scholarly journals Faculty Opinions recommendation of TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy.

2018 ◽  
Author(s):  
Willy Bogers
Keyword(s):  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Viral Reservoir

scholarly journals Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

2021 ◽  
Vol 17 (6) ◽  
pp. e1009686
Author(s):  
Taina T. Immonen ◽  
Christine M. Fennessey ◽  
Leslie Lipkey ◽  
Abigail Thorpe ◽  
Gregory Q. Del Prete ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Treatment Strategies ◽  
Viral Reservoir ◽  
Virus Population ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
The Impact ◽  
Hiv 1

Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track individual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of individual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

scholarly journals TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy

2018 ◽  
Vol 10 (439) ◽  
pp. eaao4521 ◽  
Author(s):  
So-Yon Lim ◽  
Christa E. Osuna ◽  
Peter T. Hraber ◽  
Joe Hesselgesser ◽  
Jeffrey M. Gerold ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Viral Reservoir

scholarly journals SMAC Mimetic Plus Triple-Combination Bispecific HIVxCD3 Retargeting Molecules in SHIV.C.CH505-Infected, Antiretroviral Therapy-Suppressed Rhesus Macaques

2020 ◽  
Vol 94 (21) ◽  
Author(s):  
Amir Dashti ◽  
Chevaughn Waller ◽  
Maud Mavigner ◽  
Nils Schoof ◽  
Katharine J. Bar ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Viral Reservoir ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
The Impact ◽  
Hiv 1

ABSTRACT The “shock-and-kill” human immunodeficiency virus type 1 (HIV-1) cure strategy involves latency reversal followed by immune-mediated clearance of infected cells. We have previously shown that activation of the noncanonical NF-κB pathway using an inhibitor of apoptosis (IAP), AZD5582, reverses HIV/simian immunodeficiency virus (SIV) latency. Here, we combined AZD5582 with bispecific HIVxCD3 DART molecules to determine the impact of this approach on persistence. Rhesus macaques (RMs) (n = 13) were infected with simian/human immunodeficiency virus SHIV.C.CH505.375H.dCT, and triple antiretroviral therapy (ART) was initiated after 16 weeks. After 42 weeks of ART, 8 RMs received a cocktail of 3 HIVxCD3 DART molecules having human A32, 7B2, or PGT145 anti-HIV-1 envelope (Env) specificities paired with a human anti-CD3 specificity that is rhesus cross-reactive. The remaining 5 ART-suppressed RMs served as controls. For 10 weeks, a DART molecule cocktail was administered weekly (each molecule at 1 mg/kg of body weight), followed 2 days later by AZD5582 (0.1 mg/kg). DART molecule serum concentrations were well above those considered adequate for redirected killing activity against Env-expressing target cells but began to decline after 3 to 6 weekly doses, coincident with the development of antidrug antibodies (ADAs) against each of the DART molecules. The combination of AZD5582 and the DART molecule cocktail did not increase on-ART viremia or cell-associated SHIV RNA in CD4+ T cells and did not reduce the viral reservoir size in animals on ART. The lack of latency reversal in the model used in this study may be related to low pre-ART viral loads (median, <105 copies/ml) and low preintervention reservoir sizes (median, <102 SHIV DNA copies/million blood CD4+ T cells). Future studies to assess the efficacy of Env-targeting DART molecules or other clearance agents to reduce viral reservoirs after latency reversal may be more suited to models that better minimize immunogenicity and have a greater viral burden. IMPORTANCE The most significant barrier to an HIV-1 cure is the existence of the latently infected viral reservoir that gives rise to rebound viremia upon cessation of ART. Here, we tested a novel combination approach of latency reversal with AZD5582 and clearance with bispecific HIVxCD3 DART molecules in SHIV.C.CH505-infected, ART-suppressed rhesus macaques. We demonstrate that the DART molecules were not capable of clearing infected cells in vivo, attributed to the lack of quantifiable latency reversal in this model with low levels of persistent SHIV DNA prior to intervention as well as DART molecule immunogenicity.

scholarly journals Short-Term Pegylated Interferon α2a Treatment Does Not Significantly Reduce the Viral Reservoir of Simian Immunodeficiency Virus-Infected, Antiretroviral Therapy-Treated Rhesus Macaques

2018 ◽  
Vol 92 (14) ◽  
Author(s):  
David Palesch ◽  
Steven E. Bosinger ◽  
Maud Mavigner ◽  
James M. Billingsley ◽  
Cameron Mattingly ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Virus Replication ◽  
Rhesus Macaques ◽  
Type I Interferons ◽  
Viral Reservoir ◽  
Type I ◽  
Short Term ◽  
Immunodeficiency Virus ◽  
Ifn Treatment

ABSTRACT The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and causes rapid viral rebound if treatment is interrupted. Type I interferons are immunomodulatory cytokines that induce antiviral factors and have been evaluated for the treatment of HIV-infected individuals, resulting in moderate reduction of viremia and inconclusive data about their effect on reservoir size. Here, we assessed the potential of pegylated IFN-α2a (pIFN-α2a) to reduce the viral reservoir in simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques (RMs). We found that pIFN-α2a treatment of animals in which virus replication is effectively suppressed with ART is safe and well tolerated, as no major clinical side effects were observed. By monitoring the cellular immune response during this intervention, we established that pIFN-α2a administration is not associated with either CD4 + T cell depletion or increased immune activation. Importantly, we found that interferon-stimulated genes (ISGs) were significantly upregulated in IFN-treated RMs compared to control animals, confirming that pIFN-α2a is bioactive in vivo . To evaluate the effect of pIFN-α2a administration on the viral reservoir in CD4 + T cells, we performed cell-associated proviral SIV DNA measurements in multiple tissues and assessed levels of replication-competent virus by a quantitative viral outgrowth assay (QVOA). These analyses failed to reveal any significant difference in reservoir size between IFN-treated and control animals. In summary, our data suggest that short-term type I interferon treatment in combination with suppressive ART is not sufficient to induce a significant reduction of the viral reservoir in SIV-infected RMs. IMPORTANCE The potential of type I interferons to reduce the viral reservoir has been recently studied in clinical trials in HIV-infected humans. However, given the lack of mechanistic data and the potential for safety concerns, a more comprehensive testing of IFN treatment in vivo in SIV-infected RMs is critical to provide rationale for further development of this intervention in humans. Utilizing the SIV/RM model in which virus replication is suppressed with ART, we addressed experimental limitations of previous human studies, in particular the lack of a control group and specimen sampling limited to blood. Here, we show by rigorous testing of blood and lymphoid tissues that virus replication and reservoir size were not significantly affected by pIFN-α2a treatment in SIV-infected, ART-treated RMs. This suggests that intensified and/or prolonged IFN treatment regimens, possibly in combination with other antilatency agents, are necessary to effectively purge the HIV/SIV reservoir under ART.

scholarly journals Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Samuel Long ◽  
Christine M. Fennessey ◽  
Laura Newman ◽  
Carolyn Reid ◽  
Sean P. O’Brien ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Simian Immunodeficiency Virus ◽  
Genome Sequencing ◽  
Real Time Pcr ◽  
Rhesus Macaques ◽  
Viral Reservoir ◽  
Combination Antiretroviral Therapy ◽  
Viral Dna ◽  
Immunodeficiency Virus

ABSTRACT The major obstacle to more-definitive treatment for HIV infection is the early establishment of virus that persists despite long-term combination antiretroviral therapy (cART) and can cause recrudescent viremia if cART is interrupted. Previous studies of HIV DNA that persists despite cART indicated that only a small fraction of persistent viral sequences was intact. Experimental simian immunodeficiency virus (SIV) infections of nonhuman primates (NHPs) are essential models for testing interventions designed to reduce the viral reservoir. We studied the viral genomic integrity of virus that persists during cART under conditions typical of many NHP reservoir studies, specifically with cART started within 1 year postinfection and continued for at least 9 months. The fraction of persistent DNA in SIV-infected NHPs starting cART during acute or chronic infection was assessed with a multiamplicon, real-time PCR assay designed to analyze locations that are regularly spaced across the viral genome to maximize coverage (collectively referred to as “tile assay”) combined with near-full-length (nFL) single-genome sequencing. The tile assay is used to rapidly screen for major deletions, with nFL sequence analysis used to identify additional potentially inactivating mutations. Peripheral blood mononuclear cells (PBMC) from animals started on cART within 1 month of infection, sampled at least 9 months after cART initiation, contained at least 80% intact genomes, whereas those from animals started on cART 1 year postinfection and treated for 1 year contained intact genomes only 47% of the time. The most common defect identified was large deletions, with the remaining defects caused by APOBEC-mediated mutations, frameshift mutations, and inactivating point mutations. Overall, this approach can be used to assess the intactness of persistent viral DNA in NHPs. IMPORTANCE Molecularly defining the viral reservoir that persists despite antiretroviral therapy and that can lead to rebound viremia if antiviral therapy is removed is critical for testing interventions aimed at reducing this reservoir. In HIV infection in humans with delayed treatment initiation and extended treatment duration, persistent viral DNA has been shown to be dominated by nonfunctional genomes. Using multiple real-time PCR assays across the genome combined with near-full-genome sequencing, we defined SIV genetic integrity after 9 to 18 months of combination antiretroviral therapy in rhesus macaques starting therapy within 1 year of infection. In the animals starting therapy within a month of infection, the vast majority of persistent DNA was intact and presumptively functional. Starting therapy within 1 year increased the nonintact fraction of persistent viral DNA. The approach described here allows rapid screening of viral intactness and is a valuable tool for assessing the efficacy of novel reservoir-reducing interventions.

scholarly journals Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy

Retrovirology ◽  
2014 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiao-Yong Zhan ◽  
Nina Wang ◽  
Guangjie Liu ◽  
Limei Qin ◽  
Wanwan Xu ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Viral Reservoir ◽  
Plasmodium Infection

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.

Neuro-AIDS: Current status and Challenges to Antiretroviral Drug Therapy (ART) for Its Treatment.

2020 ◽  
Vol 15 ◽  
Author(s):  
Smita P. Kakad ◽  
Sanjay J. Kshirsagar
Keyword(s):  
Nervous System ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Sensory Neuropathy ◽  
Current Status ◽  
Viral Reservoir ◽  
Viral Reservoirs ◽  
Highly Active ◽  
Aids Therapy ◽  
The Brain

Introduction: The infiltration of HIV into the brain alters the functions of the nervous system known as NeuroAIDS. It leads to neuronal defects clinically manifested by motor and cognitive dysfunctions. Materials/Methods: Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which acts as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination antiretroviral therapy. Results/Conclusions: Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful to treat neuro-AIDS and related disorders effectively.

scholarly journals Significant Depletion of CD4+T Cells Occurs in the Oral Mucosa during Simian Immunodeficiency Virus Infection with the Infected CD4+T Cell Reservoir Continuing to Persist in the Oral Mucosa during Antiretroviral Therapy

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Jeffy George ◽  
Wendeline Wagner ◽  
Mark G. Lewis ◽  
Joseph J. Mattapallil
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Simian Immunodeficiency Virus ◽  
Oral Mucosa ◽  
Mucosal Immunity ◽  
Viral Reservoir ◽  
Long Term Outcome ◽  
Immunodeficiency Virus ◽  
A Minor

Human and simian immunodeficiency virus (HIV and SIV) infections are characterized by manifestation of numerous opportunistic infections and inflammatory conditions in the oral mucosa. The loss of CD4+T cells that play a critical role in maintaining mucosal immunity likely contributes to this process. Here we show that CD4+T cells constitute a minor population of T cells in the oral mucosa and display a predominantly central memory phenotype mirroring other mucosal sites such as the rectal mucosa. Chronic SIV infection was associated with a near total depletion of CD4+T cells in the oral mucosa that appear to repopulate during antiretroviral therapy (ART). Repopulating CD4+T cells harbored a large fraction of Th17 cells suggesting that ART potentially reconstitutes oral mucosal immunity. However, a minor fraction of repopulating CD4+T cells harbored SIV DNA suggesting that the viral reservoir continues to persist in the oral mucosa during ART. Therapeutic approaches aimed at obtaining sustainable CD4+T cell repopulation in combination with strategies that can eradicate the latent viral reservoir in the oral mucosa are essential for better oral health and long-term outcome in HIV infected patients.

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