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.

scholarly journals Infectious Virus Persists in CD4+T Cells and Macrophages in Antiretroviral Therapy-Suppressed Simian Immunodeficiency Virus-Infected Macaques

2019 ◽  
Vol 93 (15) ◽  
Author(s):  
Celina M. Abreu ◽  
Rebecca T. Veenhuis ◽  
Claudia R. Avalos ◽  
Shelby Graham ◽  
Suzanne E. Queen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Infectious Virus ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Hiv Cure ◽  
Macaque Model ◽  
Immunodeficiency Virus ◽  
Latently Infected

ABSTRACTUnderstanding the cellular and anatomical sites of latent virus that contribute to human immunodeficiency virus (HIV) rebound is essential for eradication. In HIV-positive patients, CD4+T lymphocytes comprise a well-defined functional latent reservoir, defined as cells containing transcriptionally silent genomes able to produce infectious virus once reactivated. However, the persistence of infectious latent virus in CD4+T cells in compartments other than blood and lymph nodes is unclear. Macrophages (Mϕ) are infected by HIV/simian immunodeficiency virus (SIV) and are likely to carry latent viral genomes during antiretroviral therapy (ART), contributing to the reservoir. Currently, the gold standard assay used to measure reservoirs containing replication-competent virus is the quantitative viral outgrowth assay (QVOA). Using an SIV-macaque model, the CD4+T cell and Mϕ functional latent reservoirs were measured in various tissues using cell-specific QVOAs. Our results showed that blood, spleen, and lung in the majority of suppressed animals contain latently infected Mϕs. Surprisingly, the numbers of CD4+T cells, monocytes, and Mϕs carrying infectious genomes in blood and spleen were at comparable frequencies (∼1 infected cell per million). We also demonstrate thatex vivoviruses produced in the Mϕ QVOA are capable of infecting activated CD4+T cells. These results strongly suggest that latently infected tissue Mϕs can reestablish productive infection upon treatment interruption. This study provides the first comparison of CD4+T cell and Mϕ functional reservoirs in a macaque model. It is the first confirmation of the persistence of latent genomes in monocytes in blood and Mϕs in the spleen and lung of SIV-infected ART-suppressed macaques. Our results demonstrate that transcriptionally silent genomes in Mϕs can contribute to viral rebound after ART interruption and should be considered in future HIV cure strategies.IMPORTANCEThis study suggests that CD4+T cells found throughout tissues in the body can contain replication-competent SIV and contribute to rebound of the virus after treatment interruption. In addition, this study demonstrates that macrophages in tissues are another cellular reservoir for SIV and may contribute to viral rebound after treatment interruption. This new insight into the size and location of the SIV reservoir could have great implications for HIV-infected individuals and should be taken into consideration for the development of future HIV cure strategies.

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

2019 ◽  
Vol 93 (8) ◽  
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.

scholarly journals Impact of Treatment Interruption on HIV Reservoirs and Lymphocyte Subsets in Individuals Who Initiated Antiretroviral Therapy During the Early Phase of Infection

2019 ◽  
Vol 220 (2) ◽  
pp. 270-274 ◽  
Author(s):  
Erin D Huiting ◽  
Kathleen Gittens ◽  
J Shawn Justement ◽  
Victoria Shi ◽  
Jana Blazkova ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Early Phase ◽  
Lymphocyte Subsets ◽  
Treatment Interruption ◽  
Therapeutic Strategies ◽  
Clinical Protocols ◽  
Analytical Treatment ◽  
Hiv Reservoirs ◽  
Immunodeficiency Virus

Abstract Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

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

2016 ◽  
Vol 3 (2) ◽  
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.

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.

scholarly journals Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

2019 ◽  
Author(s):  
Ria Goswami ◽  
Ashley N. Nelson ◽  
Joshua J. Tu ◽  
Maria Dennis ◽  
Liqi Feng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rhesus Macaque ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Short Term ◽  
Analytical Treatment ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Infant Rhesus

ABSTRACTTo achieve long-term viral remission in HIV-infected children, novel strategies beyond early anti-retroviral therapy (ART) will be necessary. Identifying clinical predictors of 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 potential risks of treatment interruption. To facilitate identification of biomarkers predicting viral rebound, we have developed an infant rhesus macaque (RM) model of oral 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 post-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 documented that infant and adult macaques have similar SHIV replication and rebound kinetics and equally potent virus-specific humoral immune responses. Finally, we validated our models by confirming a well-established correlate of time to viral rebound, namely 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 pre-clinically assess novel therapies to achieve a pediatric HIV functional cure.IMPORTANCENovel 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, 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 non-human primate models of HIV rebound. In this study, we developed an infant RM model of oral Simian/Human Immunodeficiency virus infection expressing clade C HIV Env, and short-term ART followed by ATI, longitudinally characterizing immune responses to viral infection during ART and post-ATI. Additionally, we compared this infant RM model to an analogous adult RM rebound model and identified virologic and immunologic correlates of time to viral rebound post-ATI.

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 Circulating CD30+CD4+ T Cells Increase Before Human Immunodeficiency Virus Rebound After Analytical Antiretroviral Treatment Interruption

2019 ◽  
Vol 221 (7) ◽  
pp. 1146-1155 ◽  
Author(s):  
Cecilia A Prator ◽  
Cassandra Thanh ◽  
Shreya Kumar ◽  
Tony Pan ◽  
Michael J Peluso ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Surrogate Marker ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Time Points ◽  
Immunodeficiency Virus

Abstract Background Identification of nonviral markers of human immunodeficiency virus (HIV) infection that increase before viral rebound during analytical treatment interruption (ATI) may affect HIV persistence research. We previously showed that HIV ribonucleic acid (RNA) is enriched in CD30+CD4+ T cells in many individuals. Here, we studied CD30+CD4+ T-cell dynamics before ATI, during ATI (before detectable plasma RNA), and after HIV rebound. Methods Peripheral blood mononuclear cells from 23 participants collected longitudinally from 5 Adult AIDS Clinical Trials Group studies incorporating ATI were included in this study. Flow cytometric characterization of expression of CD30 and markers of T-cell activation and exhaustion were performed along with HIV-1 RNA and deoxyribonucleic acid quantification and measurement of soluble plasma CD30 and CD30 ligand. Results The percentage of CD4+ T cells expressing CD30 significantly increased from pre-ATI to postinterruption time points before detectible viremia (1.65 mean relative increase, P = .005). Seventy-seven percent of participants experienced an increase in CD30+ cells before viral rebound. In contrast, there were no significant differences between pre-ATI and postinterruption pre-rebound time points in percentages of lymphocytes expressing CD69, CD38/HLA-DR, or PD-1 until after HIV recrudescence. Conclusions CD30 may be a surrogate marker of early replication or viral transcriptional activity before detection by routine peripheral blood sampling.

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)

2019 ◽  
Vol 74 (7) ◽  
pp. 2039-2046 ◽  
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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