scholarly journals Decay of HIV DNA in the Reservoir and the Impact of Short Treatment Interruption in Kenyan Infants

2017 ◽  
Vol 5 (1) ◽  
Author(s):  
Mark D Pankau ◽  
Dalton Wamalwa ◽  
Sarah Benki-Nugent ◽  
Kenneth Tapia ◽  
Evelyn Ngugi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Short Treatment ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
The Impact ◽  
Dna Reservoir

Abstract We compared change in HIV reservoir DNA following continued antiretroviral therapy (ART) vs short treatment interruption (TI) in early ART-treated Kenyan infants. While HIV DNA in the reservoir decayed with continued ART, HIV DNA levels were similar to pre-TI HIV DNA reservoir levels in most children after short TI.

scholarly journals Continuous Prophylactic Antiretrovirals/Antiretroviral Therapy Since Birth Reduces Seeding and Persistence of the Viral Reservoir in Children Vertically Infected With Human Immunodeficiency Virus

2020 ◽  
Author(s):  
Marta Massanella ◽  
Thanyawee Puthanakit ◽  
Louise Leyre ◽  
Thidarat Jupimai ◽  
Panadda Sawangsinth ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Cross Sectional Study ◽  
Viral Reservoir ◽  
Cross Sectional ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
Infected Cells

Abstract Background Early antiretroviral therapy (ART) restricts the size of the human immunodeficiency virus (HIV) reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown. Methods We measured total and integrated HIV DNA, as well as the frequency of CD4 T cells producing multiply spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically infected Thai infants. Eighty-five infants were followed longitudinally for up to 3 years. We compared the size of the reservoir in children who received continuous ARV prophylaxis since birth vs those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings. Results Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous ARV prophylaxis since birth compared to those in whom ARV prophylaxis was discontinued or never initiated (P < .020 and P < .001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (P < .01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during 3 years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARVs before starting ART and those who delayed ART initiation without receiving prior prophylaxis. Conclusions Neonatal ARV prophylaxis with direct transition to ART durably limits the size of the HIV reservoir.

scholarly journals Mycobacterium tuberculosis co-infection is associated with increased surrogate marker of the HIV reservoir

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Jingna Xun ◽  
Tangkai Qi ◽  
Lei Zou ◽  
Qi Tang ◽  
Yinzhong Shen ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Baseline Viral Load ◽  
People Living With Hiv ◽  
Peripheral Blood Mononuclear ◽  
Hiv Reservoir ◽  
Hiv Dna ◽  
Interleukin 7 ◽  
Living With Hiv ◽  
The Impact

Abstract Background Tuberculosis (Tb) is the most frequent opportunistic infection among people living with HIV infection. The impact of Tb co-infection in the establishment and maintenance of the HIV reservoir is unclear. Method We enrolled 13 HIV-infected patients with microbiologically confirmed Tb and 10 matched mono-HIV infected controls. Total HIV DNA in peripheral blood mononuclear cells (PBMCs), plasma interleukin-7 (IL-7) concentrations and the activities of indoleamine 2,3-dioxygenase (IDO) were measured for all the participants prior to therapy and after antiretroviral therapy (ART). Results After a duration of 16 (12, 22) months’ ART, patients co-infected with Tb who were cured of Tb maintained higher levels of HIV DNA compared with mono-HIV infected patients [2.89 (2.65- 3.05) log10 copies/106 cells vs. 2.30 (2.11–2.84) log10 copies/106 cells, P = 0.008]. The levels of on-ART HIV DNA were positively correlated with the baseline viral load (r = 0.64, P = 0.02) in Tb co-infected group. However, neither plasma IL-7 concentration nor plasma IDO activity was correlated with the level of on-ART HIV DNA. Conclusions Tb co-infection was associated with the increased surrogate marker of the HIV reservoir, while its mechanism warrants further examination.

scholarly journals Intact Human Immunodeficiency Virus (HIV) Reservoir Estimated by the Intact Proviral DNA Assay Correlates With Levels of Total and Integrated DNA in the Blood During Suppressive Antiretroviral Therapy

2020 ◽  
Author(s):  
Emmanouil Papasavvas ◽  
Livio Azzoni ◽  
Brian N Ross ◽  
Matthew Fair ◽  
Zhe Yuan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Hiv Reservoir ◽  
Dna Assay ◽  
Proviral Dna ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Immunodeficiency Virus

Abstract Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

scholarly journals Viral rebound kinetics following single and combination immunotherapy for HIV/SIV

2019 ◽  
Author(s):  
Mélanie Prague ◽  
Jeffrey M Gerold ◽  
Irene Balelli ◽  
Chloé Pasin ◽  
Jonathan Z Li ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Immune Responses ◽  
Therapeutic Vaccine ◽  
Neutralizing Antibody ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Viral Rebound ◽  
Tlr7 Agonist ◽  
Latently Infected ◽  
The Impact

AbstractHIV infection can be treated but not cured with antiretroviral therapy, motivating the development of new therapies that instead target host immune responses. Three such immunotherapies were recently tested in non-human primates – a TLR7-agonist, therapeutic vaccine, and broadly-neutralizing antibody – and cured a subset of animals by preventing or controlling viral rebound after antiretrovirals were stopped. However, their mechanism of action remains unknown; for example, whether they reduced the pool of latently-infected cells versus boosted antiviral immunity, and whether they acted independently or synergistically. Here we conduct a detailed analysis of the kinetics of viral rebound after immunotherapy, and use mathematical models combined with rigorous statistical fitting to quantify the impact of these interventions on viral dynamics. We find that the vaccine reduced reactivation of latent virus by 4-fold, and boosted the avidity of antiviral immune responses by 17-fold when alone and 210-fold when combined with the TLR7-agonist. In the context of later initiation of antiretroviral therapy only, the TLR7-agonist reduced latent reservoir reactivation by 8-fold, but also slightly increased target cell availability (1.5-fold). The antibody boosted immune response avidity (8-fold) and displayed no detectable synergy with the TLR7-agonist. To predict the impact of these immunotherapies in clinical trials, we calibrated a model of HIV rebound to human treatment interruption trials and simulated the effect of adding each therapy. Overall, our results provide a framework for understanding the relative contributions of different mechanisms of preventing viral rebound and highlight the multifaceted roles of TLR7-agonists for HIV/SIV cure.

scholarly journals Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy

2015 ◽  
Vol 90 (3) ◽  
pp. 1369-1376 ◽  
Author(s):  
Mary F. Kearney ◽  
Ann Wiegand ◽  
Wei Shao ◽  
John M. Coffin ◽  
John W. Mellors ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Opportunistic Infections ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Proliferating Cells ◽  
Peripheral Blood Mononuclear ◽  
Hiv Reservoir ◽  
Infected Cells ◽  
Aids Clinical Trials

ABSTRACTUnderstanding the origin of HIV variants during viral rebound may provide insight into the composition of the HIV reservoir and has implications for the design of curative interventions. HIV single-genome sequences were obtained from 10 AIDS Clinical Trials Group participants who underwent analytic antiretroviral therapy (ART) interruption (ATI). Rebounding variants were compared with those in pre-ART plasma in all 10 participants and with on-ART peripheral blood mononuclear cell (PBMC)-associated DNA and RNA (CA-RNA) in 7/10 participants. The highest viral diversities were found in the DNA and CA-RNA populations. In 3 of 7 participants, we detected multiple, identical DNA and CA-RNA sequences during suppression on ART that exactly matched plasma HIV sequences. Hypermutated DNA and CA-RNA were detected in four participants, contributing to diversities in these compartments that were higher than in the pre-ART and post-ATI plasma. Shifts in the viral rebound populations could be detected in some participants over the 2- to 3-month observation period. These findings suggest that a source of initial rebound viremia could be populations of infected cells that clonally expanded prior to and/or during ART, some of which were already expressing HIV RNA before treatment was interrupted. These clonally expanding populations of HIV-infected cells may represent an important target for strategies aimed at achieving reservoir reduction and sustained virologic remission.IMPORTANCEAntiretroviral therapy alone cannot eradicate the HIV reservoir, and viral rebound is generally rapid after treatment interruption. It has been suggested that clonal expansion of HIV-infected cells is an important mechanism of HIV reservoir persistence, but the contribution of these clonally proliferating cells to the rebounding virus is unknown. We report a study of AIDS Clinical Trials Group participants who underwent treatment interruption and compared rebounding plasma virus with that found within cells prior to treatment interruption. We found several incidences in which plasma HIV variants exactly matched that of multiple proviral DNA copies from infected blood cells sampled before treatment interruption. In addition, we found that these cells were not dormant but were generating unspliced RNA transcripts before treatment was interrupted. Identification of the HIV reservoir and determining its mechanisms for persistence may aid in the development of strategies toward a cure for HIV. (This study was presented in part at the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 23 to 26 2015.)

scholarly journals Enrichment of the HIV reservoir in CD32+ CD4 T cells occurs early in blood and tissue

2017 ◽  
Author(s):  
Genevieve E Martin ◽  
Matthew Pace ◽  
John P Thornhill ◽  
Chansavath Phetsouphanh ◽  
Jodi Meyerowitz ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Treatment Interruption ◽  
Healthy Controls ◽  
Hiv Dna ◽  
Hla Dr ◽  
Latently Infected ◽  
Checkpoint Receptors

AbstractThe Fc receptor CD32 has been proposed as a marker for CD4 T cells latently infected with HIV. We demonstrate that enrichment for HIV DNA in CD32+ CD4 T cells can be found early in infection in both tissue and blood. However, we find no evidence for a correlation between CD32 expression on CD4 T cells and either HIV DNA levels or time to rebound viraemia following treatment interruption. CD32+ CD4 T cells have a more differentiated memory phenotype, and high levels of expression of immune checkpoint receptors PD-1, Tim-3 and TIGIT as well as the activation marker, HLA DR. There was no difference in the phenotype or frequency of CD32 expressing cells prior to or after the initiation of antiretroviral therapy, or compared with healthy controls, suggesting that preferential infection or survival, rather than up-regulation, may be responsible for the observed enrichment of proviral HIV DNA in CD32+ CD4 T cells.

scholarly journals Effect of Short-Term Antiretroviral Therapy Interruption on Levels of Integrated HIV DNA

2018 ◽  
Vol 92 (12) ◽  
Author(s):  
Zachary Strongin ◽  
Radwa Sharaf ◽  
D. Jake VanBelzen ◽  
Jeffrey M. Jacobson ◽  
Elizabeth Connick ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Peripheral Blood ◽  
Treatment Interruption ◽  
Viral Reservoir ◽  
Short Term ◽  
Size Selection ◽  
Hiv Dna ◽  
Aids Clinical Trials ◽  
Dna Size

ABSTRACT Analytic treatment interruption (ATI) studies are required to evaluate strategies aimed at achieving ART-free HIV remission, but the impact of ATI on the viral reservoir remains unclear. We validated a DNA size selection-based assay for measuring levels of integrated HIV DNA and applied it to assess the effects of short-term ATI on the HIV reservoir. Samples from participants from four AIDS Clinical Trials Group ATI studies were assayed for integrated HIV DNA levels. Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained for 12 participants with available samples pre-ATI and approximately 6 months after ART resumption. Four participants also had samples available during the ATI. The median duration of ATI was 12 weeks. Validation of the HIV integrated DNA size-exclusion (HIDE) assay was performed using samples spiked with unintegrated HIV DNA, HIV-infected cell lines, and participant PBMCs. The HIDE assay eliminated 99% of unintegrated HIV DNA species and strongly correlated with the established Alu- gag assay. For the majority of individuals, integrated DNA levels increased during ATI and subsequently declined upon ART resumption. There was no significant difference in the levels of integrated HIV DNA between the pre- and post-ATI time points, with a median ratio of post- to pre-ATI HIV DNA levels of 0.95. Using a new integrated HIV DNA assay, we found minimal change in the levels of integrated HIV DNA in participants who underwent an ATI, followed by 6 months of ART. This suggests that short-term ATI can be conducted without a significant impact on the levels of integrated proviral DNA in the peripheral blood. IMPORTANCE Interventions aimed at achieving sustained antiretroviral therapy (ART)-free HIV remission require treatment interruption trials to assess their efficacy. However, these trials are accompanied by safety concerns related to the expansion of the viral reservoir. We validated an assay that uses an automated DNA size-selection platform for quantifying levels of integrated HIV DNA and is less sample- and labor-intensive than current assays. Using stored samples from AIDS Clinical Trials Group studies, we found that short-term ART discontinuation had minimal impact on integrated HIV DNA levels after ART resumption, providing reassurance about the reservoir effects of short-term treatment interruption trials.

scholarly journals Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption

2017 ◽  
Vol 2 (3) ◽  
pp. 431 ◽  
Author(s):  
You Jeong Park ◽  
Behzad Etemad ◽  
Hayat Ahmed ◽  
Vivek Naranbhai ◽  
Evgenia Aga ◽  
...  
Keyword(s):  
Hla Class I ◽  
Treatment Interruption ◽  
Single Copy ◽  
Pooled Analysis ◽  
Vital Role ◽  
Class I ◽  
Viral Rebound ◽  
Peripheral Blood Mononuclear ◽  
Hiv Reservoir ◽  
Hiv Dna

Identifying host determinants associated with HIV reservoir size and viral rebound timing after an analytic treatment interruption (ATI) is an important step in the search for an HIV functional cure. A pooled analysis of 103 participants from four AIDS Clinical Trials Group ATI studies to identify the association between HLA class I alleles with HIV reservoir size and viral rebound timing. Total HIV DNA and cell-associated HIV RNA (CA-RNA) were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. HLA class I typing was performed and we generated an odds ratio (OR) of predicted HLA effect on HIV viremia control for each individual and compared this with time to viral rebound, and levels of HIV DNA and CA-RNA. There was no significant association between the HLA ORs and levels of HIV DNA or CA-RNA, but carriage of protective HLA-B alleles (lower OR scores) was associated with delayed viral rebound (P=0.02). Higher OR scores at the HLA-C locus were associated with longer duration of ART treatment (P=0.01) and this trend was also seen with the combined OR score (P=0.007). Individuals with protective HLA-B alleles had delayed viral rebound after treatment interruption that was not explained by differences in baseline reservoir size. The results indicate the vital role of cellular host immunity in preventing HIV rebound and the importance of taking into account the HLA status of study participants being evaluated in HIV cure trials.

scholarly journals STING and cGAS gene expressions were downregulated among HIV-1-infected persons after antiretroviral therapy

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lorena Leticia Peixoto de Lima ◽  
Allysson Quintino Tenório de Oliveira ◽  
Tuane Carolina Ferreira Moura ◽  
Ednelza da Silva Graça Amoras ◽  
Sandra Souza Lima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Count ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Α Level ◽  
The Impact ◽  
Hiv 1

Abstract Background The HIV-1 epidemic is still considered a global public health problem, but great advances have been made in fighting it by antiretroviral therapy (ART). ART has a considerable impact on viral replication and host immunity. The production of type I interferon (IFN) is key to the innate immune response to viral infections. The STING and cGAS proteins have proven roles in the antiviral cascade. The present study aimed to evaluate the impact of ART on innate immunity, which was represented by STING and cGAS gene expression and plasma IFN-α level. Methods This cohort study evaluated a group of 33 individuals who were initially naïve to therapy and who were treated at a reference center and reassessed 12 months after starting ART. Gene expression levels and viral load were evaluated by real-time PCR, CD4+ and CD8+ T lymphocyte counts by flow cytometry, and IFN-α level by enzyme-linked immunosorbent assay. Results From before to after ART, the CD4+ T cell count and the CD4+/CD8+ ratio significantly increased (p < 0.0001), the CD8+ T cell count slightly decreased, and viral load decreased to undetectable levels in most of the group (84.85%). The expression of STING and cGAS significantly decreased (p = 0.0034 and p = 0.0001, respectively) after the use of ART, but IFN-α did not (p = 0.1558). Among the markers evaluated, the only markers that showed a correlation with each other were STING and CD4+ T at the time of the first collection. Conclusions ART provided immune recovery and viral suppression to the studied group and indirectly downregulated the STING and cGAS genes. In contrast, ART did not influence IFN-α. The expression of STING and cGAS was not correlated with the plasma level of IFN-α, which suggests that there is another pathway regulating this cytokine in addition to the STING–cGAS pathway.

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