Targeting TNF and TNF Receptor Pathway in HIV-1 Infection: from Immune Activation to Viral Reservoirs

Pasquereau, Sébastien; Kumar, Amit; Herbein, Georges

doi:10.3390/v9040064

Cited by 109 publications

(88 citation statements)

References 142 publications

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“…It is interesting that CBL0137 could potentiate TNF‐α but not Bryo, since both act through the induction of nuclear factor κ activated B cells (NF‐κB) signaling, albeit by different mechanisms. TNF‐α binds to its receptor and activates the TNF receptor associated (TRAF) pathway that leads to NF‐κB translocation into the nucleus; whereas, Bryo‐1 induces the protein kinase C (PKC) pathway to promote the same end result . Thus, future studies targeting components in these pathways could provide mechanistic insights for CBL0137.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, CBL0137 was reported to increase chromatin accessibility by intercalating into DNA and disrupting proper DNA/protein interactions by a process termed “c‐trapping” . Therefore, hypothetically CBL0137 could further enhance HIV‐1 reactivation by increasing chromatin accessibility, which could allow for easier recruitment/processivity of the general transcriptional machinery, at an already “sensitized” HIV‐1 locus due to TNF‐α . Additionally, CBL0137 fails to considerably enhance either JQ1 or SAHA mediated latency reversal.…”

Section: Resultsmentioning

confidence: 99%

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Curaxin CBL0137 has the potential to reverse HIV‐1 latency

Jean

Zhou

Fiches

et al. 2019

Journal of Medical Virology

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A cure for human immunodeficiency virus type-1 (HIV-1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV-1 patients. One strategy proposed to eradicate these reservoirs is the "shock and kill" approach, where latency-reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells.Here, we report that curaxin CBL0137, an antitumor compound, can potentiate tumor necrosis factor-α-mediated reactivation of latently infected HIV-1cell lines.Additionally, the single use of CBL0137 is sufficient to reactivate HIV-1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV-1 positive, cART-treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the "shock and kill" approach. K E Y W O R D S curaxins, facilitates chromatin transcription complex, HIV-1 latency, human immunodeficiency virus type 1, latency-reversing agents 1 | INTRODUCTION Since the implementation of combination antiretroviral therapy (cART), rates of human immunodeficiency virus type-1 (HIV-1)mortality, morbidity, and newly acquired infections have decrease drastically. 1 However, long-term therapy is still required because the virus established a reversible state of latency in memory CD4 + T cells. To address these reservoirs, two main strategies are being investigated. First, the "shock and kill" approach aims to purge the latent reservoirs by inducing renewed viral transcription/reactivation using latency-reversing agents (LRAs) to favor viral cytopathic cell death and immune clearance. Second, another strategy coined the "block and lock" approach focuses on the development of latencypromoting agents (LPAs) to instead induce a deep state of HIV-1 resulting in permanent silencing of latently infected cells and lead to their potential decay overtime. In that regard, we have previously implicated the facilitates chromatin transcription (FACT) complex as a negative regulator of HIV-1 latency. 2 Furthermore, we showed in an earlier publication that curaxin 100 (CBL0100), a compound first described as an antitumor drug that targets FACT, is a promising LPA by targeting HIV-1 transcriptional elongation. 3,4 Interestingly, another curaxin, CBL0137, has been implicated in promoting HIV integration. Its mechanism of action involves FACT-mediated destabilization of chromatin nucleosomes to favor viral genome J Med Virol. 2019;91:1571-1576.wileyonlinelibrary.com/journal/jmv

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Curaxin CBL0137 has the potential to reverse HIV‐1 latency

Jean

Zhou

Fiches

et al. 2019

Journal of Medical Virology

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“…HIV-1 infection is associated with dysregulation of seminal cytokines (50, 51) as well as an increased semen: blood cytokine ratio (10, 50, 51). This pro-inflammatory environment has been suggested to increase viral replication as semen viral load often correlates with cytokine levels (52), as well as the fact that several cytokines, including TNF-α, directly act on the virus to increase replication (53) (reviewed in (54)). A similar phenomenon is observed in men with classical STIs such as gonorrhea or trichomonas (20).…”

Section: Discussionmentioning

confidence: 99%

Deep Sequencing Reveals Compartmentalized HIV-1 in the Semen of Men with and without STI-associated Urethritis

Zhou

McCann

Hoffman

et al. 2020

Preprint

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AbstractConcurrent sexually transmitted infections (STI) can increase the probability of HIV-1 transmission primarily by increasing the viral load present in semen. In this study, we explored the relationship of HIV-1 in blood and seminal plasma in the presence and absence of urethritis and after treatment of the concurrent STI. Primer ID deep sequencing of the V1/V3 region of the HIV-1 env gene was done for paired blood and semen samples from ART-naïve men living in Malawi with (n = 19) and without (n = 5) STI-associated urethritis; for a subset of samples full length env genes were generated for sequence analysis and to test entry phenotype. Cytokine concentrations in the blood and semen were also measured, and a reduction in the levels of pro-inflammatory cytokines was observed following STI treatment. We observed no difference in the prevalence of diverse compartmentalized semen-derived lineages in men with or without STI-associated urethritis, and these viral populations were largely stable during STI treatment. Clonal amplification of one or a few viral sequences accounted for nearly 50% of the viral population indicating a recent bottleneck followed by limited viral replication. We documented a case of superinfection where the new strain was restricted to the genital tract. We conclude that the male genital tract is a site where virus can be brought in from the blood, where localized sustained replication can occur, where a superinfecting strain can persist, and where specific genotypes can be amplified perhaps initially by cellular proliferation but further by limited viral replication.ImportanceHIV-1 is a sexually transmitted infection that co-exists with other STIs. Here we examine the impact of a concurrent STI resulting in urethritis on the HIV-1 population within the male genital tract. We found that viral populations remain largely stable even with treatment of the STI. These results show that viral populations within the male genital tract are defined by factors beyond transient inflammation associated with a concurrent STI.

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“…Generally CD4 count in HIV patient have been observed to decline as the disease progresses [1,2] and is a vascular risk factor among HIV-infected individuals [15]. The increased rates of apoptosis within blood lymphocyte subsets in HIV positive individuals [16] could contribute to lower lymphocyte levels.…”

Section: Discussionmentioning

confidence: 99%

“…CD4 and CD8 T cells form the pillar of cellular response while humoral response involves the antibody production and its related activities [2]. CD8 T cells exercise its cytotoxic effect on the virus as well as secrete some chemokines during the primary stage of HIV infection.…”

Section: Open Access Http://scidocorg/ijmaiphpmentioning

confidence: 99%