Post-treatment Control Research Articles

Early Viral Dynamics Predict HIV Post-Treatment Control After Analytic Treatment Interruption.

A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control. Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control. Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%). Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers.

HIV-1 reservoir landscape of post-treatment control.

This review explores the viral reservoir landscape in individuals who control viral replication after treatment interruption (TI), designated as post-treatment controllers (PTCs). Identifying their virologic features is crucial to inform drug-free HIV remission strategies. Traditionally characterized as small, likely due to early treatment, the viral reservoir of PTCs, after TI, exhibits limited transcriptional activity, residual viral replication and subsequent proviral diversity. Intact proviruses are found to be restricted. In nonhuman primate PTCs, this depletion of intact proviruses is already observed in lymph nodes before TI, suggesting that control mechanisms begin during antiretroviral therapy. Furthermore, recent studies suggest immune-driven proviral deep latency associated with repressive epigenetic features and integration sites in PTCs. While molecular mapping of virological features of PTCs is increasingly precise and coupled with in-depth immunologic assays, robust predictive biomarkers of PTCs are still lacking. Despite limited sample sizes and heterogeneous definitions, common virologic features of PTCs include restricted reservoir size and transcriptional activity, fewer intact proviruses and deep proviral latency. Ongoing research using innovative technologies will further elucidate the mechanisms underlying post-treatment control, paving the way for successful HIV cure interventions.

Stem cell transplantation and allogeneic immunity: post treatment control or HIV cure?

Long-lasting HIV remission has been reported in a small group of people with HIV (PWH) following allogenic hematopoietic stem cell transplants (HSCT) for the treatment of hematologic malignancies. While the mechanisms of HIV remission following release from antiretroviral therapy (ART) were not initially known, subsequent findings from clinical cases and preclinical nonhuman primate studies have implicated mechanisms of clearance. Here, we review the six currently published human cases of long-term ART-free HIV remission. Since the first report of ART-free HIV remission following HSCT, five subsequent cases of HSCT-induced sustained HIV remission have been published. While the pre- and posttransplant treatment conditions vary greatly, all but one received cells from donors homozygous for a 32 bp deletion in the gene that encodes CCR5 (ccr5Δ32), the major HIV coreceptor. Studies in nonhuman primates and the newest published individual suggest that while CCR5 deficiency can protect donor cells from infection early posttransplant, it is not required for long term remission, as ablation of the viral reservoir is likely due to allogeneic immunity mediating a graft-versus-reservoir response. Studies of HSCT in PLWH and simian immunodeficiency virus (SIV)-infected monkeys show that those with durable remission are likely cured, demonstrated by complete ablation of the replication-competent HIV reservoir, gradual loss of anti-HIV immunity, and greater than 5 years of aviremia.

Post-intervention control in HIV immunotherapy trials.

While post-treatment control following interruption of standard-of-care antiretroviral therapy (ART) is well described, post-intervention control following immunotherapy in HIV cure-related clinical trials is less well understood. We provide an overview of recent studies that have identified post-intervention controllers and review the mechanisms that may drive this biologically important phenotype. Post-intervention controllers have been identified in recent immunotherapy trials testing broadly neutralizing antibodies, immune modulators, modified T cells, checkpoint inhibitors, and gene therapy administered individually or in combination. Currently, there is substantial variability in how each trial defines post-intervention control, as well as in how the mechanisms underlying such control are evaluated. Such mechanisms include ongoing activity of both exogenous and autologous antibodies, as well as changes in HIV-specific T cell function. While no therapeutic strategy to date has succeeded in definitively inducing HIV control, many studies have identified at least a small number of post-intervention controllers. The field would benefit from a standardized approach to defining and reporting this phenotype, as well as standardization in the approach to assessment of how it is achieved. Such efforts would allow for comparisons across clinical trials and could help accelerate efforts toward an HIV cure.

Differences in HIV-1 reservoir size, landscape characteristics and decay dynamics in acute and chronic treated HIV-1 Clade C infection.

Background Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are the main barrier to cure efforts. Antiretroviral therapy (ART) intensification by early initiation has been shown to enable post-treatment viral control in some cases but the underlying mechanisms are not fully understood. We hypothesized that ART initiated during the hyperacute phase of infection before peak will affect the size, decay dynamics and landscape characteristics of HIV-1 subtype C viral reservoirs. Methods We studied 35 women at high risk of infection from Durban, South Africa identified with hyperacute HIV infection by twice weekly testing for plasma HIV-1 RNA. Study participants included 11 who started ART at a median of 456 (297-1203) days post onset of viremia (DPOV), and 24 who started ART at a median of 1 (1-3) DPOV. We used peripheral blood mononuclear cells (PBMC) to measure total HIV-1 DNA by ddPCR and to sequence reservoir viral genomes by full length individual proviral sequencing (FLIP-seq) from onset of detection of HIV up to 1 year post treatment initiation. Results Whereas ART in hyperacute infection blunted peak viremia compared to untreated individuals (p<0.0001), there was no difference in total HIV-1 DNA measured contemporaneously (p=0.104). There was a steady decline of total HIV DNA in early treated persons over 1 year of ART (p=0.0004), with no significant change observed in the late treated group. Total HIV-1 DNA after one year of treatment was lower in the early treated compared to the late treated group (p=0.02). Generation of 697 single viral genome sequences revealed a difference in the longitudinal proviral genetic landscape over one year between untreated, late treated, and early treated infection: the relative contribution of intact genomes to the total pool of HIV-1 DNA after 1 year was higher in untreated infection (31%) compared to late treated (14%) and early treated infection (0%). Treatment initiated in both late and early infection resulted in a more rapid decay of intact (13% and 51% per month) versus defective (2% and 35% per month) viral genomes. However, intact genomes were still observed one year post chronic treatment initiation in contrast to early treatment where intact genomes were no longer detectable. Moreover, early ART reduced phylogenetic diversity of intact genomes and limited the seeding and persistence of cytotoxic T lymphocyte immune escape variants in the reservoir. Conclusions Overall, our results show that whereas ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding, it was nevertheless associated with more rapid decay of intact viral genomes, decreased genetic complexity and immune escape in reservoirs, which could accelerate reservoir clearance when combined with other interventional strategies.

Soluble markers of viral rebound and post-treatment HIV control.

We focus on the different classes of biological molecules measurable in easily accessible bodily fluids that have the potential to serve as biomarkers for the HIV post-treatment controller (PTC) phenotype and/or the timing of viral rebound after stopping antiretroviral therapy (ART). Various viral components and host factors measurable in body fluids can play crucial roles in understanding and predicting the PTC phenotype. We review recent findings linking viral components, the quantitative and qualitative features of antibodies (including autologous HIV-specific antibodies), markers of inflammation and tissue damage, other host proteins (including hormones such as sex hormones), as well as metabolites, extracellular vesicles, and cell-free DNA to HIV control post-ART interruption. Several of these molecules can or have the potential to predict the time and probability of viral rebound after stopping ART and are biologically active molecules that can directly or indirectly (by modulating immune pressures) impact the size and activity of HIV reservoirs during and post-ART interruption. A comprehensive model combining multiple markers is needed to predict the PTC phenotype. This model can be leveraged to predict and understand the PTC phenotype, which can guide novel curative interventions to replicate this phenotype in post-treatment non-controllers.

Regulating material wettability through surface plastic deformation post-processing via friction modification

The wettability of engineering materials significantly influences their cleaning and antifreeze properties, making it a key consideration in aerospace applications. Methods for controlling surface plastic deformation can alter the wettability of materials and contribute to a certain level of strengthening effect, thereby presenting significant application potential. This study aimed to modify the wetting characteristics of aviation titanium alloys in harsh environments through adjustments in surface roughness via peening treatments (such as laser shock peening with coating and mechanical shot peening). The impact of various peening processes on wetting characteristics was investigated through comprehensive surface energy, macro, and nano morphology analyses. Static contact angle measurements were quantified, followed by evaluating other properties, such as surface free energy. Through adjustments in post-treatment processes and control of surface roughness, tailored acquisition of wetting characteristics was achieved. This study elucidates the beneficial effect of surface plastic deformation post-processing on controlling material wettability and introducing strengthening effects. Additionally, the study indicates the importance of accurately determining the sampling range for precise characterization of material wettability.

Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission.

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

Early antiretroviral therapy favors post-treatment SIV control associated with the expansion of enhanced memory CD8+ T-cells

HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac251-infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8+ T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission.

Neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer.

This study aimed to explore the efficacy of neoadjuvant chemotherapy plus programmed death-1 (PD-1) inhibitor camrelizumab for the treatment of locally advanced esophageal cancer. This was a retrospective analysis. 87 patients with locally advanced esophageal cancer were included who received neoadjuvant chemotherapy plus immunotherapy between June 2018 and April 2021 in our oncology department. The postoperative clinical outcomes and varying expressions of PD-1 were evaluated in all enrolled patients. The post-treatment disease control rate (DCR) was 83.91%, and the objective response rate (ORR) was 59.77%. Cancer tissues were categorized based on PD-1 expression into PD-1 negative (39 cases) and PD-1 positive (33 cases), with a PD-1 positive rate of 45.83%. Patients with PD-1-positive tumors exhibited a significantly higher ORR compared to those with PD-1-negative tumors, although DCRs did not differ significantly between the groups. The 12-month progression-free survival rate was significantly higher in PD-1-positive patients. In contrast, no significant difference was found in the 12-month overall survival rate between the two groups. The incidence of grade III adverse events was 10.34%, and no grade IV or higher adverse events were observed. In patients with locally advanced esophageal cancer, neoadjuvant chemotherapy plus immunotherapy demonstrates good efficacy and safety, especially for PD-1-positive patients, and significantly improves prognosis.

Piecewise immunosuppressive infection model with viral logistic growth and effector cell-guided therapy

&lt;abstract&gt;&lt;p&gt;This work investigated a piecewise immunosuppressive infection model that assessed the effectiveness of implementing this therapeutic regimen once the effector cell count falls below a specific threshold level by introducing a threshold strategy. The sliding mode dynamics, global dynamics, and boundary equilibrium bifurcations of the Filippov system were examined based on the global dynamics of the two subsystems. Our primary findings indicate that the HIV viral loads and effector cell counts can be stabilized within the required predetermined level. This outcome depends on the threshold level, immune intensity, and the initial values of the system. Therefore, properly combining these key factors makes it possible to effectively curb the abnormal increase of virus and keep the effector cells at a reliable level. This approach maximizes the controllable range of the HIV. The proposed switching system incorporating pseudo-equilibrium exhibits three types of equilibriums that could be bistable or tristable. It means there is a possibility of controlling the virus after administering therapy if the immune intensity $ c $ is limited within the range of the post-treatment control threshold and the elite control threshold when $ {R_0} &amp;gt; {R_{{c_1}}} &amp;gt; {R_{{c_2}}} &amp;gt; 1 $.&lt;/p&gt;&lt;/abstract&gt;

Does irrigation water applied in South Australia increase after the end of the Millennium Drought? Application of the difference-in-differences approach

Abstract The Millennium Drought drastically reduced the amount of irrigation water applied and triggered modern water reform, such as water market promotion in the southern Murray–Darling Basin (sMDB), Australia. South Australia (SA), located far downstream in the sMDB, occupies a unique and important position because the amount of water supplied for SA is guaranteed under normal weather conditions. The water availability for SA determines whether severe droughts occur in the sMDB. Based on the Murray–Darling Basin water market catchment dataset 2021, the causal inference of whether irrigation water applied in the SA Murray water system as the main water system in SA increased after water year (WY) 2011 when the percentage of water allocated to high-reliability water entitlements reached 100% was empirically analysed in this article with a difference-in-differences approach. In this article, the SA Murray water system was adopted as the sole treatment group and WY 2011 was selected as the treatment timing. When control variables and the interaction terms between the dummy variable for posttreatment periods and control variables are included, this article statistically demonstrates that irrigation water applied in the SA Murray water system increased after WY 2011.

Post-treatment control after vertical HIV transmission: decoding innate immune differences may hold the key to potential cure.

Post-treatment control after vertical HIV transmission: decoding innate immune differences may hold the key to potential cure.

Mathematical Models of HIV-1 Dynamics, Transcription, and Latency.

HIV-1 latency is a major barrier to curing infections with antiretroviral therapy and, consequently, to eliminating the disease globally. The establishment, maintenance, and potential clearance of latent infection are complex dynamic processes and can be best described with the help of mathematical models followed by experimental validation. Here, we review the use of viral dynamics models for HIV-1, with a focus on applications to the latent reservoir. Such models have been used to explain the multi-phasic decay of viral load during antiretroviral therapy, the early seeding of the latent reservoir during acute infection and the limited inflow during treatment, the dynamics of viral blips, and the phenomenon of post-treatment control. Finally, we discuss that mathematical models have been used to predict the efficacy of potential HIV-1 cure strategies, such as latency-reversing agents, early treatment initiation, or gene therapies, and to provide guidance for designing trials of these novel interventions.

Aile hekimlerinin pandemi döneminde muayene fobisi ve online görüntülü muayene hakkındaki görüşleri

Introduction: During Covid-19 pandemic, many hospitals closed their outpatient clinics because of the high number of inpatients and individuals turned to their family physicians for medical care. In this study, we aimed to evaluate the opinions of family physicians regarding examination phobia and telemedicine video examinations during the pandemic. Methods: This was a single-centered, cross-sectional study. The participating physicians completed a questionnaire with 28 questions including their sociodemographic data, whether they performed examination during the pandemic, telemedicine knowledge and opinions on telemedicine. Statistical analysis was conducted using SPSS 20 software package and statistical significance was set at p&amp;lt;0.05. Results: 364 family physicians participated in our study and 163 of them (44.8%) reported hesitation while examining patients, with the majority (53.8%; n=196) expressing anxiety about oropharyngeal examinations. 211 of them (58%) reported having knowledge of telemedicine. The majority of family physicians thought that follow-ups and prescriptions for chronic diseases, repeat prescriptions, and post-treatment control examinations could be performed online whereas pregnant, postpartum, infant, and child follow-ups could not. While 40% (n=146) didn’t want to provide services via video/telephone examination, 32.7% (n=119) wanted to and 27.2% (n=99) undecided. 86.8% (n=316) of them believed that telemedicine video/telephone examination could result in legal problems. Participants estimated that less than 25% of their daily patients were suitable for telemedicine, and that less than 25% had access to the necessary technology. However, 55.8% (n=203) of family physicians believed that patients would be interested in telemedicine, and 59.6% (n=216) thought that providing such services would increase their workload. Being undecided about providing services through telemedicine was more common among women (p=0.029), while unwillingness to provide online services increased with age and years of occupation (p=0.024, p=0.004, respectively). Conclusion: Telemedicine, which has come to the forefront with the development of technology today, was seen as an opportunity to reduce contact with patients during the pandemic. However, our study found that family physicians believed that telemedicine services would increase their workload and that a large portion of society was not ready for this system. Keywords: Telemedicine, telehealth, covid 19, family physician.

Timing of initiation of anti-retroviral therapy predicts post-treatment control of SIV replication.

One approach to 'functional cure' of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral 'setpoint' level after treatment interruption are not well understood. Here we combine data on ART interruption following SIV infection for 124 total animals from 10 independent studies across 3 institutional cohorts to understand the dynamics and predictors of post-treatment viral control. We find that the timing of treatment initiation is an important determinant of both the peak and early setpoint viral levels after treatment interruption. During the first 3 weeks of infection, every day of delay in treatment initiation is associated with a 0.22 log10 copies/ml decrease in post-rebound peak and setpoint viral levels. However, delay in initiation of ART beyond 3 weeks of infection is associated with higher post-rebound setpoint viral levels. For animals treated beyond 3 weeks post-infection, viral load at ART initiation was the primary predictor of post-rebound setpoint viral levels. Potential alternative predictors of post-rebound setpoint viral loads including cell-associated DNA or RNA, time from treatment interruption to rebound, and pre-interruption CD8+ T cell responses were also examined in the studies where these data were available. This analysis suggests that optimal timing of treatment initiation may be an important determinant of post-treatment control of HIV.

Outcomes of a Single Isocenter Brain Multi-Metastases Linear Accelerator Delivered Stereotactic Radiosurgery (SRS)

The management of brain metastases has evolved from using 2D whole brain radiotherapy (WBRT) to more complex techniques like stereotactic radiosurgery (SRS) for patients with limited disease. Long-term control of lesions is challenging with WBRT techniques but treating multiple lesions with traditional SRS, where each lesion is treated on its own isocenter, can be time-consuming and difficult on patients, especially those with claustrophobia. Single Isocenter Multiple Metastases (SIMM) SRS has emerged as an option to deliver ablative SRS doses simultaneously to multiple brain metastases using a single isocenter, thereby limiting the duration of treatments for patients. Though appealing, SIMM SRS adds technical complexity and could potentially lead to worse outcomes or more complications relative to traditional SRS treatments. Given the current paucity of clinical evidence supporting SIMM SRS, we sought to retrospectively review our institution's outcomes and complications for patients treated with SIMM SRS to determine the efficacy and safety of this approach in our hands. Patients treated at our institution with SIMM SRS with at least one post-treatment brain MRI were identified. Date on patient clinical characteristics, planning, and treatment characteristics, and outcomes were retrospectively collected. Post-treatment tumor control was evaluated with follow-up MRI imaging based on RANO criteria. Correlation between tumor control and toxicity was done by assessing radiation doses, PTV coverage, and normal brain V12 constraints. A total of 27 patients received SIMM SRS from January 2015 to February 2022. The median age at first SIMM SRS was 61 (range: 38-87). The most common disease sites were lung (63.0%), breast (18.5%), and GI (7.4%). The 27 patients had 47 SIMM SRS treatments of 163 lesions total. The median number of lesions treated per isocenter was 3 (range: 2-9). 5 patients had 2 SIMM SRS isocenters treated on the same day, treating clusters of lesions (ranging from 5-11 lesions treated on that day). The most common locations involved were frontal, cerebellar, and parietal lobes (32.52%, 21.47%, and 15.34%). The modal dose was 22 Gy (range: 18-24 Gy). Median OS from initial primary diagnosis was 23.23 months, and 9.92 months after the first SIMM SRS treatment. The median imaging follow-up was 9.8 months per lesion, and the local control rate was 95.03%. 2 lesions (1.23%) developed radiation necrosis and the median time to RT necrosis among those lesions was 5.7 months after treatment. The utilization of SIMM SRS demonstrates acceptable efficacy and safety as it has been implemented at our institution. Further studies to evaluate this planning modality are warranted to establish suitable candidates for SIMM SRS as well as evaluate the long-term outcomes for these patients.

CD8+ cells and small viral reservoirs facilitate post-ART control of SIV replication in M3+ Mauritian cynomolgus macaques initiated on ART two weeks post-infection.

Sustainable HIV remission after antiretroviral therapy (ART) withdrawal, or post-treatment control (PTC), remains a top priority for HIV treatment. We observed surprising PTC in an MHC-haplomatched cohort of MHC-M3+ SIVmac239+ Mauritian cynomolgus macaques (MCMs) initiated on ART at two weeks post-infection (wpi). None of the MCMs possessed MHC haplotypes previously associated with SIV control. For six months after ART withdrawal, we observed undetectable or transient viremia in seven of the eight MCMs, despite detecting replication competent SIV using quantitative viral outgrowth assays. In vivo depletion of CD8α+ cells induced rebound in all animals, indicating the observed PTC was mediated, at least in part, by CD8α+ cells. With intact proviral DNA assays, we found that MCMs had significantly smaller viral reservoirs two wpi than a cohort of identically infected rhesus macaques, a population that rarely develops PTC. We found a similarly small viral reservoir among six additional SIV+ MCMs in which ART was initiated at eight wpi, some of whom exhibited viral rebound. These results suggest that an unusually small viral reservoir is a hallmark among SIV+ MCMs. By evaluating immunological differences between MCMs that did and did not rebound, we identified that PTC was associated with a reduced frequency of CD4+ and CD8+ lymphocyte subsets expressing exhaustion markers. Together, these results suggest a combination of small reservoirs and immune-mediated virus suppression contribute to PTC in MCMs. Further, defining the immunologic mechanisms that engender PTC in this model may identify therapeutic targets for inducing durable HIV remission in humans.

Virological and immunological correlates of HIV post-treatment control after temporal antiretroviral therapy during acute HIV infection.

People with HIV rarely control viral replication after cessation of antiretroviral therapy (ART). We present a person with HIV with extraordinary post-treatment control (PTC) for over 23 years after temporary ART during acute HIV infection (AHI) leading to a new insight in factors contributing to PTC. Viral reservoir was determined by HIV qPCR, Intact Proviral DNA Assay and quantitative viral outgrowth assay. Viral replication kinetics were determined in autologous and donor PBMC. IgG levels directed against HIV envelope and neutralizing antibodies were measured. Immune phenotyping of T-cells and HIV-specific T-cell responses were analyzed by flow cytometry. The case presented with AHI and a plasma viral load of 2.7 million copies/mL. ART was initiated 2 weeks after diagnosis and interrupted after 26 months. Replicating virus was isolated shortly after start ART. At 18 years after treatment interruption HIV-DNA in CD4+ T-cells and low levels of HIV-RNA in plasma (<5 copies/ml) were detectable. Stable HIV envelope glycoprotein-directed IgG was present during follow-up, but lacked neutralizing activity. Strong antiviral CD8+ T-cell responses, in particular targeting HIV-gag, were detected during 25 years follow-up. Moreover, we found a P255A mutation in an HLA-B∗44:02 restricted gag-epitope, which was associated with decreased replication. We describe an exceptional case of post-treatment control, which is likely associated with sustained potent gag-specific CD8+ T-cell responses in combination with a replication attenuating escape mutation in gag. Understanding the initiation and preservation of the HIV-specific T-cell responses could guide the development of strategies to induce HIV control.

The Impact of Post-Processing Temperature on PLGA Microparticle Properties.

Biodegradable poly(lactide-co-glycolide) (PLGA) microparticles loaded with either risperidone or naltrexone were prepared from an emulsification homogenization process. The objective of this study was to determine the impact the post-treatment temperature has on the properties and subsequent performance of the microparticles. The post-treatment temperature of an ethanolic solution was characterized from 10 ~ 35ºC for the naltrexone and risperidone micropartilces. The wash temperature resulted in a typical triphasic in vitro release pattern at low wash temperatures or a biphasic pattern consisting of an elevated release rate at higher post-treatment temperatures. The post-treatment temperature largely influences the particle morphology, residual solvent levels, glass transition temperature, and drug loading and is molecule dependent, whereby these characteristics subsequently influence the drug release rate. The study highlights the importance of both the post-treatment process and control during manufacturing to obtain a formulation within the desired product profile.