scholarly journals Impact of Analytical Treatment Interruption on Burden and Diversification of HIV Peripheral Reservoir: A Pilot Study

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1403
Author(s):  
Rossana Scutari ◽  
Valentino Costabile ◽  
Laura Galli ◽  
Maria Concetta Bellocchi ◽  
Luca Carioti ◽  
...  
Keyword(s):  
Pilot Study ◽  
Dna Sequences ◽  
Viral Reservoir ◽  
P Value ◽  
Residual Viremia ◽  
Analytical Treatment ◽  
Time Points ◽  
Hiv Dna ◽  
Study Results ◽  
Hiv 1

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence <80%, and mainly occurred in APOBEC3-related sites. All MRMs persisted over-time in the 2 MODAt. C2-V3-C3 genetic-distance significantly changed from T1 to T3 in APACHE individuals (+0.36[0.11–0.41], p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap > 70%) and genealogical sorting indices (GSI > 0.50 with p-value < 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.

Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study)

2019 ◽  
Vol 74 (7) ◽  
pp. 2039-2046 ◽  
Author(s):  
Antonella Castagna ◽  
Camilla Muccini ◽  
Laura Galli ◽  
Alba Bigoloni ◽  
Andrea Poli ◽  
...  
Keyword(s):  
Viral Load ◽  
Undetectable Viral Load ◽  
Treatment Interruption ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Acute Retroviral Syndrome ◽  
Hiv 1

AbstractObjectivesDespite the fact that there are individuals who have chronic HIV infection, few studies have investigated ART interruption in this setting. The aim of this study was to evaluate the ability to spontaneously control viral replication during analytical treatment interruption (ATI) in adults with chronic HIV-1 infection, on ART, with suppressed viraemia for >10 years and with a low reservoir.Patients and methodsThis was a prospective, open-label, single-arm, non-randomized, proof-of-concept study (NCT03198325) of subjects with chronic HIV-1 infection, HIV-RNA <50 copies/mL for ≥10 years, without residual viraemia for ≥5 years, CD4+ >500 cells/mm3, HIV-DNA <100 copies/106 PBMCs and without comorbidities or AIDS-defining diseases. Enrolled patients were strictly monitored. The ART regimen in use at ATI was resumed in the case of confirmed viral rebound (CVR, two consecutive HIV-RNA >50 copies/mL). Results are reported as median (IQR).ResultsNine patients underwent ATI. All participants experienced CVR [4.84 (IQR: 3.47–6.47) HIV-RNA log10 copies/mL] after ATI at a median time of 21 days (range 14–56) and restarted ART. After ART resumption, all the subjects achieved HIV-RNA <50 copies/mL in a median of 88 days (range 15–197). No serious adverse event occurred; one subject experienced acute retroviral syndrome. No significant correlation between baseline factors and time to viral rebound was observed, while the magnitude of viral rebound was significantly associated with pre-ART HIV-1 RNA (Spearman r = 0.786, P = 0.036), nadir CD4+ (Spearman r = −0.800, P = 0.010), baseline CD4+ (Spearman r = −0.667, P = 0.049) and years with undetectable viral load (Spearman r = −0.717, P = 0.030).ConclusionsDespite a long period of HIV viral load suppression and a low viral reservoir, early and consistent viral rebound was observed during ATI in all subjects.

scholarly journals Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

2021 ◽  
Vol 17 (6) ◽  
pp. e1009686
Author(s):  
Taina T. Immonen ◽  
Christine M. Fennessey ◽  
Leslie Lipkey ◽  
Abigail Thorpe ◽  
Gregory Q. Del Prete ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Treatment Strategies ◽  
Viral Reservoir ◽  
Virus Population ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
The Impact ◽  
Hiv 1

Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track individual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of individual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

scholarly journals Modest de novo Reactivation of Single HIV-1 Proviruses in Peripheral CD4+ T Cells by Romidepsin

2021 ◽  
Vol 1 ◽  
Author(s):  
Kathrine Kjær ◽  
Steffen Leth ◽  
Christina V. Konrad ◽  
Jesper D. Gunst ◽  
Rasmus Nymann ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
De Novo ◽  
Viral Rna ◽  
Viral Reservoir ◽  
Latent Reservoir ◽  
Host Immune System ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Hiv 1

A cure for human immunodeficiency virus (HIV-1) is restricted by the continued presence of a latent reservoir of memory CD4+ T cells with proviruses integrated into their DNA despite suppressive antiretroviral therapy (ART). A predominant strategy currently pursued in HIV-1 cure-related research is the “kick and kill” approach, where latency reversal agents (LRAs) are used to reactivate transcription from integrated proviruses. The premise of this approach is that “kicking” latent virus out of hiding allows the host immune system to recognize and kill infected cells. Clinical trials investigating the efficacy of LRAs, such as romidepsin, have shown that these interventions do induce transient spikes in viral RNA in HIV-1-infected individuals. However, since these trials failed to significantly reduce viral reservoir size or significantly delay time to viral rebound during analytical treatment interruptions, it is questioned how much each individual latent provirus is actually “kicked” to produce viral transcripts and/or proteins by the LRA. Here, we developed sensitive and specific digital droplet PCR-based assays with single-provirus level resolution. Combining these assays allowed us to interrogate the level of viral RNA transcripts from single proviruses in individuals on suppressive ART with or without concomitant romidepsin treatment. Small numbers of proviruses in peripheral blood memory CD4+ T cells were triggered to become marginally transcriptionally active upon romidepsin treatment. These novel assays can be applied retrospectively and prospectively in HIV-1 cure-related clinical trials to gain crucial insights into LRA efficacy at the single provirus level.

scholarly journals Evaluating predictive markers for viral rebound and safety assessment in blood and lumbar fluid during HIV-1 treatment interruption

2020 ◽  
Vol 75 (5) ◽  
pp. 1311-1320
Author(s):  
Marie-Angélique De Scheerder ◽  
Clarissa Van Hecke ◽  
Henrik Zetterberg ◽  
Dietmar Fuchs ◽  
Nele De Langhe ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neuronal Injury ◽  
Treatment Interruption ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Neurofilament Light Chain ◽  
Rna Transcripts ◽  
Hiv 1 ◽  
Potential Biomarkers

Abstract Background Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health. Objectives ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated. Methods PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation. Results Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption. Conclusions ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.

HIV-1 non-R5 tropism correlates with a larger size of the cellular viral reservoir and a detectable residual viremia in patients under suppressive ART

2018 ◽  
Vol 103 ◽  
pp. 57-62 ◽  
Author(s):  
Francesca Lombardi ◽  
Simone Belmonti ◽  
Lucrezia Rapone ◽  
Alberto Borghetti ◽  
Arturo Ciccullo ◽  
...  
Keyword(s):  
Viral Reservoir ◽  
Residual Viremia ◽  
Hiv 1

scholarly journals HIV-1: Tackling the Obstacles that Limit the Effectiveness of CRISPR-Cas9 Gene Editing of the T Cell Co-receptor CCR5

2020 ◽  
Author(s):  
Tatiana Hillman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Sequences ◽  
Point Mutations ◽  
Viral Escape ◽  
Hiv Replication ◽  
Gene Therapies ◽  
Hiv Dna ◽  
Latent Hiv ◽  
Hiv 1

HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of zinc fingers, and most of all the applications of CRISPR-Cas9 technology, has given researchers new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR, possibly treating more diseases such as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of HIV-1, inhibiting HIV-1 gene expression. Since 2013, several other researchers have blocked HIV replication and infection through CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells, which consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus cannot bind to T-cells, blocking the initial attachment stage, and discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improving the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission or a functional cure.

Systematic Review and Meta-analysis of Treatment Interruptions in Human Immunodeficiency Virus (HIV) Type 1–infected Patients Receiving Antiretroviral Therapy: Implications for Future HIV Cure Trials

2019 ◽  
Author(s):  
Melanie Stecher ◽  
Annika Claßen ◽  
Florian Klein ◽  
Clara Lehmann ◽  
Henning Gruell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Current Evidence ◽  
P Value ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Immunodeficiency Virus ◽  
Hiv 1

AbstractBackgroundSafety and tolerability of analytical treatment interruptions (ATIs) as a vital part of human immunodeficiency virus type 1 (HIV-1) cure studies are discussed. We analyzed current evidence for the occurrence of adverse events (AEs) during TIs.MethodsOur analysis included studies that reported on AEs in HIV-1–infected patients undergoing TIs. All interventional and observational studies were reviewed, and results were extracted based on predefined criteria. The proportion of AEs was pooled using random-effects models. Metaregression was used to explore the influence of baseline CD4+ T-cell count, viral load, study type, previous time on combined antiretroviral therapy, and follow-up interval during TIs.ResultsWe identified 1048 studies, of which 22 studies including 7104 individuals fulfilled the defined selection criteria. Included studies had sample sizes between 6 and 5472 participants, with durations of TI cycles ranging from 7 days to 27 months. The intervals of HIV-1-RNA testing varied from 2 days to 3 months during TIs. The overall proportion of AEs during TIs >4 weeks was 3% (95% confidence interval [CI], 0%–7%) and was lower in studies with follow-up intervals ≤14 days (0%; 95% CI, 0%–1%) than in studies with wider follow-up intervals (6%; 95% CI, 2%–13%; P value for interaction = .01).ConclusionsWe found moderate-quality evidence indicating that studies with narrow follow-up intervals did not show a substantial increase in AEs during TIs. Our findings indicate that ATI may be a safe strategy as part of HIV-1 cure trials by closely monitoring for HIV-1 rebound.

scholarly journals HIV-1: Tackling the Obstacles, Which Limit the Effectiveness of the CRISPR-Cas9 Gene Editing of the T Cell Co-Receptor, CCR5

2019 ◽  
Author(s):  
Tatiana Hillman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Sequences ◽  
Point Mutations ◽  
Viral Escape ◽  
Hiv Replication ◽  
Gene Therapies ◽  
Hiv Dna ◽  
Latent Hiv ◽  
Hiv 1

HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of Zinc fingers, and most of all the application of CRISPR-Cas9 technology, has given researchers a new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. The CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR possibly curing more diseases as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of the HIV-1, inhibiting HIV-1 gene expression. Since 2013 several other researchers have blocked HIV replication and infection through the CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells that consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus can not bind to T-cells, blocking the initial attachment stage, discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improve the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission.

Penatalaksanaan IMD pada Ibu Postpartum Sectio Caesarea Mempengaruhi Status Gizi dan Kecepatan Produksi ASI

2020 ◽  
Vol 2 (2) ◽  
pp. 112-120
Author(s):  
Nursari Abdul Syukur ◽  
Susi Purwanti
Keyword(s):  
Breast Milk ◽  
Nutritional Status ◽  
Milk Production ◽  
Quantitative Research ◽  
Milk Protein ◽  
Sectio Caesarea ◽  
Control Group ◽  
P Value ◽  
Study Results

Many mothers who give birth to Sectio Caesarea (SC) do not Initiate Early Breastfeeding (IMD), which fails exclusive breastfeeding. This study aimed to determine the effect of IMD management in postpartum SC mothers on nutritional status, speed of milk production, and quality of breast milk protein. Method: quantitative research with quasi approach experiment. The research design used was a pre-post-test control non-equivalent control group. A sampling of this study used the Consecutive method sampling with a sample of 20 mothers who gave birth by cesarean section (SC). Hypothesis testing uses the independent t-test and the Mann-Whitney test. The study results showed an influence on the management of IMD in postpartum SC mothers on the speed of ASI production (p-value=0.004) and nutritional status (p-value=0.028). There was no effect of IMD management on postpartum SC mothers on the quality of breast milk protein (p-value = 0.543). This study recommends that the hospital implement an IMD promotion program before the abdominal wall is closed as a form of intervention to increase milk production and maternal nutritional status

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