Recommendations for measuring HIV reservoir size in cure-directed clinical trials.
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ABSTRACT:
SUBMITTER: Abdel-Mohsen M
PROVIDER: S-EPMC7703694 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The latent reservoir (LR) of HIV-1 in resting memory CD4(+) T cells serves as a major barrier to curing HIV-1 infection. While many PCR- and culture-based assays have been used to measure the size of the LR, correlation between results of different assays is poor and recent studies indicate that no available assay provides an accurate measurement of reservoir size. The discrepancies between assays are a hurdle to clinical trials that aim to measure the efficacy of HIV-1 eradication strategies. Here we describe the advantages and disadvantages of various approaches to measuring the LR.
| S-EPMC4386620 | biostudies-literature
Project description:Traumatic brain injury (TBI) involves several aspects of a patient's condition, including physical, mental, emotional, cognitive, social, and functional changes. Therefore, a clinical trial with individuals with TBI should consider outcome measures that reflect their global status.We present the work of the National Institute of Child Health and Development-sponsored Traumatic Brain Injury Clinical Trials Network Outcome Measures subcommittee and its choice of outcome measures for a phase III clinical trial of patients with complicated mild to severe TBI.On the basis of theoretical and practical considerations, the subcommittee recommended the adoption of a core of 9 measures that cover 2 different areas of recovery: functional and cognitive. These measures are the Extended Glasgow Outcome Scale; the Controlled Oral Word Association Test; the Trail Making Test, Parts A and B; the California Verbal Learning Test-II; the Wechsler Adult Intelligence Scale-III Digit Span subtest; the Wechsler Adult Intelligence Scale-III Processing Speed Index; and the Stroop Color-Word Matching Test, Parts 1 and 2.The statistical methods proposed to analyze these measures using a global test procedure, along with research and methodological and regulatory issues involved with the use of multiple outcomes in a clinical trial, are discussed.
| S-EPMC2939167 | biostudies-literature
Project description:Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Substances that activate HIV production in the latently infected cells have recently received much attention. By turning on expression of latent HIV proviruses, reactivation strategies could contribute to the eradication HIV infection. Compounds that are currently being or soon to be tested in clinical trials are emphasized. The results from these trials will provide important clues as to whether or not reactivating strategies could become significant components of a cure for HIV.
| S-EPMC3903897 | biostudies-literature
Project description:Monitoring the efficacy of novel reservoir-reducing treatments for HIV is challenging. The limited ability to sample and quantify latent infection means that supervised antiretroviral therapy (ART) interruption studies are generally required. Here we introduce a set of mathematical and statistical modeling tools to aid in the design and interpretation of ART-interruption trials. We show how the likely size of the remaining reservoir can be updated in real-time as patients continue off treatment, by combining the output of laboratory assays with insights from models of reservoir dynamics and rebound. We design an optimal schedule for viral load sampling during interruption, whereby the frequency of follow-up can be decreased as patients continue off ART without rebound. While this scheme can minimize costs when the chance of rebound between visits is low, we find that the reservoir will be almost completely reseeded before rebound is detected unless sampling occurs at least every two weeks and the most sensitive viral load assays are used. We use simulated data to predict the clinical trial size needed to estimate treatment effects in the face of highly variable patient outcomes and imperfect reservoir assays. Our findings suggest that large numbers of patients-between 40 and 150-will be necessary to reliably estimate the reservoir-reducing potential of a new therapy and to compare this across interventions. As an example, we apply these methods to the two "Boston patients", recipients of allogeneic hematopoietic stem cell transplants who experienced large reductions in latent infection and underwent ART-interruption. We argue that the timing of viral rebound was not particularly surprising given the information available before treatment cessation. Additionally, we show how other clinical data can be used to estimate the relative contribution that remaining HIV+ cells in the recipient versus newly infected cells from the donor made to the residual reservoir that eventually caused rebound. Together, these tools will aid HIV researchers in the evaluating new potentially-curative strategies that target the latent reservoir.
| S-EPMC4847932 | biostudies-literature
Project description:PURPOSE OF REVIEW:Gallant efforts are ongoing to achieve sustained antiretroviral therapy (ART)-free HIV remission in the HIV-infected person; however, most, if not all, current human clinical studies have primarily focused these efforts on targeting viral persistence in CD4 T cells in blood and tissue sanctuaries. The lack of myeloid centered HIV clinical trials, either as primary or secondary end points, has hindered our understanding of the contribution of myeloid cells in unsuccessful trials but may also guide successes in future HIV eradication clinical strategies. RECENT FINDINGS:Recent advances have highlighted the importance of myeloid reservoirs as sanctuaries of HIV persistence and therefore may partially be responsible for viral recrudescence following ART treatment interruption in several clinical trials where HIV was not detectable or recovered from CD4 T cells. Given these findings, novel innovative therapeutic approaches specifically focused on HIV clearance in myeloid cell populations need to be vigorously pursued if we are to achieve additional cases of sustained ART-free remission. This review will highlight new research efforts defining myeloid persistence and recent advances in HIV remission and cure trials that would be relevant in targeting this compartment and make an argument as to their clinical relevancy as we progress towards sustained ART-free HIV remission in all HIV-infected persons.
| S-EPMC6589351 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.ppat.1005535.].
| S-EPMC5500350 | biostudies-literature
Project description:[This corrects the article DOI: 10.1371/journal.ppat.1005535.].
| S-EPMC4943732 | biostudies-literature
Project description:Despite significant advances in HIV drug treatment regimens, which grant near-normal life expectancies to infected individuals who have good virological control, HIV infection itself remains incurable. In recent years, novel gene- and cell-based therapies have gained increasing attention due to their potential to provide a functional or even sterilizing cure for HIV infection with a one-shot treatment. A functional cure would keep the infection in check and prevent progression to AIDS, while a sterilizing cure would eradicate all HIV viruses from the patient. Genome editing is the most precise form of gene therapy, able to achieve permanent genetic disruption, modification, or insertion at a predesignated genetic locus. The most well-studied candidate for anti-HIV genome editing is CCR5, an essential coreceptor for the majority of HIV strains, and the lack of which confers HIV resistance in naturally occurring homozygous individuals. Genetic disruption of CCR5 to treat HIV has undergone clinical testing, with seven completed or ongoing trials in T cells and hematopoietic stem and progenitor cells, and has shown promising safety and potential efficacy profiles. Here we summarize clinical findings of CCR5 editing for HIV therapy, as well as other genome editing-based approaches under pre-clinical development. The anticipated development of more sophisticated genome editing technologies should continue to benefit HIV cure efforts.
| S-EPMC5144849 | biostudies-other
Project description:ObjectiveTo study the contribution of ?? T cells to the persistent HIV reservoir.DesignFifteen HIV-seropositive individuals on suppressive ART were included. We performed parallel quantitative viral outgrowth assays (QVOA) of resting CD4 T (rCD4) cells in the presence or absence of ?? T cells.MethodsResting ??+CD4 T cells were magnetically isolated from PBMCs using two different custom cocktails, only one kit contained antibodies to deplete ?? T cells, resulting in two populations: rCD4 cells and rCD4 cells depleted of ?? cells. Frequency of infection was analyzed by QVOA and DNA measurements.ResultsRecovery of replication-competent HIV from cultures of rCD4 cells was similar in 11 individuals despite the presence of ?? T cells. In four donors, HIV recovery was lower when ?? T cells were present. Expression of the cytotoxic marker CD16 on V?2 cells was the only variable associated with the lower HIV recovery. Our results highlight the potency of those responses since a mean of 10?000 ?? T cells were present within 2.5 million rCD4 cells. However, despite the low frequency of ?? T cells, the presence of cytotoxic V?2 cells correlated with lower HIV recovery from cultures of rCD4 cells.ConclusionResults of this study show that quantification of the contribution of ?? T cells to the reservoir is challenging because of their low numbers compared with conventional rCD4 cells and highlights the potent antiviral function of ?? T cells and the impact of their presence on the frequency of latent HIV infection.
| S-EPMC6994336 | biostudies-literature
Project description:Antiretroviral therapy fails to cure HIV-1 infection because latent proviruses persist in resting CD4(+) T cells. T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, we reconstructed full-length intact noninduced proviral clones and demonstrated growth kinetics comparable to reconstructed induced proviruses from the same patients. Noninduced proviruses have unmethylated promoters and are integrated into active transcription units. Thus, it cannot be excluded that they may become activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated.
| S-EPMC3896327 | biostudies-literature