Faculty Opinions recommendation of HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

ABSTRACT In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P < 0.001 for each cytokine compared to W0) measured, predominantly against Gag and Pol/Env, and an increase in HIV-specific CD8+ T cells producing interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-α) (P = 0.001 and 0.013, respectively), predominantly against Pol/Env and Nef. However, analysis of T-cell subsets by mass cytometry in a subpopulation showed an increase in the W28/W0 ratio for memory CD8+ T cells coexpressing exhaustion and senescence markers such as PD-1/TIGIT (P = 0.004) and CD27/CD57 (P = 0.044) in vaccinees compared to the placebo group. During ATI, all patients experienced viral rebound, with the maximum observed HIV RNA level at W42 (median, 4.63 log10 copies [cp]/ml; interquartile range [IQR], 4.00 to 5.09), without any difference between arms. No patient resumed cART for CD4 cell count drop. Globally, the vaccine strategy was safe. However, a secondary HIV transmission during ATI was observed. These data show that the prime-boost combination of DNA and LIPO-5 vaccines elicited broad and polyfunctional T cells. The contrast between the quality of immune responses and the lack of potent viral control underscores the need for combined immunomodulatory strategies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01492985.) IMPORTANCE In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually. Compared to the placebo group, vaccinees elicited strong and polyfunctional HIV-specific CD4+ and CD8+ T-cell responses. However, these immune responses presented some qualitative defects and were not able to control viremia following antiretroviral treatment interruption, as no difference in HIV viral rebound was observed in the vaccine and placebo groups. Several lessons were learned from these results, pointing out the urgent need to combine vaccine strategies with other immune-based interventions.

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HIV-1 DNA predicts disease progression and post-treatment virological control

eLife ◽

10.7554/elife.03821 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 183

Author(s):

James P Williams ◽

Jacob Hurst ◽

Wolfgang Stöhr ◽

Nicola Robinson ◽

Helen Brown ◽

...

Keyword(s):

Disease Progression ◽

Treatment Interruption ◽

Viral Rebound ◽

Clinical Progression ◽

Clinical Trial Registration ◽

Plasma Virus ◽

Latently Infected ◽

Infected Cells ◽

Multivariable Analyses ◽

Hiv 1

In HIV-1 infection, a population of latently infected cells facilitates viral persistence despite antiretroviral therapy (ART). With the aim of identifying individuals in whom ART might induce a period of viraemic control on stopping therapy, we hypothesised that quantification of the pool of latently infected cells in primary HIV-1 infection (PHI) would predict clinical progression and viral replication following ART. We measured HIV-1 DNA in a highly characterised randomised population of individuals with PHI. We explored associations between HIV-1 DNA and immunological and virological markers of clinical progression, including viral rebound in those interrupting therapy. In multivariable analyses, HIV-1 DNA was more predictive of disease progression than plasma viral load and, at treatment interruption, predicted time to plasma virus rebound. HIV-1 DNA may help identify individuals who could safely interrupt ART in future HIV-1 eradication trials.Clinical trial registration: ISRCTN76742797 and EudraCT2004-000446-20

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Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption

Journal of Virology ◽

10.1128/jvi.01920-18 ◽

2019 ◽

Vol 93 (8) ◽

Cited By ~ 13

Author(s):

Line K. Vibholm ◽

Julio C. C. Lorenzi ◽

Joy A. Pai ◽

Yehuda Z. Cohen ◽

Thiago Y. Oliveira ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Treatment Interruption ◽

Latent Reservoir ◽

Lymphoid Tissues ◽

Viral Rebound ◽

Analytical Treatment ◽

Latent Hiv ◽

Hiv 1

ABSTRACT The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.

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Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw100 ◽

2016 ◽

Vol 3 (2) ◽

Cited By ~ 5

Author(s):

Kathryn E. Stephenson ◽

George H. Neubauer ◽

Christine A. Bricault ◽

Jennifer Shields ◽

Madeleine Bayne ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Treatment Interruption ◽

Antibody Responses ◽

Viral Rebound ◽

Analytic Treatment ◽

Antibody Maturation ◽

Neutralizing Capacity ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract The examination of antibody responses in human immunodeficiency virus (HIV)-1-infected individuals in the setting of antiretroviral treatment (ART) interruption can provide insight into the evolution of antibody responses during viral rebound. In this study, we assessed antibody responses in 20 subjects in AIDS Clinical Trials Group A5187, wherein subjects were treated with antiretroviral therapy during acute/early HIV-1 infection, underwent analytic treatment interruption, and subsequently demonstrated viral rebound. Our data suggest that early initiation of ART arrests the maturation of HIV-1-specific antibody responses, preventing epitope diversification of antibody binding and the development of functional neutralizing capacity. Antibody responses do not appear permanently blunted, however, because viral rebound triggered the resumption of antibody maturation in our study. We also found that antibody responses measured by these assays did not predict imminent viral rebound. These data have important implications for the HIV-1 vaccine and eradication fields.

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Viral Rebound Syndrome in Two HIV-1–Positive Patients after Structured Treatment Interruption

Viral Immunology ◽

10.1089/vim.2005.18.579 ◽

2005 ◽

Vol 18 (3) ◽

pp. 579-581 ◽

Cited By ~ 2

Author(s):

Brygida Knysz ◽

Jacek Gasiorowski ◽

Marcin Czarnecki ◽

Andrzej Gladysz

Keyword(s):

Treatment Interruption ◽

Viral Rebound ◽

Hiv 1 ◽

Rebound Syndrome

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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)

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz138 ◽

2019 ◽

Vol 74 (7) ◽

pp. 2039-2046 ◽

Cited By ~ 9

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.

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Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption

Journal of Virology ◽

10.1128/jvi.00603-17 ◽

2017 ◽

Vol 91 (15) ◽

Cited By ~ 7

Author(s):

Wen Shi Lee ◽

Anne B. Kristensen ◽

Thomas A. Rasmussen ◽

Martin Tolstrup ◽

Lars Østergaard ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Treatment Interruption ◽

Viral Rebound ◽

Analytical Treatment ◽

Antigenic Stimulus ◽

Latently Infected ◽

Infected Cells ◽

Functional Antibodies ◽

Hiv 1 ◽

Reversing Agents

ABSTRACT There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells in vitro. These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. IMPORTANCE The “shock and kill” HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined in vivo, but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.

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Measuring Proviral HIV-1 DNA: Hurdles and Improvements to an Assay Monitoring Integration Events Utilising Human Alu Repeat Sequences

Life ◽

10.3390/life11121410 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1410

Author(s):

Eva Malatinkova ◽

Jordan Thomas ◽

Ward De Spiegelaere ◽

Sofie Rutsaert ◽

Anna Maria Geretti ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Treatment Interruption ◽

Viral Rebound ◽

Assay Sensitivity ◽

Standard Curve ◽

Repeat Sequences ◽

Alu Repeat ◽

Increased Sensitivity ◽

Hiv 1

Integrated HIV-1 DNA persists despite antiretroviral therapy and can fuel viral rebound following treatment interruption. Hence, methods to specifically measure the integrated HIV-1 DNA portion only are important to monitor the reservoir in eradication trials. Here, we provide an up-to-date overview of the literature on the different approaches used to measure integrated HIV-1 DNA. Further, we propose an implemented standard-curve free assay to quantify integrated HIV-1 DNA, so-called Alu-5LTR PCR, which utilises novel primer combinations. We tested the Alu-5LTR PCR in 20 individuals on suppressive ART for a median of nine years; the results were compared to those produced with the standard-free Alu-gag assay. The numbers of median integrated HIV-1 DNA copies were 5 (range: 1–12) and 14 (5–26) with the Alu-gag and Alu-5LTR, respectively. The ratios between Alu-gag vs Alu-5LTR results were distributed within the cohort as follows: most patients (12/20, 60%) provided ratios between 2–5, with 3/20 (15%) and 5/20 (25%) being below or above this range, respectively. Alu-5LTR assay sensitivity was also determined using an “integrated standard”; the data confirmed the increased sensitivity of the assay, i.e., equal to 0.25 proviruses in 10,000 genomes. This work represents an improvement in the field of measuring proviral HIV-1 DNA that could be employed in future HIV-1 persistence and eradication studies.

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Models of SIV rebound after treatment interruption that involve multiple reactivation events

10.1101/2020.07.28.221226 ◽

2020 ◽

Author(s):

Christiaan H. van Dorp ◽

Jessica M. Conway ◽

James B. Whitney ◽

Dan H. Barouch ◽

Alan S. Perelson

Keyword(s):

Growth Rate ◽

Viral Load ◽

Antiretroviral Therapy ◽

Treatment Interruption ◽

Latent Reservoir ◽

Viral Rebound ◽

Viral Growth ◽

Art Initiation ◽

Reactivation Event ◽

Hiv 1

AbstractIn order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate, and a 11% decrease of the viral growth rate. We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.Author SummaryHIV-1 persists during suppressive antiretroviral therapy (ART) due to a reservoir of latently infected cells. When ART is stopped, HIV generally rebounds within a few weeks. However, there is a small fraction of patients that do not rebound over a period of months or years. A variety of treatments are being tested for their ability to reduce the size of the latent reservoir, to induce effective immune responses against the virus, or to prevent or prolong the time to viral rebound after ART interruption. These novel treatments are typically first tested in SIV infected macaques, and the efficacy of the treatment assessed by interrupting ART and measuring the time to viral rebound. Here, we develop and test a mathematical and statistical model that describes the process of viral rebound. The model can be used for statistical inference of the efficacy of newly developed treatments. Importantly, the model takes into account that multiple recrudescence events can precede rebound. We test the model using data from early treated SIV infected macaques.

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