HIV Type 1 (HIV-1) Proviral Reservoirs Decay Continuously Under Sustained Virologic Control in HIV-1–Infected Children Who Received Early Treatment

Luzuriaga, Katherine; Tabak, Barbara; Garber, Manuel; Chen, Ya Hui; Ziemniak, Carrie; McManus, Margaret; Murray, Danielle; Strain, Matthew C.; Richman, Douglas D.; Chun, Tae Wook; Cunningham, Coleen K.; Persaud, Deborah

doi:10.1093/infdis/jiu297

Cited by 126 publications

(117 citation statements)

References 32 publications

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“…In the case of the Mississippi baby and the Visconti cohort, cART was used to initiate treatment very early (before seroconversion), which is thought to have reduced the seeding of viral reservoirs, whilst preserving anti-HIV-1 immune function. This observation has been repeated in several other studies and highlights the potential benefits of early cART treatment to HIV-1 cure efforts [17-20]. Nevertheless, each of these cases has provided new information and strengthened the belief that a HIV-1 cure is indeed feasible.…”

Section: Hiv-1 Curementioning

confidence: 64%

Is the central nervous system a reservoir of HIV-1?

Gray¹,

Roche²,

Flynn³

et al. 2014

Current Opinion in HIV and AIDS

108

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Purpose of the review To summarize the evidence in the literature that supports the CNS as a viral reservoir for HIV-1 and to prioritise future research efforts. Recent findings HIV-1 DNA has been detected in brain tissue of patients with undetectable viral load or neurocognitive disorders, and is associated with long-lived cells such as astrocytes and microglia. In neurocognitively normal patients, HIV-1 can be found at high frequency in these cells (4% of astrocytes and 20% of macrophages). CNS cells have unique molecular mechanisms to suppress viral replication and induce latency, which include increased expression of dominant negative transcription factors and suppressive epigenetic factors. There is also evidence of continued inflammation in patients lacking a CNS viral load, suggesting the production and activity of viral neurotoxins (for example Tat). Summary Together, these findings provide evidence that the CNS can potentially act as a viral reservoir of HIV-1. However, the majority of these studies were performed in historical cohorts (absence of cART or presence of viral load) which do not reflect modern day patients (cART-treated and undetectable viral load). Future studies will need to examine patient samples with these characteristics to conclusively determine if the CNS represents a relevant and important viral reservoir.

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Section: Hiv-1 Curementioning

confidence: 64%

Is the central nervous system a reservoir of HIV-1?

Gray¹,

Roche²,

Flynn³

et al. 2014

Current Opinion in HIV and AIDS

108

View full text Add to dashboard Cite

show abstract

“…This difference is linked to the duration of uncontrolled viral replication between initial infection and effective treatment. The lower level of HIV DNA in children treated early versus late correlates with a lower level of replication-competent virus (75).…”

Section: Time From Hiv-1 Infection To Treatment Initiation Influencesmentioning

confidence: 97%

“…More recently, an assay that dispenses with the extraction step has been proposed (70). Recent technical progress has permitted the development of HIV DNA quantification by digital droplet PCR (ddPCR), which does not require an external quantification standard (71)(72)(73)(74)(75)(76)(77). However, some false-positive signals have been observed with ddPCR, which can be a problem when this method is used for diagnosis (76).…”

Section: Dna Load In Resting Cd4mentioning

confidence: 99%

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

et al. 2016

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SUMMARYHIV-1 DNA persists in infected cells despite combined antiretroviral therapy (cART), forming viral reservoirs. Recent trials of strategies targeting latent HIV reservoirs have rekindled hopes of curing HIV infection, and reliable markers are thus needed to evaluate viral reservoirs. Total HIV DNA quantification is simple, standardized, sensitive, and reproducible. Total HIV DNA load influences the course of the infection and is therefore clinically relevant. In particular, it is predictive of progression to AIDS and death, independently of HIV RNA load and the CD4 cell count. Baseline total HIV DNA load is predictive of the response to cART. It declines during cART but remains quantifiable, at a level that reflects both the history of infection (HIV RNA zenith, CD4 cell count nadir) and treatment efficacy (residual viremia, cumulative viremia, immune restoration, immune cell activation). Total HIV DNA load in blood is also predictive of the presence and severity of some HIV-1-associated end-organ disorders. It can be useful to guide individual treatment, notably, therapeutic de-escalation. Although it does not distinguish between replication-competent and -defective latent viruses, the total HIV DNA load in blood, tissues, and cells provides insights into HIV pathogenesis, probably because all viral forms participate in host cell activation and HIV pathogenesis. Total HIV DNA is thus a biomarker of HIV reservoirs, which can be defined as all infected cells and tissues containing all forms of HIV persistence that participate in pathogenesis. This participation may occur through the production of new virions, creating new cycles of infection and disseminating infected cells; maintenance or amplification of reservoirs by homeostatic cell proliferation; and viral transcription and synthesis of viral proteins without new virion production. These proteins can induce immune activation, thus participating in the vicious circle of HIV pathogenesis.

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“…Some clinical studies have shown that early ART not only inhibits HIV-1 replication but also limits the size of viral reservoirs. Continued ART with a reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies Jain et al 2013;Li and Gandhi 2014;Luzuriaga et al 2014).…”

Section: Current Potential Hiv Cure Strategiesmentioning

confidence: 99%

Might dolutegravir be part of a functional cure for HIV?

2016

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Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a secondgeneration integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.Key words: dolutegravir, drug resistance, HIV, cure. Résumé :Les traitements antirétroviraux (TAR) ont considérablement réduit la morbidité et la mortalité associées au VIH. Or, le VIH peut établir des réservoirs viraux pour se soustraire au système immunitaire et aux TAR. Le dolutégravir (DTG) est un inhibiteur du transfert de brin par l'intégrase (integrase strand transfer inhibitor, INSTI) de deuxième génération qui s'apparente au raltégravir (RAL) et à l'elvitégravir (EVG), des INSTI de première génération. Comparativement au RAL et à l'EVG, le DTG présente une plus grande barrière génétique au dével-oppement de la résistance chez le VIH. On remarque avec intérêt que des mutations menant à la résistance clinique au DTG chez des patients jamais traités auparavant n'ont pas encore été observées. La présente revue fait la synthèse des études récentes abordant des stratégies visant à éliminer le VIH, explore les profils de résistance au DTG et discute de la possibilité de mettre au point un remède contre le VIH à l'aide du DTG. [Traduit par la Rédaction]

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HIV Type 1 (HIV-1) Proviral Reservoirs Decay Continuously Under Sustained Virologic Control in HIV-1–Infected Children Who Received Early Treatment

Abstract: Initiation of early effective cART during infancy significantly limits circulating levels of proviral and replication-competent HIV-1 and promotes continuous decay of viral reservoirs. Continued cART with reduction in HIV-1 reservoirs over time may facilitate HIV-1 eradication strategies.

Cited by 126 publications

References 32 publications

Is the central nervous system a reservoir of HIV-1?

Is the central nervous system a reservoir of HIV-1?

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

Might dolutegravir be part of a functional cure for HIV?

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