scholarly journals Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yannic C. Bartsch ◽  
Carolin Loos ◽  
Evan Rossignol ◽  
Jesse M. Fajnzylber ◽  
Dansu Yuan ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Transcriptional Activity ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Hiv Disease ◽  
Plasma Viremia ◽  
Immunological Factors ◽  
Kinetics Of

ABSTRACT Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies. IMPORTANCE Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.

scholarly journals Kinetics of Plasma HIV Rebound in the Era of Modern Antiretroviral Therapy

2020 ◽  
Vol 222 (10) ◽  
pp. 1655-1659 ◽  
Author(s):  
Michael C Sneller ◽  
Erin D Huiting ◽  
Katherine E Clarridge ◽  
Catherine Seamon ◽  
Jana Blazkova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Therapeutic Efficacy ◽  
Historical Data ◽  
Modern Art ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Kinetics Of

Abstract Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.

scholarly journals Modeling of Antilatency Treatment in HIV: What Is the Optimal Duration of Antiretroviral Therapy-Free HIV Remission?

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Deborah Cromer ◽  
Mykola Pinkevych ◽  
Thomas A. Rasmussen ◽  
Sharon R. Lewin ◽  
Stephen J. Kent ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Drug Exposure ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Viral Transmission ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Complete Elimination ◽  
Major Question ◽  
Uncertainty Interval

ABSTRACT A number of treatment strategies are currently being developed to promote antiretroviral therapy-free HIV cure or remission. While complete elimination of the HIV reservoir would prevent recurrence of infection, it is not clear how different remission lengths would affect viral rebound and transmission. In this work, we use a stochastic model to show that a treatment that achieves a 1-year average time to viral remission will still lead to nearly a quarter of subjects experiencing viral rebound within the first 3 months. Given quarterly viral testing intervals, this leads to an expected 39 (95% uncertainty interval [UI], 22 to 69) heterosexual transmissions and up to 262 (95% UI, 107 to 534) homosexual transmissions per 1,000 treated subjects over a 10-year period. Thus, a balance between high initial treatment levels, risk of recrudescence, and risk of transmission should be considered when assessing the “useful” or optimal length of antiretroviral therapy-free HIV remission to be targeted. We also investigate the trade-off between increasing the average duration of remission versus the risk of treatment failure (viral recrudescence) and the need for retreatment. To minimize drug exposure, we found that the optimal target of antilatency interventions is a 1,700-fold reduction in the size of the reservoir, which leads to an average time to recrudescence of 30 years. Interestingly, this is a significantly lower level of reduction than that required for complete elimination of the viral reservoir. Additionally, we show that when shorter periods are targeted, there is a real probability of viral transmission occurring between tests for viral rebound. IMPORTANCE Current treatment of HIV involves patients taking antiretroviral therapy to ensure that the level of virus remains very low or undetectable. Continuous therapy is required, as the virus persists in a latent state within cells, and when therapy is stopped, the virus rebounds, usually within 2 weeks. A major question is how to reduce the amount of persistent virus and therefore allow a delay or remission until the virus returns after ceasing therapy. In this work, we consider the probability that HIV will still rebound even after this reduction and ask what the likelihood of viral transmission would be in this case.

scholarly journals Associations between HIV-1 DNA copy number, proviral transcriptional activity, and plasma viremia in individuals off or on suppressive antiretroviral therapy

Virology ◽  
2018 ◽  
Vol 521 ◽  
pp. 51-57 ◽  
Author(s):  
Feiyu Hong ◽  
Jana L. Jacobs ◽  
Evgenia Aga ◽  
Anthony R. Cillo ◽  
Elizabeth Fyne ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Copy Number ◽  
Transcriptional Activity ◽  
Plasma Viremia ◽  
Dna Copy Number ◽  
Hiv 1

scholarly journals Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

2015 ◽  
Vol 89 (15) ◽  
pp. 7521-7535 ◽  
Author(s):  
Iart Luca Shytaj ◽  
Gabrielle Nickel ◽  
Eric Arts ◽  
Nicholas Farrell ◽  
Mauro Biffoni ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Drug Combination ◽  
Viral Reservoir ◽  
Intermittent Control ◽  
Viral Rebound ◽  
Immunodeficiency Virus

ABSTRACTOff-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4+T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir.IMPORTANCEThe HIV reservoir in CD4+T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4+T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.

scholarly journals Early Antiretroviral Therapy Prevents Viral Infection of Monocytes and Inflammation in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2020 ◽  
Vol 94 (22) ◽  
Author(s):  
Henintsoa Rabezanahary ◽  
Julien Clain ◽  
Gina Racine ◽  
Guadalupe Andreani ◽  
Ghita Benmadid-Laktout ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Simian Immunodeficiency Virus ◽  
Systemic Inflammation ◽  
Rhesus Macaques ◽  
Productive Infection ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Art Initiation ◽  
Immunodeficiency Virus

ABSTRACT Despite early antiretroviral therapy (ART), treatment interruption is associated with viral rebound, indicating early viral reservoir (VR) seeding and absence of full eradication of human immunodeficiency virus type 1 (HIV‐1) that may persist in tissues. Herein, we address the contributing role of monocytes in maintaining VRs under ART, since these cells may represent a source of viral dissemination due to their ability to replenish mucosal tissues in response to injury. To this aim, monocytes with classical (CD14+), intermediate (CD14+ CD16+), and nonclassical (CD16+) phenotypes and CD4+ T cells were sorted from the blood, spleen, and intestines of untreated and early-ART-treated simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) before and after ART interruption. Cell-associated SIV DNA and RNA were quantified. We demonstrated that in the absence of ART, monocytes were productively infected with replication-competent SIV, especially in the spleen. Reciprocally, early ART efficiently (i) prevented the establishment of monocyte VRs in the blood, spleen, and intestines and (ii) reduced systemic inflammation, as indicated by changes in interleukin-18 (IL-18) and IL-1 receptor antagonist (IL-1Ra) plasma levels. ART interruption was associated with a rebound in viremia that led to the rapid productive infection of both CD4+ T cells and monocytes. Altogether, our results reveal the benefits of early ART initiation in limiting the contribution of monocytes to VRs and SIV-associated inflammation. IMPORTANCE Despite the administration of antiretroviral therapy (ART), HIV persists in treated individuals and ART interruption is associated with viral rebound. Persistent chronic immune activation and inflammation contribute to disease morbidity. Whereas monocytes are infected by HIV/SIV, their role as viral reservoirs (VRs) in visceral tissues has been poorly explored. Our work demonstrates that monocyte cell subsets in the blood, spleen, and intestines do not significantly contribute to the establishment of early VRs in SIV-infected rhesus macaques treated with ART. By preventing the infection of these cells, early ART reduces systemic inflammation. However, following ART interruption, monocytes are rapidly reinfected. Altogether, our findings shed new light on the benefits of early ART initiation in limiting VR and inflammation.

Antiretroviral Therapy in Advanced HIV Disease: Which is the Best Regimen?

Aids Reviews ◽  
2018 ◽  
Vol 20 (1) ◽  
Author(s):  
Joaquim Burgos ◽  
Esteban Ribera ◽  
Vicenç Falcó
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Disease ◽  
Advanced Hiv Disease

Evaluating the efficacy of intra-articular injections of platelet rich plasma (PRP) in rheumatoid arthritis patients and its impact on inflammatory cytokines, disease activity and quality of life.

2020 ◽  
Vol 16 ◽  
Author(s):  
Dalia S. Saif ◽  
Nagwa N. Hegazy ◽  
Enas S. Zahran
Keyword(s):  
Quality Of Life ◽  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Inflammatory Cytokines ◽  
Platelet Rich Plasma ◽  
Joint Inflammation ◽  
Monthly Interval ◽  
Post Injection ◽  
Tnf Α

Background: Among rheumatoid arthritis patients (RA), general disease activity is well regulated by diseasemodifying anti-rheumatic medications (DMARDS), but sometimes local inflammation still persists among a few joints. Adjuvant modern molecular interventions as Platelet Rich Plasma (PRP) with a suggested down regulating effect on inflammatory mediators has a proven effect in management of RA. We aim to evaluate the therapeutic effect of intra-articular PRP versus steroid in RA patients and their impact on inflammatory cytokines IL1B , TNF α, local joint inflammation, disease activity and quality of life (QL). Methods: Open labeled parallel randomized control clinical trial was carried out on 60 RA patients randomly divided into 2 groups, Group 1: included 30 patients received 3 intra-articular injections of PRP at monthly interval, Group 2: included 30 patients received single intra-articular injection of steroid. They were subjected to clinical, laboratory, serum IL1B and TNF α assessment at baseline and at 3, 6 months post injection. Results: Patients of both groups showed improvements in their scores of evaluating tools at 3months post injection and this improvement was persistent in the PRP group up to 6 months post injection while it was continued only for 3 months in the steroid group. Conclusions: PRP is a safe, effective and useful therapy in treating RA patients who had insufficient response and persistent pain and inflammation in just one or two joints through its down regulating effect on inflammatory cytokines IL1B, TNF α with subsequent improvement of local joint inflammation, disease activity and QL.

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