A generic radio channel emulator to evaluate higher layer protocols in a CDMA system

Currently, we are involved in the standardisation process to specify the next mobile system generation. A wideband code division multiple access (WCDMA) system is considered in most of the region versions. It would be very useful to count on a radio channel emulator which allows one to evaluate higher layers protocols within this context. This paper presents a radio channel emulator developed for a code division multiple access (CDMA) based system. Its versatility and low complexity have been exposed, and the validation process to check the model accuracy has also been shown for this system as an example.Peer ReviewedPostprint (published version

A radio channel emulator for WCDMA, based on the hidden Markov model (HMM)

One of the main development and research subjects within the telecommunications area activity is the 3G mobile systems standardisation. The radio access is, of course, the main trouble in mobile systems, so it is important to investigate its implication. This paper describes a radio channel emulator for the UTRA-FDD made, based on the hidden Markov model (HMM). Since a statistical system behaviour is needed to train the HMM, off-line simulations have been made. The results between simulated and emulated statistics are presented. The use of emulation models implies a loss of accuracy with respect to simulation models, but is adequate to operate in real time. Certainly, the main advantage of using HMM in the emulator is the huge reduction in time, resources and effort with regard to a real simulation of the system. The emulator will allow in future works, for fast testing and comparison of several higher layer protocols and error control schemes.Peer ReviewedPostprint (published version

Emulador de canales radio para sistemas de comunicaciones móviles

Peer ReviewedPostprint (published version

Real-time HSPA emulator for end-to-edge QoS evaluation in all-IP beyond 3G heterogeneous wireless networks

This paper is aimed at presenting the real-time High Speed Packet Access (HSPA) emulator that has been developed in the framework of the AROMA project. Real-time emula- tors allow reproducing realistic scenarios to test algorithms, strategies, protocols and applications under realistic condi- tions. Therefore, real-time emulators constitute a powerful tool to evaluate the end-user's Quality of Experience (QoE), which could not be achieved by means of o -line simulations. The presented emulator is integrated in the AROMA real- time testbed, which has been developed to provide a frame- work for demonstrating the bene ts of the common radio re- source management algorithms as well as the proposed end- to-edge Quality of Service (QoS) management techniques developed for all-IP beyond 3G heterogeneous wireless net- works in the context of the AROMA project. This paper presents a qualitative description of the developed tool, em- phasizing some interesting implementation details that may result helpful in the development of similar emulation plat- forms. Some illustrative results, showing the capabilities of the developed tool, are also presented and analyzed.Postprint (published version

In vivo effects of romidepsin on T-Cell activation, apoptosis and function in the BCN02 HIV-1 kick&Kill clinical trial

Romidepsin (RMD) is a well-characterized histone deacetylase inhibitor approved for the treatment of cutaneous T-cell lymphoma. in vitro and in vivo studies have demonstrated that it is able to induce HIV-1 gene expression in latently infected CD4+ T cells from HIV-1+ individuals on suppressive antiretroviral therapy. However, in vitro experiments suggested that RMD could also impair T-cell functionality, particularly of activated T cells. Thus, the usefulness of RMD in HIV-1 kick&kill strategies, that aim to enhance the immune system elimination of infected cells after inducing HIV-1 viral reactivation, may be limited. In order to address whether the in vitro observations are replicated in vivo, we determined the effects of RMD on the total and HIV-1-specific T-cell populations in longitudinal samples from the BCN02 kick&kill clinical trial (NCT02616874). BCN02 was a proof-of-concept study in 15 early treated HIV-1+ individuals that combined MVA.HIVconsv vaccination with three weekly infusions of RMD given as a latency reversing agent. Our results show that RMD induced a transient increase in the frequency of apoptotic T cells and an enhanced activation of vaccine-induced T cells. Although RMD reduced the number of vaccine-elicited T cells secreting multiple cytokines, viral suppressive capacity of CD8+ T cells was preserved over the RMD treatment. These observations have important implications for the design of effective kick&kill strategies for the HIV-1 cure

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control

Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

Background Strong and broad antiviral T-cell responses targeting vulnerable sites of HIV-1 will likely be a critical component for any effective cure strategy. Methods BCN01 trial was a phase I, open-label, non-randomized, multicenter study in HIV-1-positive individuals diagnosed and treated during early HIV-1 infection to evaluate two vaccination regimen arms, which differed in the time (8 versus 24 week) between the ChAdV63.HIVconsv prime and MVA.HIVconsv boost vaccinations. The primary outcome was safety. Secondary endpoints included frequencies of vaccine-induced IFN-γ+ CD8+ T cells, in vitro virus-inhibitory capacity, plasma HIV-1 RNA and total CD4+ T-cells associated HIV-1 DNA. (NCT01712425). Findings No differences in safety, peak magnitude or durability of vaccine-induced responses were observed between long and short interval vaccination arms. Grade 1/2 local and systemic post-vaccination events occurred in 22/24 individuals and resolved within 3 days. Weak responses to conserved HIV-1 regions were detected in 50% of the individuals before cART initiation, representing median of less than 10% of their total HIV-1-specific T cells. All participants significantly elevated these subdominant T-cell responses, which after MVA.HIVconsv peaked at median (range) of 938 (73-6,805) IFN-γ SFU/106 PBMC, representing on average 58% of their total anti-HIV-1 T cells. The decay in the size of the HIV-1 reservoir was consistent with the first year of early cART initiation in both arms

Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756

iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy

Background: HIV therapeutic vaccination aims to improve the immune responses against HIV in order to control viral replication without the need for combined antiretroviral therapy (cART). iHIVARNA-01 is a novel vaccine combining mRNA delivery and T-cell immunogen (HTI) based on conserved targets of effective antiviral T-cell responses. In addition, it holds adequate stimuli required for activating antigen presenting cells (APC)s and co-activating specific T-cells (TriMix), including human CD40L, constitutively active TLR4 (caTLR4) and CD70. We propose that in-vivo targeting of dendritic cells (DCs) by direct administration of a HIV mRNA encoding these immune modulating proteins might be an attractive alternative to target DCs in vitro. Methods/design: This is a phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in chronically HIV-1 infected patients under stable cART. One of the three study arms is randomly allocated to subjects. Three vaccinations with either HIVACAT T-cell immunogen (HTI)-TriMix (iHIVARNA-01), TriMix or water for injection (WFI) (weeks 0, 2 and 4) are administered by intranodal injection in the inguinal region. Two weeks after the last immunization (week 6) cART is stopped for 12 weeks. The two primary endpoints are: (1) safety and tolerability of intranodal iHIVARNA-01 vaccination compared with TriMix or WFI and (2) induced immunogenicity, i.e., increase in the frequency of HIV-specific T-cell responses between baseline, week 6 and 12 weeks after treatment interruption in iHIVARNA-01-treated patients as compared to the control groups, immunized with TriMix-mRNA or WFI measured by an IFNγ ELISPOT assay. Secondary endpoints include the evaluation of time to viral rebound, plasma viral load (pVL) at w18, the proportion of patients with control of viral load, induction of T-cell responses to new HIV epitopes, polyfunctionality of HIV-specific T-cells, CD8+ T-cell in-vitro HIV suppressive capacity, the effect on viral reservoir (measured by proviral DNA and cell-associated RNA), assessment of viral immune escape by mutation and mRNA expression profiles of host immune genes. Discussion: This trial aims to direct target DC in situ with mRNA encoding HTI and TriMix for co-stimulation. Intranodal injection circumvents laborious DC isolation and handling in the laboratory. The trial extends on the safety results of a phase-I dose-escalating trial. This candidate vaccine could complement or even replace cART for chronic HIV infection and could be applicable to improve the care and cost of HIV infection