Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy

Whitney, James B.; Lim, So-Yon; Osuna, Christa E.; Kublin, Jessica; Chen, Elsa; Yoon, Gyeol; Liu, Po Ting; Abbink, Peter; Borducci, Erica N.; Hill, Alison L.; Lewis, Mark G.; Geleziunas, Romas; Robb, Merlin L.; Michael, Nelson L.; Barouch, Dan H.

doi:10.1038/s41467-018-07881-9

Cited by 58 publications

(74 citation statements)

References 23 publications

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“…Whitney et al confirmed this for SIVmac in rhesus macaques and showed that three days' delay before starting ART would allow establishment of the viral reservoir [11,12]. Even after 6 months of complete virological control on ART, with no circulating virus detected, four of four [11] or five of five macaques rebounded within a few weeks of ART interruption [12]. In general, rebound competency depends on several factors, including: dose of SIV, route of infection, timing of ART initiation, and duration of ART treatment, as well as the challenge virus.…”

Section: Discussionmentioning

confidence: 87%

“…We infected eight macaques with SIVmac251 and initiated ART 3 days later, to allow sufficient time to seed the viral reservoir. If we started ART too early, it could reduce the number of viral rebounds in the control group after ART release [10,12]. But if we waited too long, the expanded viral reservoir could overwhelm immune control in the vaccine group.…”

Section: Discussionmentioning

confidence: 99%

“…Tsai et al originally demonstrated that ART can be delayed up to one day after infection and still prevent seeding of the latent reservoir for SIVmne (SIV isolated from a pigtailed macaque) in cynomolgus macaques [10]. Whitney et al confirmed this for SIVmac in rhesus macaques and showed that three days' delay before starting ART would allow establishment of the viral reservoir [11,12]. Even after 6 months of complete virological control on ART, with no circulating virus detected, four of four [11] or five of five macaques rebounded within a few weeks of ART interruption [12].…”

Section: Discussionmentioning

confidence: 99%

“…During Stage III, we withdrew ART and monitored plasma viremia for signs of a viral rebound. If a three day head start was sufficient to seed the viral reservoir, this would be shown by viral rebound in the control group within 4 to 8 weeks [11,12]. If immunotherapy had an antiviral effect, it could prevent or delay viral rebound in the vaccine group.…”

Section: Methodsmentioning

confidence: 99%

“…In our study, we exposed macaques to high dose mucosal challenge with pathogenic SIV-mac251. We gave the infection a three-day head start before initiating ART, using a triple drug regimen employed previously by Whitney et al [11,12]. Under these conditions three to seven days were sufficient to establish a rebound competent viral reservoir in most animals, as shown by rebound viremia when ART was withdrawn after 6 months of treatment.…”

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confidence: 99%

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Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques

et al. 2020

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Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine "take" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral PLOS ONE PLOS ONE | https://doi.org/10.rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans. PLOS ONE SIV remissionPLOS ONE | https://doi.org/10.Fig 1. Study plan.Stage I: high-dose mucosal challenge of rhesus macaques with SIVmac251 by the intra-rectal route. ART was delayed until day 3 to allow establishment of the latent viral reservoir. Stage II: the vaccine group was immunized with DNA/gag expression plasmid followed by rubella/gag vectors, while on ART. Controls received control DNA and empty rubella vaccine. Stage III: after 27 weeks, ART was withdrawn, and the animals were followed for viral rebound. Subsequently, CD8 + T cells were depleted to release latent virus.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques

et al. 2020

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Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Yang

Feng

et al. 2019

Advanced Science

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The latent viral reservoir is the source of viral rebound after interruption of antiretroviral therapy (ART) and is the major obstacle in eradicating the latent human immunodeficiency virus‐1 (HIV‐1). In this study, arsenic class of mineral, arsenic trioxide, clinically approved for treating acute promyelocytic leukemia, is demonstrated to reactivate latent provirus in CD4+ T cells from HIV‐1 patients and Simian immunodeficiency virus (SIV)‐infected macaques, without significant systemic T cell activation and inflammatory responses. In a proof‐of‐concept study using chronically SIVmac239‐infected macaques, arsenic trioxide combined with ART delays viral rebound after ART termination, reduces the integrated SIV DNA copies in CD4+ T cells, and restores CD4+ T cells counts in vivo. Most importantly, half of arsenic trioxide‐treated macaques show no detectable viral rebound in the plasma for at least 80 days after ART discontinuation. Mechanistically, the study reveals that CD4 receptors and CCR5 co‐receptors of CD4+ T cells are significantly downregulated by arsenic trioxide treatment, which reduces susceptibility to infection after provirus reactivation. Furthermore, an increase in SIV‐specific immune responses after arsenic trioxide treatment may contribute to suppression of viral rebound. This work suggests that arsenic trioxide in combination with ART is a novel regimen in down‐sizing or even eradicating latent HIV‐1 reservoir.

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Clinical trials and recent progress in HIV vaccine development

Zubair,

Bibi,

Habib

et al. 2024

Funct Integr Genomics

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Prevention of SIVmac251 reservoir seeding in rhesus monkeys by early antiretroviral therapy

Cited by 58 publications

References 23 publications

Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques

Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques

Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Clinical trials and recent progress in HIV vaccine development

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