Residual Viremia in Treated HIV+ Individuals

Conway, Jessica M.; Perelson, Alan S.

doi:10.1371/journal.pcbi.1004677

Cited by 67 publications

(84 citation statements)

References 61 publications

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“…Unfortunately, viremia returned 27 months after stopping ART. Each of these cases of late viral rebound were consistent with temporal models of the reemergence of virus upon discontinuation of ART that were developed by the Siliciano group [15–18], and demonstrate the challenges faced by HIV-1 cure researchers in developing measures of the success of potential cure interventions.…”

Section: Introductionsupporting

confidence: 76%

Novel AIDS therapies based on gene editing

Khalili

White

Jacobson

2017

Cell. Mol. Life Sci.

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HIV/AIDS remains a major public health issue. In 2014, it was estimated that 36.9 million people are living with HIV worldwide, including 2.6 million children. Since the advent of combination anti-retroviral therapy (cART) in the 1990s, treatment has been so successful that in many parts of the world, HIV has become a chronic condition in which progression to AIDS has become increasingly rare. However, while people with HIV can expect to live a normal life span with cART, lifelong medication is required and cardiovascular, renal, liver and neurologic diseases are still possible, which continues to prompt research for a cure for HIV. Infected reservoir cells such as CD4+ T-cells and myeloid cells allow persistence of HIV as an integrated DNA provirus and serve as a potential source for the re-emergence of virus. Attempts to eradicate HIV from these cells have focused mainly on the so-called “shock and kill” approach where cellular reactivation is induced so as to trigger the purging of virus producing cells by cytolysis or immune attack. This approach has several limitations and its usefulness in clinical applications remains to be assessed. Recent advances in gene editing technology have allowed the use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells or knocking out HIV receptors. Here we review this strategy and its potential to eliminate the latent HIV reservoir resulting in a sterile cure of AIDS.

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Section: Introductionsupporting

confidence: 76%

Novel AIDS therapies based on gene editing

Khalili

White

Jacobson

2017

Cell. Mol. Life Sci.

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“…Furthermore, unlike HIV and HBV, clinical benefit for HSV may require disruption of only a fraction of the persistent viral genomes. For example, cure of HIV has often been assumed to require complete elimination of all viral genomes, and even the more optimistic models suggest that clinically meaningful interventions would require a reduction by 2 logs (39) to 4 logs in replication-competent virus (40). In contrast, the frequency of HSV reactivation appears to be related to ganglionic viral load (41, 42), suggesting that reduction of the ganglionic viral load by one log or even less might provide substantial clinical benefit.…”

Section: Discussionmentioning

confidence: 99%

In vivo disruption of latent HSV by designer endonuclease therapy

Aubert¹,

Madden²,

Loprieno³

et al. 2016

JCI Insight

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A large portion of the global population carries latent herpes simplex virus (HSV), which can periodically reactivate, resulting in asymptomatic shedding or formation of ulcerative lesions. Current anti-HSV drugs do not eliminate latent virus from sensory neurons where HSV resides, and therefore do not eliminate the risk of transmission or recurrent disease. Here, we report the ability of HSV-specific endonucleases to induce mutations of essential HSV genes both in cultured neurons and in latently infected mice. In neurons, viral genomes are susceptible to endonuclease-mediated mutagenesis, regardless of the time of treatment after HSV infection, suggesting that both HSV lytic and latent forms can be targeted. Mutagenesis frequency after endonuclease exposure can be increased nearly 2-fold by treatment with a histone deacetylase (HDAC) inhibitor. Using a mouse model of latent HSV infection, we demonstrate that a targeted endonuclease can be delivered to viral latency sites via an adeno-associated virus (AAV) vector, where it is able to induce mutation of latent HSV genomes. These data provide the first proof-of-principle to our knowledge for the use of a targeted endonuclease as an antiviral agent to treat an established latent viral infection in vivo.

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“…We also note that individuals in marginalized and low‐income populations are more likely to have reduced or inconsistent adherence to ART due to social, economic and psychological barriers (Boyer et al., 2011) and may be less likely to be represented in longitudinal studies of ART efficacy. Given the limited information available, we arbitrarily set low, medium and high estimates of ART efficacy to r T = 1, 1.5 and 2, respectively, which are broadly consistent with other models (Conway & Perelson, 2016). …”

Section: Methodsmentioning

confidence: 99%

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

Mideo

2017

Evolutionary Applications

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Average HIV‐1 virulence appears to have evolved in different directions in different host populations since antiretroviral therapy first became available, and models predict that HIV drugs can select for either higher or lower virulence, depending on how treatment is administered. However, HIV virulence evolution in response to “leaky” therapy (treatment that imperfectly suppresses viral replication) and the use of preventive drugs (pre‐exposure prophylaxis) has not been explored. Using adaptive dynamics, we show that higher virulence can evolve when antiretroviral therapy is imperfectly effective and that this evolution erodes some of the long‐term clinical and epidemiological benefits of HIV treatment. The introduction of pre‐exposure prophylaxis greatly reduces infection prevalence, but can further amplify virulence evolution when it, too, is leaky. Increasing the uptake rate of these imperfect interventions increases selection for higher virulence and can lead to counterintuitive increases in infection prevalence in some scenarios. Although populations almost always fare better with access to interventions than without, untreated individuals could experience particularly poor clinical outcomes when virulence evolves. These findings predict that antiretroviral drugs may have underappreciated evolutionary consequences, but that maximizing drug efficacy can prevent this evolutionary response. We suggest that HIV virulence evolution should be closely monitored as access to interventions continues to improve.

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Residual Viremia in Treated HIV+ Individuals

Cited by 67 publications

References 61 publications

Novel AIDS therapies based on gene editing

Novel AIDS therapies based on gene editing

In vivo disruption of latent HSV by designer endonuclease therapy

Modelling the evolution of HIV‐1 virulence in response to imperfect therapy and prophylaxis

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