HIV-1 Latency and Latency Reversal: Does Subtype Matter?

Sarabia, Indra; Bosque, Alberto

doi:10.3390/v11121104

Cited by 17 publications

(19 citation statements)

References 166 publications

(265 reference statements)

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“…Non-B subtypes show differences in disease progression (summarised in [34]) and present genetic signatures and polymorphisms in amino acid residues associated to resistance in subtype B. Subtypes C, F, G, or CRF02_AG show different susceptibility to specific antiretrovirals and may develop RAMs, which are not favoured in subtype B strains [35,36]. Our analysis detected two specific RAMs significantly associated to A6 viruses: A62V RT and G190S RT .…”

Section: Discussionmentioning

confidence: 71%

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

Schlösser

Kartashev

Mikkola

et al. 2020

Viruses

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Russia has one of the largest and fastest growing HIV epidemics. However, epidemiological data are scarce. Sub-subtype A6 is most prevalent in Russia but its identification is challenging. We analysed protease/reverse transcriptase-, integrase-sequences, and epidemiological data from 303 patients to develop a methodology for the systematisation of A6 identification and to describe the HIV epidemiology in the Russian Southern Federal District. Drug consumption (32.0%) and heterosexual contact (27.1%) were the major reported transmission risks. This study successfully established the settings for systematic identification of A6 samples. Low frequency of subtype B (3.3%) and large prevalence of sub-subtype A6 (69.6%) and subtype G (23.4%) were detected. Transmitted PI- (8.8%) and NRTI-resistance (6.4%) were detected in therapy-naive patients. In therapy-experienced patients, 17.3% of the isolates showed resistance to PIs, 50.0% to NRTI, 39.2% to NNRTIs, and 9.5% to INSTIs. Multiresistance was identified in 52 isolates, 40 corresponding to two-class resistance and seven to three-class resistance. Two resistance-associated-mutations significantly associated to sub-subtype A6 samples: A62VRT and G190SRT. This study establishes the conditions for a systematic annotation of sub-subtype A6 to normalise epidemiological studies. Accurate knowledge on South Russian epidemiology will allow for the development of efficient regional frameworks for HIV-1 infection management.

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Section: Discussionmentioning

confidence: 71%

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

Schlösser

Kartashev

Mikkola

et al. 2020

Viruses

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“…The key challenge to cure for HIV-1 infection is represented by the more extensively studied therapeutic strategies known as "Shock and kill". These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms [155,156]. Borducchi et al show that administration of the V3 glycan-dependent bNAb PGT121 together with GS-9620 during ART delayed viral rebound following discontinuation of ART in simianehuman immunodeficiency virus (SHIV)-SF162P3infected rhesus monkeys in which ART was initiated during early acute infection [157].…”

Section: Pyrimidine and Purine Base Derivativesmentioning

confidence: 99%

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

Patinote

Karroum

Moarbess

et al. 2020

European Journal of Medicinal Chemistry

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a b s t r a c tThe discovery of the TLRs family and more precisely its functions opened a variety of gates to modulate immunological host responses. TLRs 7/8 are located in the endosomal compartment and activate a specific signaling pathway in a MyD88-dependant manner. According to their involvement into various autoimmune, inflammatory and malignant diseases, researchers have designed diverse TLRs 7/8 ligands able to boost or block the inherent signal transduction. These modulators are often small synthetic compounds and most act as agonists and to a much lesser extent as antagonists. Some of them have reached preclinical and clinical trials, and only one has been approved by the FDA and EMA, imiquimod. The key to the success of these modulators probably lies in their combination with other therapies as recently demonstrated. We gather in this review more than 360 scientific publications, reviews and patents, relating the extensive work carried out by researchers on the design of TLRs 7/8 modulators, which are classified firstly by their biological activities (agonist or antagonist) and then by their chemical structures, which total syntheses are not discussed here. This review also reports about 90 clinical cases, thereby showing the biological interest of these modulators in multiple pathologies.

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“…This could be due to subtype specific factors. Subtype C LTR can harbor up to 3 NF-κB binding sites, instead of two found in subtype B, that could explain a higher response to certain stimuli that activate NF-κB (33). However, further work needs to be done with other subtype C clones or primary viral isolates to determine whether this is intrinsic to that particular HIV-1 molecular clone or whether it is subtypespecific.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Omondi (32). Currently, it is unclear if subtype also plays a role in the establishment of latency or its reversal (for a review, see (33)). Further, Pierson and colleagues showed that the majority of viruses in the latent reservoir utilize CCR5 (R5) for entry, though some CXCR4 usage was also observed (34).…”

Section: Introductionmentioning

confidence: 99%

The Intact Noninducible Latent HIV-1 Reservoir Is Established in an In Vitro Primary T _CM Cell Model of Latency

Sarabia

Huang

Ward

et al. 2021

J Virol

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The establishment of HIV-1 latency has hindered an HIV-1 cure. “Shock and Kill” strategies to target this reservoir aim to induce the latent provirus with latency reversing agents (LRAs). However, recent studies have shown that the majority of the intact HIV-1 viral reservoir found in ART-suppressed HIV infected individuals is not inducible. We sought to understand whether this non-inducible reservoir is established, and thus able to be studied, in an in vitro primary TCM model of latency. Furthermore, we wanted to expand this model system to include R5-tropic and non-B subtype viruses. To that end, we generated our TCM model of latency with an R5 subtype B virus, AD8 and an R5 subtype C virus, MJ4. Our results demonstrate that both intact and defective proviruses are generated in this model. Less than 50% of intact proviruses are inducible regardless of viral strain in the context of maximal stimulation through the TCR or with different clinically relevant LRAs including the HDAC inhibitors SAHA and MS-275, the PKC agonist Ingenol 3,20-dibenzoate or the SMAC mimetic AZD-5582. Our findings suggest that current LRA strategies are insufficient to effectively reactivate intact latent HIV-1 proviruses in primary CD4 TCM cells and that the mechanisms involved in the generation of the non-inducible HIV-1 reservoir can be studied using this primary in vitro model. Importance: HIV-1 establishes a latent reservoir that persists under antiretroviral therapy. Antiretroviral therapy is able to stop the spread of the virus and the progression of the disease but does not target this latent reservoir. If antiretroviral therapy is stopped, the virus is able to resume replication and the disease progresses. Recently, it has been demonstrated that most of the latent reservoir capable of generating replication competent virus cannot be induced in the laboratory setting. However, the mechanisms that influence the generation of this intact and non-inducible latent reservoir are still under investigation. Here we demonstrate the generation of defective, intact and intact non-inducible latent HIV-1 in a TCM model of latency using different HIV-1 strains. Thus, the mechanisms which control inducibility can be studied using this primary cell model of latency, which may accelerate our understanding of the latent reservoir and the development of curative strategies.

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HIV-1 Latency and Latency Reversal: Does Subtype Matter?

Cited by 17 publications

References 166 publications

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

The Intact Noninducible Latent HIV-1 Reservoir Is Established in an In Vitro Primary T _CM Cell Model of Latency

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HIV-1 Latency and Latency Reversal: Does Subtype Matter?

Cited by 17 publications

References 166 publications

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

HIV-1 Sub-Subtype A6: Settings for Normalised Identification and Molecular Epidemiology in the Southern Federal District, Russia

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

The Intact Noninducible Latent HIV-1 Reservoir Is Established in an In Vitro Primary T CM Cell Model of Latency

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The Intact Noninducible Latent HIV-1 Reservoir Is Established in an In Vitro Primary T _CM Cell Model of Latency