Viremic Relapse after HIV-1 Remission in a Perinatally Infected Child

Luzuriaga, Katherine; Gay, Hannah; Ziemniak, Carrie; Sanborn, Keri B.; Somasundaran, Mohan; Rainwater-Lovett, Kaitlin; Mellors, John W.; Rosenbloom, Daniel; Persaud, Deborah

doi:10.1056/nejmc1413931

Cited by 230 publications

(185 citation statements)

References 8 publications

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“…In the context of eradication studies, this underestimation of the HIV reservoir is misleading if the absence of detection is interpreted as the detection of absence. The "Boston" patients (97) and the "Mississippi baby" (98) confirmed that the latent reservoir can persist below the limit of detection of current assays, allowing the infection to recur months to years later. As with remission after cancer chemotherapy, although no residual malignant disease can be detected, it can persist and recur years later.…”

Section: Discussionmentioning

confidence: 84%

Measuring the latent reservoir in vivo

Massanella¹,

Richman²

2016

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 84%

Measuring the latent reservoir in vivo

Massanella¹,

Richman²

2016

Journal of Clinical Investigation

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“…During the curative strategies, the presence of cART will prevent CD4 ϩ T cells from becoming infected by residual virus. However, if any reservoirs of HIV-1 persist when cART is discontinued, a rebound in viremia is likely to eventually occur (3)(4)(5). For this reason, a CD8 ϩ T cell response capable of control must be developed in order to prevent residual latently infected CD4 ϩ T cells from reestablishing chronic infection.…”

Section: Discussionmentioning

confidence: 99%

Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4⁺T Cells to HIV-1-Specific CD8⁺T Cells

Walker-Sperling

Cohen

Tarwater

et al. 2015

J Virol

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The "shock and kill" model of human immunodeficiency virus type 1 (HIV-1) eradication involves the induction of transcription of HIV-1 genes in latently infected CD4 ؉ T cells, followed by the elimination of these infected CD4 ؉ T cells by CD8 ؉ T cells or other effector cells. CD8؉ T cells may also be needed to control the spread of new infection if residual infected cells are present at the time combination antiretroviral therapy (cART) is discontinued. In order to determine the time frame needed for CD8 ؉ T cells to effectively prevent the spread of HIV-1 infection, we examined the kinetics of HIV transcription and virus release in latently infected cells reactivated ex vivo. Isolated resting, primary CD4 ؉ T cells from HIV-positive (HIV؉) subjects on suppressive regimens were found to upregulate cell-associated HIV-1 mRNA within 1 h of stimulation and produce extracellular virus as early as 6 h poststimulation. In spite of the rapid kinetics of virus production, we show that CD8 ؉ T cells from 2 out of 4 viremic controllers were capable of effectively eliminating reactivated autologous CD4؉ cells that upregulate cell-associated HIV-1 mRNA. The results have implications for devising strategies to prevent rebound viremia due to reactivation of rare latently infected cells that persist after potentially curative therapy. T he goal of "shock and kill" human immunodeficiency virus (HIV) cure strategy is to selectively reactivate latent HIV type 1 (HIV-1) transcription without causing global T cell activation in order for the immune system to be able to recognize and eliminate latently infected cells (reviewed in references 1 and 2). The presence of antiretroviral drugs during treatment with latency reversal agents will prevent reactivated virus from infecting other CD4 ϩ T cells even if the kill component of the shock-and-kill strategy is not effective. However, subjects will eventually cease antiretroviral therapy (ART) after treatment is deemed to be successful. As several recent cases have shown, residual latently infected cells may lead to a rebound in viremia and the reestablishment of a chronic HIV-1 infection (3-5) even when the frequency of infected cells is lower than 1 in 150 million peripheral CD4 ϩ T cells (3). Therefore, the ability of CD8 ϩ T cells to kill newly reactivated, latently infected cells before the completion of the viral life cycle may be very important.Through viral dynamics modeling combined with viral load data, the lifetime of an infected cell has been estimated using viral load data to be around 2 days from attachment of the virion to the death of the cell (6-9). Reactivated latently infected cells, on the other hand, reinitiate the viral life cycle from proviral transcription onwards, cutting down the time from activation to virus release. When activation of latently infected CD4 ϩ T cells occurs, there is translocation of transcription factors such as NF-B and NFAT (nuclear factor of activated T cells) that allow for reactivation of the HIV-1 provirus (10-13). HIV-1-infect...

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“…In the case of the “Mississippi Child,” a perinatally infected infant who received cART from 30 hours to 18 months of age, plasma virus levels remained below the limit of detection for more than 2 years after cART interruption (Persaud et al 2013). The frequency of latently infected cells in this child was at least 2.5 logs lower than in a typical treated adult, but the child experienced sudden viral rebound 27.6 months after cART discontinuation (Luzuriaga et al 2015; Hill et al 2016). What is particularly interesting in these “near cure” cases is that the HIV + individuals had very little adaptive immunity to HIV-1, either as a result of the transplant process or very early treatment (Henrich et al 2014; Persaud et al 2013).…”

Section: Challenges Of Reservoir Reductionmentioning

confidence: 65%

“…The latent reservoir decays slowly, with a t ½ of 3.6 years, so even prolonged cART cannot to eradicate the infection in a patient’s lifetime (Finzi 1999; Siliciano et al 2003; Strain et al 2003; Crooks et al 2015). Even in HIV + individuals who are treated early or who have extremely small reservoirs as a result of bone marrow transplantation, rebound can occur, and therefore these individuals must stay on cART indefinitely (Chun et al 1999; Kaufmann et al 2004; Persaud et al 2013; Henrich et al 2014; Luzuriaga et al 2015). …”

Section: Introduction: the Case For An Hiv-1 Curementioning

confidence: 99%

Targeting the Latent Reservoir for HIV-1

2018

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Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

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Viremic Relapse after HIV-1 Remission in a Perinatally Infected Child

Cited by 230 publications

References 8 publications

Measuring the latent reservoir in vivo

Measuring the latent reservoir in vivo

Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4⁺T Cells to HIV-1-Specific CD8⁺T Cells

Targeting the Latent Reservoir for HIV-1

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Viremic Relapse after HIV-1 Remission in a Perinatally Infected Child

Cited by 230 publications

References 8 publications

Measuring the latent reservoir in vivo

Measuring the latent reservoir in vivo

Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4+T Cells to HIV-1-Specific CD8+T Cells

Targeting the Latent Reservoir for HIV-1

Contact Info

Product

Resources

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Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4⁺T Cells to HIV-1-Specific CD8⁺T Cells