A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection

Sneller, Michael C.; Justement, J. Shawn; Gittens, Kathleen; Petrone, Mary E.; Clarridge, Katherine E.; Proschan, Michael A.; Kwan, Richard; Shi, Victoria; Blažková, Jana; Refsland, Eric W.; Morris, Daryl E.; Cohen, Kristen W.; McElrath, M. Juliana; Xu, Rong; Egan, Michael A.; Eldridge, John H.; Benko, Erika; Kovacs, Colin; Moir, Susan; Chun, Tae‐Wook; Fauci, Anthony S.

doi:10.1126/scitranslmed.aan8848

Cited by 101 publications

(98 citation statements)

References 35 publications

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“…Here, we used the extensive sampling available in the clinical trial A5340 to assess the effect of ATIs in HIV-infected individuals who initiated ART during chronic infection. We assessed peripheral latent virus after at least 6 months higher levels of viremia prior to ART reinitiation (37), these types of analyses should be reconsidered.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

Salantes¹,

Zheng²,

Mampe³

et al. 2018

Journal of Clinical Investigation

121

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Section: Discussionmentioning

confidence: 99%

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

Salantes¹,

Zheng²,

Mampe³

et al. 2018

Journal of Clinical Investigation

121

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show abstract

“…Up until now, the best-studied PTCs are the VISCONTI cohort (3,22), but other isolated cases of PTCs have also been described (18,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). In the VISCONTI study, 14 acutely treated participants were found to have levels of HIV DNA that were substantially lower than that of ART-treated individuals previously described in the literature (3).…”

Section: Discussionmentioning

confidence: 99%

“…Defective proviral genome copies are associated with levels of CA-RNA and timing to viral rebound. Levels of intracellular HIV RNA expression have been shown to predict the timing of viral rebound after treatment interruption (1,18). Thus, we assessed whether levels of intact provirus correlated with both levels of CA-RNA, as well as timing to viral rebound.…”

Section: No Differences Between Ptcs and Ncs In The Clonal Expansion mentioning

confidence: 99%

HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers

Sharaf

Lee

Sun

et al. 2018

Journal of Clinical Investigation

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HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

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“…Sneller et al [3] conducted a clinical trial of immunotherapy with a DNA vaccine prime followed by a VSV/gag vector boost in HIV-infected adults. The subjects started ART during the acute or early phase of HIV infection, within 28 days (median) after diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is not currently possible to cure HIV infection with ART drugs alone. In adults, even after years of complete viral control by ART, withdrawal of ART leads to viral rebound within four to six weeks in most cases [2,3]. The drugs must be taken for life.…”

mentioning

confidence: 99%

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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A randomized controlled safety/efficacy trial of therapeutic vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection

Cited by 101 publications

References 35 publications

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption

HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers

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

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