 103 AML patients were dissected at different time points after haploidentical HCT (haploHCT). Statistical analyses showed that the absolute number of Vδ2+ T cells on day 90 was an independent risk factor for predicting 2-year OS in AML patients following haploHCT. The survival advantage from the improved recovery of day-90 Vδ2+ T cells was attributed to reducing the infection-related mortality. Consistently, lower 2-year non-relapse mortality was found in recipients with higher day-90 levels of Vδ2+ T cells. Notably, day-270 Vδ2+ T cell numbers reversely correlated to both 2-year and 5-year probabilities of relapse in this scenario. These results highlighted the significant correlation of Vδ2+ T cells recovery with long-term survival and relapse after alloHCT, suggesting that Vδ2+ T cells-based immune strategies may help control infectious complications and leukemia recurrence in AML patients. [ABSTRACT FROM AUTHOR]

Introduction. Data for the long-term effects of SARS-CoV-2/HIV co-infection on immune restoration, as well as the level of post-exposure and post-vaccination immunity at the current stage of SARS-CoV-2 pandemic in HIV+ individuals is still scarce. We assessed SARS-CoV-2-specific immune responses, and the effects of SARS-CoV-2 infection on the immune recovery in HIV+cART+ patients with different exposure history. Materials and methods. HIV+cART+ patients 9 (2-18) months after mild/moderate COVID-19 and completed immunization with anti-SARS-CoV-2 vaccine (n=13, group A), convalescent, not immunized (n=11, group B), or with no history of exposure to SARS-CoV-2 (n=11, group C) were included in the study. CD4AC and CD4/CD8 ratio were determined before and after the documented/probable contact with SARS-CoV-2 by 4-color flow cytometry (TRUCount, MultiTest, FACSCanto II). Virus-specific immunity was characterized by the SARS-CoV-2 specific IFNγ production (SARS-CoV-2 IGRA, Euroimmun) and the levels of RBD-IgG ((Euroimmun ELISA). Results. SARS-CoV-2 specific T-cell and IgG responses were highly correlated and present, respectively, in 92% and 100%; 64% and 54%, 36% and 50% from group A, B and C patients. SARS-CoV-2 specific IFNy+T cells and RDB-IgG were significantly higher in the group with hybrid exposure (A) as compared to convalescent (B) and asymptomatic (C) patients. No significant difference existed between background and actual CD4AC (mean 836 vs 799 cells/µl, p>0.05, Mann-Whitney), and the CD4/CD8 ratio significantly increased in the group with hybrid exposure (0.92 vs 1.07, p

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Approximately two-thirds of Romanian HIV patients were parenterally infected with the F subtype of HIV in early childhood. They are now in the context of immunological aging, with immunosuppression posing an additional challenge in developing the most effective and well-tolerated regimens. The risk of an improper immune recovery is higher in these patients than in newly diagnosed patients. The primary goal of this retrospective study was to conduct a comparative analysis of the immune recovery, measured at three time points, on 462 HIV-infected patients who were registered at the “Matei Balş National Institute of Infectious Diseases”, Bucharest, Romania, between 2018 and 2021, as follows: darunavir (DRV) 600 mg plus ritonavir (RTV) 100 mg (twice daily) was given to 384 patients, while DRV 800 mg plus cobicistat (COBI) 150 mg was given to 78 patients (once daily). The immune response was assessed by counting T lymphocytes, CD4 count cells/mm3, and the CD4/CD8 lymphocyte count ratio. Additionally, the study assessed the relationship between the immune and virological responses to therapy. Using various statistical tests, the results revealed that the immune response is normal in both groups, but with a statistically significant difference (p

Dolutegravir (DTG) based dual therapies for treating PLWHIV are a standard of care nowadays. Switching to DTG and lamivudine (3TC) safety and efficacy were proven in TANGO randomized clinical trial. This multicenter retrospective study included 1032 HIV virologically suppressed patients switching to DTG+3TC from 13 Spanish hospitals. DTG+3TC provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. The analysis for paired data showed an increase in CD4+ cell count. A statistically significant increase in CD4+ lymphocyte count was found in those without comorbidities in the three-time series analyzed [average increase at 24 weeks: 48.7 (SD: 215.3) vs. 25.8 (SD: 215.5), p-value = 0.050; a mean increase at 48 weeks: 75.1 (SD: 232.9) vs. 42.3 (SD: 255.6), p-value = 0.003; a mean increase at 96 weeks: 120.1 (SD: 205.0) vs. 63.8 (SD:275.3), p-value = 0.003]. In conclusion, our cohort demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy. [ABSTRACT FROM AUTHOR]

Background: Immune recovery in people living with HIV (PLWHIV) is a residual aspect of antiretroviral treatment (ART) in most patients, but in a non-negligible proportion of them, the CD4+ lymphocytes count, or CD4/CD8 ratio remains suboptimal. Methods: We performed a model of the immune response after 24 weeks of switching to a 2DR with DTG plus 3TC in a retrospective multicenter cohort of undetectable and experienced patients using significant predictor variables associated with the parameters or situations defined as success and failure. Clinical variables studied were CD4+ and CD8+ lymphocyte count, percentage of CD4, and CD4/CD8 ratio. These parameters were assessed at baseline and 24 weeks after the switch. Based on the evolution of each variable, four categories of immune response and four categories of non-immune response were defined. Immune response was defined as CD4+ count > 500 cells/mm3, %CD4 > 30%, CD8+ count < 1000 cells/mm3 and CD4/CD8 ratio ≥ 0.9. Non-response is just the opposite. Results: In our different models of immunological response, the presence of stage of AIDS (p = 0.035, p = 0.065) and current age over 50 years (p = 0.045) are postulated as statistically significative limiting factors in achieving an improvement in CD4, %CD4, CD8, and CD4/CD8 ratio. Late HIV diagnosis (p = 0.156), without statistical significance, enhanced late the previous variables. In contrast, conditions where patients start with CD4 > 500 cells/mm3 (p = 0.054); CD4 > 30% (p = 0.054, p = 0.084); CD8 < 1000 cells/mm3 (p = 0.018), and CD4/CD8 ≥ 0.9 (p = 0.013, p = 0.09) are detected as stimulating or conducive to DTG plus 3TC treatment success. Conclusion: These models represent a proof of concept that could become a valuable tool for clinicians to predict the effects of DTG plus 3TC on immunological responses prior to the switch in undetectable pre-treated PLWHIV with immune dysfunction. The main predictors for immunological failure were late HIV diagnosis, stage of AIDS, and current age over 50 years. In contrast, starting with a normalized immune status was detected as stimulating or conducive to DTG plus 3TC treatment success. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells and their interactions with B cells within the germinal center play extensive roles in human immunodeficiency virus (HIV) pathology. However, their association with immune reconstitution during antiretroviral therapy (ART) is still unclear. The aim of this study was to determine the impact of Tfh and memory B cell function on T helper cell recovery in patients with acute or chronic HIV infection. A total of 100 HIV‐infected individuals were enrolled in our study, classified into acute and chronic HIV infection groups (60 and 40, respectively), and subsequently classified into immunological responder (IR) and immunological nonresponder (INR) subgroups according to immune recovery outcomes after 96 weeks of ART. Liquid chromatography‐mass spectrometry was used to quantify the temporal regulation patterns of B and CD4+ T‐cell profiles among patients, and flow cytometry was used to investigate certain subsets of B and T cells. Here we showed that the prevalence of Tfh cells in the T helper cell population correlated negatively with CD4+ T‐cell recovery. The proportion of CXCR3− Tfh cells in patients with acute or chronic infection was associated with CD4+ T‐cell count recovery, and the proportion of CD21+ memory B cells at baseline was significantly higher in those with improved immune recovery outcomes. Universal proteomic dysregulation of B and CD4+ T cells at baseline was detected in patients with acute infected and poor CD4+ T‐cell recovery. Proteomics analysis revealed distinct temporal regulation profiles of both T helper cells and B cells between IRs and INRs among patients with acute infection. Our results suggest that the functions of memory B cells in INRs are dysregulated at the early stage of ART, possibly through disruption of Tfh cell function. The frequency and function of Tfh cells and their subsets are potential predictors of poor immune recovery. [ABSTRACT FROM AUTHOR]

Introduction: Despite the high level of efficacy of modern antiretroviral therapy (ART) in reducing HIV viremia and the control of viral replication, some people living with HIV (PLWH) do not recover their CD4+ T cell count. Methods: To evaluate the frequency and predictive factors of discordant immune responses, we performed a retrospective cohort study of 324 antiretroviral-naïve PLWH who initiated first-line ART between 2008 and 2018 and maintained HIV RNA < 50 copies/ml during 36 months of follow-up. PLWH were defined as immunological non-responders (INRs) when CD4+ T cell count was < 20% compared with baseline (INR20%), or < 500 cells/mm³ (INR500) or < 200 cells/mm³ (INR200) at 36 months. Results: The prevalence of INR20%, INR500, and INR200 was 12.5%, 34.6%, and 1.5%, respectively. After adjustment for possible confounders, CD4 nadir showed a significant association with all INR definitions, with lower values predicting INR500 (aOR 0.98, 95% CI 0.98-0.99, p < 0.001) and INR200 (aOR 0.98, 95% CI 0.95-1.01, p = 0.096). Moreover, a higher baseline CD4/CD8 ratio was inversely related to the probability of being INR500 (OR 0.03, 95% CI 0.01-0.12, p < 0.001) and INR200 (OR 0.002, 95% CI 18-7-67.72, p = 0.255). By contrast, INR20% had a higher CD4 nadir and CD4/CD8 ratio than other INRs, suggesting the identification of an heterogenous population with such definition. Discussion: The present study highlights how INR200 has become rare in the contemporary ART era, and about one-third of PLWH meet the criteria for INR500. Overcoming the threshold of 500 CD4/mm³ could be an appropriate definition of immune response, in contrast with the older definitions of INR200 and INR20%. Early diagnosis and rapid treatment initiation, before CD4 counts and the CD4/CD8 ratio begin to decline, are critical for achieving an optimal immune response. [ABSTRACT FROM AUTHOR]

Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/mL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%, P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ Tcell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/mL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/ mL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery. [ABSTRACT FROM AUTHOR]

Abstract Objectives Despite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of both non-AIDS-related and AIDS-related events. The aim of this study was to investigate determinants potentially associated with suboptimal CD4 + T cell count recovery during free ART with sustained viral suppression among an HIV-infected Yi ethnicity population in Liangshan Prefecture, an area in China with high HIV prevalence. Methods This retrospective study included HIV-infected Yi adults (≥ 18 years and baseline CD4 + T cell count less than 500 cells/μL) for whom ART supported by National Free Antiretroviral Treatment Program was initiated between January 2015 and December 2018 in Zhaojue County, Liangshan Prefecture. Virological suppression (viral load

Abstract Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery.

IntroductionDespite the high level of efficacy of modern antiretroviral therapy (ART) in reducing HIV viremia and the control of viral replication, some people living with HIV (PLWH) do not recover their CD4+ T cell count.MethodsTo evaluate the frequency and predictive factors of discordant immune responses, we performed a retrospective cohort study of 324 antiretroviral-naïve PLWH who initiated first-line ART between 2008 and 2018 and maintained HIV RNA

Currently, there are limited data related to the efficacy and safety of ART regimens, as well as factors influencing immune recovery in antiretroviral therapy (ART)-naïve patients with advanced HIV infection, especially in China. We designed a single-center, retrospective cohort study from March 1, 2019, to May 31, 2022, at The Second Hospital of Nanjing, China. ART-naïve adults with advanced HIV infection (CD4+ T-cell count < 200 cells/μL) who met the study criteria were included. The plasma viral load (VL), CD4+ T-cell count, CD4/CD8 ratio, treatment discontinuation, and immune reconstitution inflammatory syndrome (IRIS) events were collected to compare the efficacy and safety of the dolutegravir (DTG) and the efavirenz (EFV) regimens. Factors of immune recovery were analyzed using the Cox regression model. Study enrolled 285 ART-naïve adults with advanced HIV-1 infection, of which 95 (33.3%) started regimens including DTG and 190 (66.7%) were treated with EFV. After ART initiation, the proportion of patients with HIV-1 RNA < 50 copies/mL was higher (22.5% versus 6.5%, P < 0.001) in those on DTG-based regimens at month 1, but no significant difference at other follow-up points. Compared to the baseline, the median CD4+ T-cell count and CD4/CD8 ratio increased significantly during follow-up both in the EFV and the DTG groups. However, the CD4+ T-cell count increased greater in patients on DTG-based regimens at months 6, 12, 24, and 36 (P < 0.05). A total of 52 (18.2%) patients discontinued treatment, with no significant difference between ART regimens in treatment discontinuation rates. Only 7 patients reported IRIS, without significant difference between ART regimens (P=0.224). Overall, 34.0% (97/285) achieved a CD4+ T-cell count ≥ 350 cells/μL during follow-up. Age (P < 0.001), baseline CD4+ T-cell count (P < 0.001), baseline VL (P < 0.001) and ART regimens (P = 0.019) were associated with the CD4+ T-cell count ≥ 350 cells/μL after adjusting for potential confounders. Among ART-naïve adults with advanced HIV infection, it appeared that DTG-based regimens were better options for initial therapy compared to regimens including EFV; in addition, ART regimens, age, baseline VL and CD4+ T-cell count were associated with immune recovery.

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. [ABSTRACT FROM AUTHOR]

Background: Reactive oxygen species (ROS) are generated at physiological levels as a result of cellular metabolism and contribute to cellular interaction and immune response. Elevated ROS may cause cell stress, damage, and apoptosis, and have been detected in different pathological states of infectious and non-infectious etiology. Aim: To evaluate the association between intracellular ROS in T-cell subsets and HIV VL in chronic HIV infection. Material and methods: Whole blood samples (Li-heparin, n=33) were analyzed during routine immune monitoring in two groups of HIV+ patients: A (n=21), on continuous cART for at least 2y, with sustained viral suppression (HIV VL0.05), unlike the CD4/CD8 ratio (1.2 vs. 0.6, p0.05). Noteworthy, CD4+T intracellular ROS correlated positively with HIV VL (R=0.5, p

Summary: Background: Late HIV diagnosis (i.e CD4≤350 cells/µL) is associated with poorer outcomes. However, determinants of long-term mortality and factors influencing immune recovery within the first years after antiretroviral treatment (ART) initiation are poorly defined. Methods: From PISCIS cohort, we included all HIV-positive adults, two-year survivors after initiating ART between 2005–2019. The primary outcome was all-cause mortality according to the two-year CD4 count. We used Poisson regression. The secondary outcome was incomplete immune recovery (i.e., two-year CD4500 cells/µL, reference population). Overall, 113 patients (4·2%) died. Mortality was higher among LP with two-year CD4 count 200–500 cells/µL (aMRR 1·95[95%CI:1·06-3·61]) or 500 cells/µL, regardless of being initially LP or non-LP (aMRR 1·05[0·50-2·21]). Mortality rates within each two-year CD4 strata were not affected by the initial CD4 count at ART initiation (test-interaction, p = 0·48). The stronger factor influencing immune recovery was the CD4 count at ART initiation. First-line integrase-inhibitor-(INSTI)-based regimens were associated with reduced mortality compared to other regimens (aMRR 0·54[0·31-0·93]) and reduced risk of incomplete immune recovery in LP (aOR 0·70[0·52-0·95]). Interpretation: Two-year immune recovery is a good early predictor of long-term mortality in LP after surviving the first high-risk 2 years. Nearly half experienced a favorable immune recovery with a life expectancy similar to non-LP. INSTI-based regimens were associated with higher rates of successful immune recovery and better survival compared to non-INSTI regimens. Funding: Southern-Denmark University, Danish AIDS-foundation, and Region of Southern Denmark.

Cytomegalovirus (CMV) infection remains a frequent complication after hematopoietic stem cell transplantation (HSCT) and causes significant morbidity and mortality in transplantation recipients. In this review, we highlight the role of major risk factors that are associated with the incidence of CMV infection. Advances in immunosurveillance may predict CMV infection, allowing early interventions to prevent severe infection. Furthermore, numerous therapeutic strategies against CMV infection after HSCT are summarized. A comprehensive understanding of the current situation of CMV treatment may provide a hint for clinical practice and even promote the development of novel strategies for precision medicine.

Abstract Background Antiretroviral therapy (ART) can reduce opportunistic infections and mortality rates among individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals exhibit poor immune recovery after ART. Hence, we explored the association between metabolome profiles and immune recovery in HIV-infected individuals following ART. Methods An untargeted metabolomics approach was used to analyze plasma samples from 18 HIV-negative individuals and 20 HIV-infected individuals, including 10 immunological non-responders (INR, CD4+ T cell rise 300 cells/μl) after 2 years of ART. These individuals were followed for the next 6 years and viral loads and CD4+ T cell count were measured regularly. Orthogonal projection on latent structures discriminant analysis (OPLS-DA), ANOVA, correlation, receiver operating characteristic (ROC), and survival analyses were used for selection of discriminant metabolites. Results Eighteen lipid metabolites were identified which could distinguish among control, INR, and IR groups. Among them, myristoylcarnitine (MC), palmitoylcarnitine (PC), stearoylcarnitine (SC), and oleoylcarnitine (OC) were significantly elevated in INR plasma samples compared with those from the IR and control groups and were negatively associated with CD4+ T cell count. Additionally, ROC analysis using a combination of MC, PC, SC, and OC had high sensitivity and specificity for differentiating INR from IR (AUC = 0.94). Finally, survival analysis for the combination of MC, PC, SC, and OC demonstrated that it could predict CD4+ T cell count in patients undergoing long-term ART. Conclusions High levels of lipid metabolites, MC, PC, SC, and OC are associated with poor immune recovery in patients receiving ART and these data provide potential new insights into immune recovery mechanisms.

Background: Perinatally HIV-acquired infants benefit from an early antiretroviral treatment initiation. Thanks to a short viral exposure time, their immune system can be maintained or reconstituted, allowing a "normal" immune development. Methods: In this study, we mathematically modeled and quantified individual CD4+ T-cell reconstitution of a subset of 276 children who started treatment within 6 months of age and achieved sustained viral suppression. Considering natural age differences in CD4+ T-cell dynamics, we fitted distances to age-matched healthy reference values with a linear model approaching an asymptote. Results: Depleted CD4+ percentages (CD4%) and CD4+ counts (CD4ct) restored healthy levels during treatment. CD4ct recovered with a median rate of 4 cells/ [micro]L /d, and individual recovery rates were correlated negatively with their initial CD4ct. CD4 values at onset of treatment decrease with age, whereas recovery times and levels seem to be age-independent. CD4 recovery correlates positively with viral suppression, and the stabilization of CD4 levels usually occurs after viral suppression. CD4 levels stabilize within 3-13 months after treatment initiation. The recovery dynamics of the CD4% is comparable with those of the CD4ct. Conclusions: In early-treated children with successful viral suppression, the CD4 depletion is typically mild and CD4+ T cells tend to "fully" recover in numbers. [ABSTRACT FROM AUTHOR]

B-cell lymphoma and lymphoproliferative diseases represent a heterogeneous and complex group of neoplasms that are accompanied by a broad range of immune regulatory disorder phenotypes. Clinical features of autoimmunity, hyperinflammation, immunodeficiency and infection can variously dominate, depending on the immune pathway most involved. Immunological imbalance can play a role in lymphomagenesis, also supporting the progression of the disease, while on the other hand, lymphoma acts on the immune system to weaken immunosurveillance and facilitate immunoevasion. Therefore, the modulation of immunity can have a profound effect on disease progression or resolution, which makes the immune system a critical target for new therapies. In the current therapeutic scenario enriched by chemo-free regimens, it is important to establish the effect of various drugs on the disease, as well as on the restoration of immune functions. In fact, treatment of B-cell lymphoma with passive immunotherapy that targets tumor cells or targets the tumor microenvironment, together with adoptive immunotherapy, is becoming more frequent. The aim of this review is to report relevant data on the evolution of the immune system during and after treatment with targeted therapy of B-cell lymphomas. [ABSTRACT FROM AUTHOR]

Anti-retroviral therapy (ART) effectively suppresses viral replication in HIV-infected patients, however CD4 + cell restoration to normal value is not achieved by 15–20% of patients who are called immune non-responders. Gut microbiota composition has been shown to influence host immunity. Herein, to identify intestinal microbial agents that may influence the CD4 recovery in HIV-infected patients, we utilized a “Quasi-paired cohort” method to analyze intestinal metagenome data from immunological responders (IRs) and immunological non-responders (INRs). This method identified significant enrichment for Streptococcus sp. and related lactate-producing bacteria (LAB) in IRs. In a validation cohort, positive correlations between the abundance of these LAB and the post-ART CD4 + recovery was observed, and a prediction model based on these LAB performed well in predicting immune recovery. Finally, experiments using a germ-free mouse model of antibody-induced CD4 + cell depletion showed that supplementation with a lactate-producing commensal Streptococcus thermophilus strongly promoted CD4 recovery. In conclusion, our study identified a group of LAB that was associated with enhanced immune recovery in post-ART HIV-infected patients and promotes CD4 + cell restoration in a mouse model. These findings favour supplementation of LAB commensal as a therapeutic strategy for CD4 + cell count improvement in HIV-infected patients.

Taking inspiration from percutaneous ethanol injection (PEI) for tumor ablation, an acetaldehyde generator (SC@ZIF@ADH) is constructed for tumor treatment by modifying a metal–organic framework nanocarrier (ZIF), which is loaded with alcohol dehydrogenase (ADH), onto the surface of Saccharomyces cerevisiae (SC). Oral administration of SC@ZIF@ADH can target tumor via mannose‐mediated targeting to tumor associated macrophages (TAMs) and generate ethanol at the hypoxic tumor areas. Ethanol is subsequently catalyzed to toxic acetaldehyde by ADH, inducing tumor cells apoptosis and polarizing TAMs toward the anti‐tumor phenotype. In vivo animal results show that this acetaldehyde generator can cause a temulence‐like reaction in the tumor, significantly inhibiting tumor progression, and might provide an intelligent and nonsurgical substitute for PEI therapy. [ABSTRACT FROM AUTHOR]

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants. Covariate analysis accounting for immune activation showed that older age was significantly associated with faster apparent elimination rate of the naïve T-cells. In addition, female sex predicted slower apparent elimination rate of memory T-cells. Simulations showed that the median maximal CD4+ T-cell count on ART treatment was 593 cells/μL (IQR 442-794) in patients aged 50 years or above and 738 cells/μL (IQR 548-1002) in patients aged 18-35 years. The differences in the percentage of subjects achieving sufficient immune reconstitution (CD4+ T-cell count> 500 cells/μL) between the two age groups were 15, 21 and 26% at year 1, 4 years and steady state, respectively, suggesting that advanced age may have a greater impact on long-term CD4+ T-cell recovery. [ABSTRACT FROM AUTHOR]

Purpose: To explore the all-cause mortality in patients with acquired immune deficiency syndrome (AIDS) and Cytomegalovirus (CMV) retinitis.Methods: A retrospective cohort study of patients with CMV retinitis (CMVR) presented to a tertiary referral center in Singapore from January 1, 2004, through December 31, 2015.Results: A total of 144 patients were studied (87 survived, 11 lost to follow up, 46 died). Patients with bilateral CMVR and six-month follow up CD4 + T cell count < 50 cells/mm3 have shorter time to mortality, compared to patients with CD4 + T cell count > 50 cells/mm3 (p < .001) and unilateral disease (p = .043). Baseline CD4 + T cell count, size and zone of initial primary retinitis lesions, recurrences of retinitis, and timing of combined antiretroviral therapy (cART) are not significantly associated with mortality.Conclusion: Bilateral ocular involvement and lack of immune recovery in patients with AIDS and CMVR are associated with shorter survival time. [ABSTRACT FROM AUTHOR]

Abstract Background Infection with the Human Immunodeficiency Virus (HIV) dramatically increases the risk of developing active tuberculosis (TB). Several studies have indicated that co-infection with TB increases the risk of HIV progression and death. Sub-Saharan Africa bears the brunt of these dual epidemics, with about 2.4 million HIV-infected people living with TB. The main objective of our study was to assess whether the pre-HAART CD4+ T-lymphocyte counts and percentages could serve as biomarkers for post-HAART treatment immune-recovery in HIV-positive children with and without TB co-infection. Methods The data analyzed in this retrospective study were collected from a cohort of 305 HIV-infected children being treated with HAART. A Lehmann family of ROC curves were used to assess the diagnostic performance of pre- HAART treatment CD4+ T-lymphocyte count and percentage as biomarkers for post-HAART immune recovery. The Kaplan–Meier estimator was used to compare differences in post-HAART recovery times between patients with and without TB co-infection. Results We found that the diagnostic performance of both pre-HARRT treatment CD4+ T-lymphocyte count and percentage was comparable and achieved accuracies as high as 74%. Furthermore, the predictive capability of pre-HAART CD4+ T-lymphocyte count and percentage were slightly better in TB-negative patients. Our analyses also indicate that TB-negative patients have a shorter recovery time compared to the TB-positive patients. Conclusions Pre-HAART CD4+ T-lymphocyte count and percentage are stronger predictors of immune recovery in TB-negative pediatric patients, suggesting that TB co-infection complicates the treatment of HIV in this cohort. These findings suggest that the detection and treatment of TB is essential for the effectiveness of HAART in HIV-infected pediatric patients.

Dolutegravir (DTG) based dual therapies for treating PLWHIV are a standard of care nowadays. Switching to DTG and lamivudine (3TC) safety and efficacy were proven in TANGO randomized clinical trial. This multicenter retrospective study included 1032 HIV virologically suppressed patients switching to DTG+3TC from 13 Spanish hospitals. DTG+3TC provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. The analysis for paired data showed an increase in CD4+ cell count. A statistically significant increase in CD4+ lymphocyte count was found in those without comorbidities in the three-time series analyzed [average increase at 24 weeks: 48.7 (SD: 215.3) vs. 25.8 (SD: 215.5), p-value = 0.050; a mean increase at 48 weeks: 75.1 (SD: 232.9) vs. 42.3 (SD: 255.6), p-value = 0.003; a mean increase at 96 weeks: 120.1 (SD: 205.0) vs. 63.8 (SD:275.3), p-value = 0.003]. In conclusion, our cohort demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy.

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of "long COVID-19", and defines key cells and cytokines that delineate true and quasi-convalescent states. [ABSTRACT FROM AUTHOR]

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.

Background: Antiretroviral therapy (ART) can reduce opportunistic infections and mortality rates among individuals infected with human immunodeficiency virus (HIV); however, some HIV-infected individuals exhibit poor immune recovery after ART. Hence, we explored the association between metabolome profiles and immune recovery in HIV-infected individuals following ART.Methods: An untargeted metabolomics approach was used to analyze plasma samples from 18 HIV-negative individuals and 20 HIV-infected individuals, including 10 immunological non-responders (INR, CD4+ T cell rise < 100 cells/μl) and 10 immunological responders (IR, CD4+ T cell rise > 300 cells/μl) after 2 years of ART. These individuals were followed for the next 6 years and viral loads and CD4+ T cell count were measured regularly. Orthogonal projection on latent structures discriminant analysis (OPLS-DA), ANOVA, correlation, receiver operating characteristic (ROC), and survival analyses were used for selection of discriminant metabolites.Results: Eighteen lipid metabolites were identified which could distinguish among control, INR, and IR groups. Among them, myristoylcarnitine (MC), palmitoylcarnitine (PC), stearoylcarnitine (SC), and oleoylcarnitine (OC) were significantly elevated in INR plasma samples compared with those from the IR and control groups and were negatively associated with CD4+ T cell count. Additionally, ROC analysis using a combination of MC, PC, SC, and OC had high sensitivity and specificity for differentiating INR from IR (AUC = 0.94). Finally, survival analysis for the combination of MC, PC, SC, and OC demonstrated that it could predict CD4+ T cell count in patients undergoing long-term ART.Conclusions: High levels of lipid metabolites, MC, PC, SC, and OC are associated with poor immune recovery in patients receiving ART and these data provide potential new insights into immune recovery mechanisms. [ABSTRACT FROM AUTHOR]

Background Multiple host factors may influence immune reconstitution in HIV-infected people after the initiation of suppressive antiretroviral therapy (ART). Aberrant metabolic pathways have been reported in people with HIV (PWH) on ART. We hypothesized that alterations in plasma metabolites were associated with immune recovery following ART. Methods In this cross-sectional study, the plasma metabolomic profiles of PWH on ART were evaluated. PWH of slow and fast immune recovery were classified by increase in CD4 T cells following 2 years of ART. Targeted plasma metabolite profiling by liquid chromatography–mass spectrometry and gas chromatography–mass spectrometry to determine metabolite signatures for HIV recovery identified >200 metabolites. Results Notably, indole-3-propionic acid was downregulated during HIV, possibly reflecting impaired gastrointestinal epithelium homeostasis. The most important metabolite discriminating between the PWH with fast and slow immune recovery was cysteine. Upregulated cysteine and cysteine pathways may contribute to redox-balance maintenance and T-cell function in PWH with fast immune recovery. Additionally, serine and glycine metabolism and bile acid biosynthesis were the most perturbed metabolic pathways in PWH. Conclusions These results provide a starting point for developing biomarker candidates for immune recovery in PWH on ART and provide insight into the interplay of metabolism and immune response in HIV infection. [ABSTRACT FROM AUTHOR]

Purpose: To predict the course of immune recovery (IR) in HIV-1-infected patients after initiation of combined antiretroviral therapy (cART) by determination of the plasma concentration of Torque Teno Virus (TTV). TTV has been identified as marker for risk assessment in immunosuppressed patients after transplantation procedures. Here, TTV was analyzed in HIV-1-infected therapy-naïve patients to evaluate its use as predictor of the course of IR for guidance of individualized treatment. Methods: TTV DNA was quantified in plasma samples of 301 therapy-naïve HIV-1-infected patients and correlated to CD4+ cell count, HIV viral load, presence of the herpes viruses CMV, EBV and HHV-8, age and sex. Patients were classified according to their initial CD4+ cell count and to the extent of CD4+ T-cell increase within the first year of cART. Results: TTV DNA was detectable in 96% of the patients' plasma samples with a median TTV plasma concentration of 5.37 log10 cop/ml. The baseline CD4+ cell count was negatively correlated with TTV plasma concentration (p = 0.003). In patients with a CD4+ cell recovery < 50 cells/µl, the median TTV plasma concentration was significantly higher compared to patients with a CD4+ cell recovery of > 200 CD4+ cells/µl (5.68 log10 cop/ml versus 4.99 log10 cop/ml; p = 0.011). TTV plasma concentration in combination with baseline CD4+ cell count were significantly correlated to CD4+ cell recovery (p = 0.004). For all other parameters considered, no significant correlation for CD4+ cell recovery was found. Conclusion: Within the cohort, the significantly elevated TTV plasma concentration in patients with diminished CD4+ cell recovery indicates a more profound immune defect. Baseline TTV plasma concentrations and CD4+ cell count are predictive for the course of immune recovery in HIV-1-infected patients with severe immunodeficiency. [ABSTRACT FROM AUTHOR]

• A mortality gap remains for late presenters, particularly, AIDS presenters, in recent years. • Increased mortality for AIDS presenters was driven by AIDS events in the first year. • Two-year immune recovery is the key for long-term mortality in short-term AIDS survivors. • Late and AIDS presenters still show a higher risk treatment failure. • Urgent public health strategies are needed for emerging unknown HIV infections. Limited data are available on the long-term outcomes in recent years for late HIV diagnosis (LD). All subjects with HIV enrolled in the ICONA cohort in 2009-2022 who started antiretroviral treatment (ART) within 4 months from diagnosis were included and divided into: (i) pre-ART CD4 count ≥350/mm3 without AIDS (non-LD), (ii) pre-ART CD4 count <350/mm3 without AIDS (LD asymptomatic), and (iii) with AIDS events pre-ART (LD-AIDS). The estimated probability and independent risk for mortality (all-cause and cause-specific) and treatment failure were evaluated. Of 6813 participants (2448 non-LD, 3198 LD asymptomatic, and 1167 LD-AIDS), 161 (2.4%) died after ART initiation. At survival analysis, a higher probability of all-cause mortality has been identified for LD than non-LD (P <0.001) and within the former, for LD-AIDS over LD asymptomatic (P <0.001). After adjusting for confounders, LD showed a higher risk of all-cause mortality (vs non-LD adjusted hazard ratio (aHR) 5.51, P <0.001) and, in particular, being an AIDS presenter predicted a greater risk of all-cause (aHR = 4.42, P <0.001), AIDS-related (adjusted subhazard ratio [aSHR] = 16.86, P <0.001), and non-AIDS–related mortality (aSHR = 1.74, P = 0.022) than the rest of the late presenters. Among the short-term survivors in the LD-AIDS group, the long-term mortality was mediated by the lack of immune recovery at 2 years. Finally, LD compared with non-LD and, particularly, among the former, LD-AIDS over LD asymptomatic showed a greater risk of treatment failure. In recent years, LD subjects, particularly, AIDS presenters, remained at a higher risk of poorer outcomes. Public health strategies for early HIV diagnosis are urgently needed to constrain the mortality gap. [ABSTRACT FROM AUTHOR]

ObjectivesThe immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed long COVID, are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms.MethodsWe performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of long COVID using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated.ResultsWe identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines.ConclusionWe demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance.

Background Human immunodeficiency virus type 1 (HIV-1) clades and clusters have different epidemic patterns and phenotypic profiles. It is unclear if they also affect patients' immune recovery (IR) in combination antiretroviral therapy (cART). Methods We conducted a cohort study on 853 patients under cART for evaluating the impacts of viral factor on host IR. We used generalized estimating equations for factors affecting CD4 recovery, Kaplan-Meier curves for probability of achieving IR, and Cox hazards model for factors influencing IR capability. Results Besides low baseline CD4 and old age, CRF01_AE and its cluster 4 were independently associated with lower CD4 cell level (P ≤.003), slower IR (P ≤.022), fewer patients (P <.001), and longer time achieving IR (P <.001), compared with CRF07_BC and CRF01_AE cluster 5. Higher percentage of CXCR4 (X4) viruses in the CRF01_AE and cluster 4–infected patients, compared with their respective counterparts (P <.001), accounted for the poor IR in infected patients (P <.001). Finally, we revealed that greater X4 receptor binding propensity of amino acids was exhibited in CRF01_AE clade (P <.001) and its cluster 4 (P ≤.004). Conclusions Our study demonstrates that the CRF01_AE clade and cluster are associated with poor IR in patients under cART, which is ascribed to a high proportion of viruses with X4 tropism. HIV-1 genotyping and phenotyping should be used as a surveillance tool for patients initiating cART. CCR5 inhibitors should be used with caution in regions with high prevalence of X4 viruses. [ABSTRACT FROM AUTHOR]

Objectives: The immunological and inflammatory changes following acute COVID-19 are hugely variable. Persistent clinical symptoms following resolution of initial infection, termed long COVID , are also hugely variable, but association with immunological changes has not been described. We investigate changing immunological parameters in convalescent COVID-19 and interrogate their potential relationships with persistent symptoms. Methods: We performed paired immunophenotyping at initial SARS-CoV-2 infection and convalescence (n=40, median 68 days) and validated findings in 71 further patients at median 101 days convalescence. Results were compared to 40 pre-pandemic controls. Fatigue and exercise tolerance were assessed as cardinal features of long COVID using the Chalder Fatigue Scale and 6-minute-walk test. The relationships between these clinical outcomes and convalescent immunological results were investigated. Results: We identify persistent expansion of intermediate monocytes, effector CD8+, activated CD4+ and CD8+ T cells, and reduced naïve CD4+ and CD8+ T cells at 68 days, with activated CD8+ T cells remaining increased at 101 days. Patients >60 years also demonstrate reduced naïve CD4+ and CD8+ T cells and expanded activated CD4+ T cells at 101 days. Ill-health, fatigue, and reduced exercise tolerance were common in this cohort. These symptoms were not associated with immune cell populations or circulating inflammatory cytokines. Conclusion: We demonstrate myeloid recovery but persistent T cell abnormalities in convalescent COVID-19 patients more than three months after initial infection. These changes are more marked with age and are independent of ongoing subjective ill-health, fatigue and reduced exercise tolerance. [ABSTRACT FROM AUTHOR]

Objectives: We conducted a longitudinal cohort analysis to evaluate the association of pre‐treatment body mass index (BMI) with CD4 recovery, virological failure (VF) and cardiovascular risk disease (CVD) markers among people living with HIV (PLHIV). Methods: Participants who were enrolled between January 2003 and March 2019 in a regional Asia HIV cohort with weight and height measurements prior to antiretroviral therapy (ART) initiation were included. Factors associated with mean CD4 increase were analysed using repeated‐measures linear regression. Time to first VF after 6 months on ART and time to first development of CVD risk markers were analysed using Cox regression models. Sensitivity analyses were done adjusting for Asian BMI thresholds. Results: Of 4993 PLHIV (66% male), 62% had pre‐treatment BMI in the normal range (18.5–25.0 kg/m2), while 26%, 10% and 2% were underweight (< 18.5 kg/m2), overweight (25–30 kg/m2) and obese (> 30 kg/m2), respectively. Both higher baseline and time‐updated BMI were associated with larger CD4 gains compared with normal BMI. After adjusting for Asian BMI thresholds, higher baseline BMIs of 23–27.5 and > 27.5 kg/m2 were associated with larger CD4 increases of 15.6 cells/µL [95% confidence interval (CI): 2.9–28.3] and 28.8 cells/µL (95% CI: 6.6–50.9), respectively, compared with normal BMI (18.5–23 kg/m2). PLHIV with BMIs of 25–30 and > 30 kg/m2 were 1.27 times (95% CI: 1.10–1.47) and 1.61 times (95% CI: 1.13–2.24) more likely to develop CVD risk factors. No relationship between pre‐treatment BMI and VF was observed. Conclusions: High pre‐treatment BMI was associated with better immune reconstitution and CVD risk factor development in an Asian PLHIV cohort. [ABSTRACT FROM AUTHOR]

Purpose of Review: Sub-Saharan Africa (SSA) is disproportionately burdened by the twin epidemics of food insecurity and HIV infection, and protein-calorie undernutrition is common among persons with HIV (PWH) initiating antiretroviral therapy (ART) in the region. In this review, we discuss the intersection of HIV infection and undernutrition, health outcomes among undernourished PWH starting ART, and the demonstrated and potential benefits of therapeutic interventions such as micro/macronutrient supplementation and pharmacological agents. Recent Findings: A low body mass index (BMI), used as a general indicator of poor nutrition in most studies, is associated with impaired immune recovery and increased mortality in the early ART period. The increased risk of mortality is multifactorial, and contributors include undernutrition-related immune system dysfunction, increased susceptibility to opportunistic infections, and metabolic and cardiovascular dysregulation. Clinical trials of micro/macronutrient supplementary feeding, appetite stimulants (hormones and anabolic agents), and recombinant adipokines have shown a benefit for weight gain and metabolic health, but there are few data on mortality or immune recovery. Summary: A substantial proportion of PWH in SSA are undernourished, and undernutrition contributes to an increased risk of mortality and other adverse health outcomes. To date, there have been few prospective trials of nutritional supplementation and/or pharmacologic therapy among undernourished PWH in SSA, though findings from other settings suggest a potential benefit in this population. [ABSTRACT FROM AUTHOR]