Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1-infected patients; however, cART must be continued indefinitely to prevent viral rebound and ...associated disease progression. Inducing HIV-1-specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to "cART for life." We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4(+) >450 cells/mm(3) were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC-HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1-specific T cell responses. These data suggest that HIV-1-specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1-infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.
A double-blinded, controlled study of vaccination of untreated patients with chronic human immunodeficiency virus type 1 (HIV-1) infection with 3 doses of autologous monocyte-derived dendritic cells ...(MD-DCs) pulsed with heat inactivated autologous HIV-1 was performed. Therapeutic vaccinations were feasible, safe, and well tolerated. At week 24 after first vaccination (primary end point), a modest significant decrease in plasma viral load was observed in vaccine recipients, compared with control subjects (P = .03). In addition, the change in plasma viral load after vaccination tended to be inversely associated with the increase in HIV-specific T cell responses in vaccinated patients but tended to be directly correlated with HIV-specific T cell responses in control subjects. Clinical trial.gov NCT00402142
The emerging relationship between microRNAs (miRNA) and viral-control is a topic of interest in the field of HIV. Host-genome might play an important role in the control of viremia. The aim of this ...study was to assess the specific miRNA profile that could contribute to the control of HIV replication in Elite Controllers.
After adequate normalization, expression profile of 286 human miRNAs (hsa-miR) was evaluated in phytohaemagglutinin-stimulated PBMCs from 29 individuals classified in 4 groups: 8 elite controllers (EC; viral load <50 cp/ml without treatment), 8 viremic progressors (VP; VL>5000 cp/ml without treatment), 8 patients under antiretroviral treatment (ART; VL<200 cp/ml) and 5 uninfected individuals (HIV-) through TaqMan Array Human microRNA Cards v3.0. A differential expression pattern consisting of 23 miRNAs became significantly different when comparing EC and VP. Profiling analysis segregated the population in two different blocks: while EC and HIV- clustered together in the same block (EC/HIV-_block 1), VP and ART individuals clustered together in a second block (VP/ART_block 2). Two inversely expressed miRNA patterns were determined within those two blocks: a set of 4 miRNAs (hsa-miR-221, -27a, -27b and -29b) was up-expressed in EC/HIV-_block and down-expressed in VP/ART_block while 19 miRNAs were down-expressed in block 1 and up-expressed in block 2. Differential miRNAs were successfully validated through individual RT-qPCR assays.
Profile in EC resembled HIV- and differentially clusters with VP and ART. Therefore, differential clustering does not rely on undetectable viremia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
HIV-1 elite controllers (EC) maintain undetectable viral loads (VL) in the absence of antiretroviral treatment. However, these subjects have heterogeneous clinical outcomes, including a proportion ...that loses HIV-1 control over time. In this work, we compared, in a longitudinal design, transient EC, analyzed before and after the loss of virological control, with persistent EC. The aim was to identify factors leading to the loss of natural virological control of HIV-1 infection with a longitudinal retrospective study design. Gag-specific T-cell responses were assessed by
intracellular polycytokine production quantified by flow cytometry. Viral diversity determinations and sequence dating were performed in proviral DNA by PCR amplification at limiting dilution of
and
genes. The expression profile of 70 serum cytokines and chemokines was assessed by multiplex immunoassays. We identified transient EC as subjects with low Gag-specific T-cell polyfunctionality, high viral diversity, and high proinflammatory cytokine levels before the loss of control. Gag-specific T-cell polyfunctionality was inversely associated with viral diversity in transient controllers before the loss of control (
= -0.8;
= 0.02). RANTES was a potential biomarker of transient control. This study identified virological and immunological factors, including inflammatory biomarkers associated with two different phenotypes within EC. These results may allow a more accurate definition of EC, which could help in better clinical management of these individuals and in the development of future curative approaches.
There is a rare group of HIV-infected patients who have the extraordinary capacity to maintain undetectable viral load levels in the absence of antiretroviral treatment, the so-called HIV-1 elite controllers (EC). However, there is a proportion within these subjects that eventually loses this capability. In this work, we found differences in virological and immune factors, including soluble inflammatory biomarkers, between subjects with persistent control of viral replication and EC that will lose virological control. The identification of these factors could be a key point for a right medical care of those EC who are going to lose natural control of viral replication and for the design of future immunotherapeutic strategies using as a model the natural persistent control of HIV infection.
A proportion of patients who spontaneously control viral load (controllers) experienced clinical progression. We hypothesized that microbial translocation would independently determine the rate of ...disease progression in controllers.
sCD14, lipopolysaccharide-binding protein (LBP) and EndoCab levels were assessed in 114 antiretroviral-naive patients with CD4(+) T cells above 500 cells/μl (including 63 controllers and 51 noncontrollers). The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, non-AIDS event, initiation of combination antiretroviral therapy (cART) or CD4(+) cell count less than 500 cells/μl was assessed using a Cox regression model.
Most of the patients progressed to a combined endpoint (60%). Clinical progression in controllers was significantly lower than in noncontrollers (P = 0.02). Controllers with lower than the median baseline CD4(+) T-cell count and higher than the median baseline viral load, sCD14 and EndoCab levels had a worse prognosis (P < 0.0001, P = 0.007, P = 0.05 and P = 0.012), while noncontrollers with higher than the median baseline LBP level also had a worse prognosis (P = 0.019). sCD14 and LBP increased and EndoCab decreased over time from baseline (median values: 1486, 17604 ng/ml and 68 MMU/ml, respectively, to the date of event or the last determination (median values: 1663, 20230 ng/ml and 49 MMU/ml), respectively in controllers (P = 0.04, 0.08 and 0.0006, respectively).
Microbial translocation seems to be an important determinant of clinical progression in HIV-infected controllers independently of viremia. Measures to improve the intestinal mucosa damage or decrease translocation could influence the outcome in these patients.
Proteomic signature was associated with spontaneous loss of virological control, which is characterized by inflammation, transendothelial migration, and coagulation. This is the first “omics” ...approach showing potential biomarkers for the prediction of this virological progression and as therapeutic targets in elite controllers.
Abstract
Background
Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers.
Methods
Plasma samples from ECs who spontaneously lost virological control (transient controllers TCs), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers PCs). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry.
Results
Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers.
Conclusions
The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs.
Background:
Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and ...therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to
in vitro
assays.
Objective:
The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity.
Methods:
We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC;
n
= 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC;
n
= 14).
Results:
Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34–65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (−17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA;
p
< 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (
p
< 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity.
Conclusions:
In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.
Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a ...new approach to simplify follow-up appointments and facilitate access to healthcare professionals.
We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out.
Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters level of CD4+ T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels >90% (p = 0.58) nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care.
Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection.
Clinical-Trials.gov: NCT01117675.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could ...help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control.
A case-control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares-class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model.
Herein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control.
These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights ► Safety and immunogenicity of HIV/AIDS MVA-B. ► This first phase I trial with candidate MVA-B in healthy volunteers showed that this immunogen was safe and well tolerated. ► This vaccine ...elicited strong and durable T-cell responses in 75% of volunteers. ► This vaccine elicited antibody responses against HIV-1 Env in 95% of volunteers and 33% generated neutralizing antibodies ► These data support further exploration of MVA-B as an HIV-1 vaccine candidate.
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