scholarly journals Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?

2021 ◽  
Vol 12 ◽  
Author(s):  
Alexander O. Pasternak ◽  
Christina K. Psomas ◽  
Ben Berkhout
Keyword(s):  
Post Treatment ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Proviral Integration ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Therapy Interruption ◽  
Integration Sites

Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function. However, due to the persistence of long-lived HIV reservoirs, therapy interruption almost inevitably leads to a fast viral rebound. A small percentage of individuals who are able to control HIV replication for extended periods after therapy interruption are of particular interest because they may represent a model of long-term HIV remission without ART. These individuals are characterized by a limited viral reservoir and low reservoir measures can predict post-treatment HIV remission. However, most individuals with a low reservoir still experience fast viral rebound. In this Perspective, we discuss the possible reasons behind this and propose to develop an integral profile, composed of viral and host biomarkers, that could allow the accurate prediction of post-treatment HIV remission. We also propose to incorporate information on the chromatin context of the proviral integration sites into the characterization of the HIV reservoir, as this likely influences the reactivation capacity of latent proviruses and, together with the actual number of intact proviruses, contributes to the replication competence of the reservoir.

scholarly journals Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag-Specific T-Cell Responses

2015 ◽  
Vol 2 (4) ◽  
Author(s):  
Sabine Kinloch-de Loes ◽  
Lucy Dorrell ◽  
Hongbing Yang ◽  
Gareth A. D. Hardy ◽  
Sabine Yerly ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Viral Reservoir ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Cellular Immune ◽  
Drug Free ◽  
Human Immunodeficiency Virus 1

Abstract Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4+/CD8+ T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome.

scholarly journals Continuous Viral Escape and Selection by Autologous Neutralizing Antibodies in Drug-Naïve Human Immunodeficiency Virus Controllers

2008 ◽  
Vol 83 (2) ◽  
pp. 662-672 ◽  
Author(s):  
Madhumita Mahalanabis ◽  
Pushpa Jayaraman ◽  
Toshiyuki Miura ◽  
Florencia Pereyra ◽  
E. Michael Chester ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Time Frame ◽  
Continuous Selection ◽  
Viral Escape ◽  
Elite Controllers ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Short Time

ABSTRACT We assessed differences in the character and specificity of autologous neutralizing antibodies (ANAbs) against individual viral variants of the quasispecies in a cohort of drug-naïve subjects with long-term controlled human immunodeficiency virus type 1 (HIV-1) infection and moderate levels of broad heterologous neutralizing antibodies (HNAb). Functional plasma virus showed continuous env evolution despite a short time frame and low levels of viral replication. Neutralization-sensitive variants dominated in subjects with intermittent viral blips, while neutralization-resistant variants predominated in elite controllers. By sequence analysis of this panel of autologous variants with various sensitivities to neutralization, we identified more than 30 residues in envelope proteins (Env) associated with resistance or sensitivity to ANAbs. The appearance of new sensitive variants is consistent with a model of continuous selection and turnover. Strong ANAb responses directed against autologous Env variants are present in long-term chronically infected individuals, suggesting a role for these responses in contributing to the durable control of HIV replication.

scholarly journals Characterization of Human Immunodeficiency Virus Type 1 vif Gene in Long-Term Asymptomatic Individuals

Virology ◽  
2000 ◽  
Vol 276 (1) ◽  
pp. 169-180 ◽  
Author(s):  
Gherici Hassaı̈ne ◽  
Isabelle Agostini ◽  
Daniel Candotti ◽  
Gilles Bessou ◽  
Miguel Caballero ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Asymptomatic Individuals

Myeloid Expansion after Insertional Activation of MDS1/EVI1, PRDM16 and SETBP1 in a Successful Chronic Granulomatous Gene Therapy Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 198-198
Author(s):  
Kerstin Schwarzwaelder ◽  
Manfred Schmidt ◽  
Marion G. Ott ◽  
Stefan Stein ◽  
Hanno Glimm ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Side Effects ◽  
High Efficiency ◽  
Post Treatment ◽  
Multiple Time ◽  
Gene Therapy Trial ◽  
Vector Integration ◽  
Integration Sites ◽  
Therapy Trial

Abstract Successful gene therapy trials of ADA-SCID and SCID-X1 demonstrated the curative potential of oncoretroviral gene transfer. Integration of the retroviral vectors used in these studies has been thought to be a random process but severe side effects in gene therapy and in vitro studies revealed preferred insertion of these vectors mainly around transcription start sites. In SCID patients proliferation advantage of gene corrected cells was one reason for the success of the trials, whereas in the most recent chronic granulomatous disease (CGD) gene therapy trial corrected cells do not have any selective advantage therefore the two patients received mild busulfan treatment before transplantation. High efficiency transduction and conditioning have helped in the successful correction of the patients. Peripheral blood granulocytes show a stable expression (>10%) of the transgene (gp91phox) in patient 1 (15 months post treatment) as well as in patient 2 (11 months post treatment). We reasoned that, unlike T cells, which have the capability to proliferate independent of their bone marrow progenitors, granulocytes more directly reflect the influence of retrovirus insertion, and should therefore allow to closely monitor clonal fate in vivo and its potential relation to vector insertion. To study the clonality of the corrected myelopoiesis, the long term activity of individual cell clones, and the distribution of integration sites in active cells we carried out high sensitive LAM-PCR. The highly polyclonal composition of transduced cells forming myelopoiesis caused the sustained expression of gp91phox. Individual clones carrying the transgene could be detected at multiple time points. To define whether corrected cells have a proliferation advantage due to their vector integration we started large-scale sequencing and mapping of involved insertion sites. We here present >700 unique mappable integration sites of the two treated patients. The distribution of the SFFV based retroviral vector integration sites in this trial turned non random 5 months after transplantation. Corrected long-term myelopoiesis expanded 3- to 5- fold in the two patients due to activating common integration sites (CIS) in the zinc finger transcription factor homologs MDS1/EVI1, PRDM16, or in SETBP1, suggesting that these genes influence regulation of normal long-term hematopoiesis in humans. Our data indicate that the therapeutic benefit in this trial was activated through insertional side effects, therefore our findings have important implications in novel gene therapy approaches.

scholarly journals Viral Dynamics during Structured Treatment Interruptions of Chronic Human Immunodeficiency Virus Type 1 Infection

2002 ◽  
Vol 76 (3) ◽  
pp. 968-979 ◽  
Author(s):  
Simon D. W. Frost ◽  
Javier Martinez-Picado ◽  
Lidia Ruiz ◽  
Bonaventura Clotet ◽  
Andrew J. Leigh Brown
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
Immune Responses ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Viral Dynamics ◽  
Viral Loads ◽  
Treatment Interruptions ◽  
Immunodeficiency Virus

ABSTRACT Although antiviral agents which block human immunodeficiency virus (HIV) replication can result in long-term suppression of viral loads to undetectable levels in plasma, long-term therapy fails to eradicate virus, which generally rebounds after a single treatment interruption. Multiple structured treatment interruptions (STIs) have been suggested as a possible strategy that may boost HIV-specific immune responses and control viral replication. We analyze viral dynamics during four consecutive STI cycles in 12 chronically infected patients with a history (>2 years) of viral suppression under highly active antiretroviral therapy. We fitted a simple model of viral rebound to the viral load data from each patient by using a novel statistical approach that allows us to overcome problems of estimating viral dynamics parameters when there are many viral load measurements below the limit of detection. There is an approximate halving of the average viral growth rate between the first and fourth STI cycles, yet the average time between treatment interruption and detection of viral loads in the plasma is approximately the same in the first and fourth interruptions. We hypothesize that reseeding of viral reservoirs during treatment interruptions can account for this discrepancy, although factors such as stochastic effects and the strength of HIV-specific immune responses may also affect the time to viral rebound. We also demonstrate spontaneous drops in viral load in later STIs, which reflect fluctuations in the rates of viral production and/or clearance that may be caused by a complex interaction between virus and target cells and/or immune responses.

Long-Term Polyclonal and Stable Gene Transfer into Rhesus Repopulating Hematopoietic Stem Cells Using a Simian Immunodeficiency Virus-Based Lentiviral Vector System.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3259-3259
Author(s):  
Yoo-Jin Kim ◽  
Nadia L. Hussein ◽  
Peiman Hematti ◽  
Bum-Kee Hong ◽  
Boris Calmels ◽  
...  
Keyword(s):  
B Cells ◽  
Gene Transfer ◽  
Simian Immunodeficiency Virus ◽  
Vector System ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Immunodeficiency Virus ◽  
Integration Sites ◽  
High Level

Abstract Murine leukemia virus (MLV) vectors have been studied extensively in animal models and utilized for over a decade in clinical trials of gene therapy directed at hematopoietic stem and progenitor cells MLV have a number of limitations, including inefficient transduction of quiescent cells and difficulty in maintaining stable high-level expression. More recently concerns have arisen regarding their safety regarding activation of adjacent proto-oncogenes and resultant leukemogenesis. We have previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus CD34+ cells, resulting in high-level in vivo marking with transduced progeny cells up to one year post-transplantation.(Hanawa et al, 2004) A comparison of vector integration sites in these animals compared to animals receiving MLV-transduced cells revealed different patterns, showing that SIV integrants strongly favored entire transcription units and gene-dense regions of the genome, compared to MLV that favored regions surrounding transcription start sites.(Hematti et al, 2004). Animals receiving MLV-transduced cells had highly non-random engraftment with integrants in or near the the MDS1/EVI1 gene complex. To evaluate long-term safety implications of the SIV vector-mediated CD34+ cell gene transfer, we analyzed the insertional sites in granulocytes, T cell, and B cells from 3 rhesus macaques which were transplanted three years ago with transduced, autologous cytokine-mobilized peripheral blood CD34+ cells. All three animals continued to show significant marking and expression levels in T cells, B cells and granulocytes, with mean GFP + levels of 6.7% (range, 3.3–13.0%), 7.4% (4.2–13.4%) and 5.6% (3.1–10.5%), respectively. Vector insertion site analysis by linear amplification-mediated PCR method at three years continued to show highly polyclonal reconstitution. Subsequent cloning and sequencing data confirmed long-term polyclonality with vector-containing cells and there was no evidence for any worrisome common integration sites, with no integrants detected in the MDS1/EVI1 region, in contrast to results with the MLV vector. These results indicate that the SIV vector system can result in stable and efficient long-term expression in progeny of transduced CD34+ cells, without the worrisome integration profile previously reported in our model with MLV vectors.

scholarly journals Residual Proviral Reservoirs: A High Risk for HIV Persistence and Driving Forces for Viral Rebound after Analytical Treatment Interruption

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 335
Author(s):  
Xiaolei Wang ◽  
Huanbin Xu
Keyword(s):  
Driving Forces ◽  
Treatment Interruption ◽  
Current Treatment ◽  
The Body ◽  
Viral Rebound ◽  
Hiv Replication ◽  
Analytical Treatment ◽  
Hiv Persistence ◽  
Immunodeficiency Virus ◽  
Undetectable Viremia

Antiretroviral therapy (ART) has dramatically suppressed human immunodeficiency virus (HIV) replication and become undetectable viremia. However, a small number of residual replication-competent HIV proviruses can still persist in a latent state even with lifelong ART, fueling viral rebound in HIV-infected patient subjects after treatment interruption. Therefore, the proviral reservoirs distributed in tissues in the body represent a major obstacle to a cure for HIV infection. Given unavailable HIV vaccine and a failure to eradicate HIV proviral reservoirs by current treatment, it is crucial to develop new therapeutic strategies to eliminate proviral reservoirs for ART-free HIV remission (functional cure), including a sterilizing cure (eradication of HIV reservoirs). This review highlights recent advances in the establishment and persistence of HIV proviral reservoirs, their detection, and potential eradication strategies.

scholarly journals Analytical Treatment Interruption after Short-Term Antiretroviral Therapy in a Postnatally Simian-Human Immunodeficiency Virus-Infected Infant Rhesus Macaque Model

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Ria Goswami ◽  
Ashley N. Nelson ◽  
Joshua J. Tu ◽  
Maria Dennis ◽  
Liqi Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Short Term ◽  
Analytical Treatment ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Immunodeficiency Virus

ABSTRACT To achieve long-term viral remission in human immunodeficiency virus (HIV)-infected children, novel strategies beyond early antiretroviral therapy (ART) will be necessary. Identifying clinical predictors of the time to viral rebound upon ART interruption will streamline the development of novel therapeutic strategies and accelerate their evaluation in clinical trials. However, identification of these biomarkers is logistically challenging in infants, due to sampling limitations and the potential risks of treatment interruption. To facilitate the identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral simian-human immunodeficiency virus (SHIV) SHIV.CH505.375H.dCT challenge and analytical treatment interruption (ATI) after short-term ART. We used this model to characterize SHIV replication kinetics and virus-specific immune responses during short-term ART or after ATI and demonstrated plasma viral rebound in 5 out of 6 (83%) infants. We observed a decline in humoral immune responses and partial dampening of systemic immune activation upon initiation of ART in these infants. Furthermore, we monitored SHIV replication and rebound kinetics in infant and adult RMs and found that both infants and adults demonstrated equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of the time to viral rebound, namely, the pre-ART plasma viral load, as well as identified additional potential humoral immune correlates. Thus, this model of infant ART and viral rebound can be used and further optimized to define biomarkers of viral rebound following long-term ART as well as to preclinically assess novel therapies to achieve a pediatric HIV functional cure. IMPORTANCE Novel interventions that do not rely on daily adherence to ART are needed to achieve sustained viral remission for perinatally infected children, who currently rely on lifelong ART. Considering the risks and expense associated with ART interruption trials, the identification of biomarkers of viral rebound will prioritize promising therapeutic intervention strategies, including anti-HIV Env protein therapeutics. However, comprehensive studies to identify those biomarkers are logistically challenging in human infants, demanding the need for relevant nonhuman primate models of HIV rebound. In this study, we developed an infant RM model of oral infection with simian-human immunodeficiency virus expressing clade C HIV Env and short-term ART followed by ATI, longitudinally characterizing the immune responses to viral infection during ART and after ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of the time to viral rebound after ATI.

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