NF-κB Duplications in the Promoter-Variant HIV-1C LTR Impact Inflammation Without Altering Viral Replication in the Context of Simian Human Immunodeficiency Viruses and Opioid-Exposure

Dave, Rajnish S.; Ali, Haider; Sil, Susmita; Knight, Lindsey A.; Pandey, Kabita; Madduri, Lepakshe S. V.; Qiu, Fang; Ranga, Udaykumar; Buch, Shilpa; Byrareddy, Siddappa N.

doi:10.3389/fimmu.2020.00095

Cited by 10 publications

(8 citation statements)

References 35 publications

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“…Similarly, we observed that the length of this part of clade C LTRs is also increasing, and that an increasing length is frequently associated with additional putative NF-κB sites. Notably, it has been reported that HIV-1 clade C strains containing an additional NF-κB, NF-κB-like, or RBEIII site in the viral promoter are replacing the prototype subtype C viruses containing three NF-κB sites in India ( Bachu et al, 2012 ; Dave et al, 2020 ). Notably, RBEIII sites for RBF-2 binding are commonly found in the MFNLP region of clade B LTRs ( Estable et al, 1998 ), and the frequency of LTR sequences containing additional RBEIII sites increased independently of their country of origin (data not shown).…”

Section: Discussionmentioning

confidence: 99%

An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins

et al. 2021

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SUMMARY Subtype C is the most prevalent clade of human immunodeficiency virus type 1 (HIV-1) worldwide. The reasons for this are poorly understood. Here, we demonstrate that a characteristic additional third nuclear factor κB (NF-κB) binding site in the long terminal repeat (LTR) promoter allows subtype C HIV-1 strains to evade restriction by nuclear PYHIN proteins, which sequester the transcription factor Sp1. Further, other LTR alterations are responsible for rare PYHIN resistance of subtype B viruses. Resistance-conferring mutations generally reduce the dependency of HIV-1 on Sp1 for virus production and render LTR transcription highly responsive to stimulation by NF-κB/p65. A third NF-κB binding site increases infectious virus yield in primary CD4 + T cells in an γ-interferon-inducible protein 16 (IFI16)-dependent manner. Comprehensive sequence analyses suggest that the frequency of circulating PYHIN-resistant HIV-1 strains is increasing. Our finding that an additional NF-κB binding site in the LTR confers resistance to nuclear PYHIN proteins helps to explain the dominance of clade C HIV-1 strains.

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Section: Discussionmentioning

confidence: 99%

An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins

et al. 2021

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“…Many other viruses (PRSSV (see Glossary) (Wang et al 2013 ), RSV (see Glossary) (Masaki et al 2011 ), HIV-1C (see Glossary) (Dave et al 2020 ; Hiscott et al 2001 ), HBV (see Glossary) (Hiscott et al 2001 ; Liu et al 2020 ), HCV (Hiscott et al 2001 ), HIV (Pahl 1999 ), EBV (see Glossary) (Hiscott et al 2001 )) have been proven to use the described NF-κB pathway for replication. This offers a wide area of therapeutic applications for vagal nerve stimulation.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Autonomic balance determines the severity of COVID-19 courses

et al. 2020

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COVID-19 has left mankind desperately seeking how to manage dramatically rising infection rates associated with severe disease progressions. COVID-19 courses range from mild symptoms up to multiple organ failure and death, triggered by excessively high serum cytokine levels (IL 1β, IL 6, TNF α, IL 8). The vagally driven cholinergic anti-inflammatory pathway (CAP) stops the action of nuclear factor κB (NF-κB), the transcriptional factor of pro-inflammatory cytokines. Thus, well-balanced cytokine release depends on adequate vagal signaling. Coronaviruses replicate using NF-κB transcriptional factor as well. By degrading the cytoplasmatic inhibitor of NF-κB subunits (IκB), coronaviruses induce unrestricted NF-κB expression accelerating both, virus replication and cytokine transcription.We hypothesize that CAP detriment due to depressed vagal tone critically determines the severity of COVID-19.

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“…Opioids have been shown to upregulate the expression of CCR5 while downregulating the expression of its cognate β-chemokine production by acting through µ-opioid receptor in macrophages and microglia, thereby boosting the entry of R5 tropic viruses in these target cells (21)(22)(23)(24). Opioids and HIV synergistically act to activate glia and upregulate the expression of cytokines and chemokines, leading, in turn, to neuronal damage and development of hyperalgesia (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Chronic Morphine Administration Differentially Modulates Viral Reservoirs in a Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaque Model

Acharya

Olwenyi

Thurman

et al. 2021

J Virol

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HIV persists in cellular reservoirs despite effective combined antiretroviral therapy (cART) and there is viremia flare up upon therapy interruption. Opioids modulate the immune system and suppress antiviral gene responses, which significantly impact people living with HIV (PLWH). However, the effect of opioids on viral reservoir dynamics remain elusive. Herein, we developed a morphine dependent SIVmac251 infected Rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. RMs on a morphine (or saline control) regimen were infected with SIVmac251. The cART was initiated in approximately half the animals five weeks post-infection, and morphine/saline administration continued until the end of the study. Among the untreated RM, we did not find any difference in plasma/CSF or in cell-associated DNA/RNA viral load in anatomical tissues. On the other hand, within the cART suppressed macaques, there was a reduction in cell-associated DNA load, intact proviral DNA levels, and in inducible SIV reservoir in lymph nodes (LNs) of morphine administered RMs. In distinction to LNs, in the CNS, the size of latent SIV reservoirs was higher in the CD11b+ microglia/macrophages in morphine dependent RMs. These results suggest that in the proposed model, morphine plays a differential role in SIV reservoirs by reducing the CD4+ T-cell reservoir in lymphoid tissues, while increasing the microglia/reservoir size in CNS tissue. The findings from this pre-clinical model will serve as a tool for screening therapeutic strategies to reduce/eliminate HIV reservoirs in opioid dependent PLWH. IMPORTANCE Identification and clearance of HIV reservoirs is a major challenge in achieving a cure for HIV. This is further complicated by co-morbidities that may alter the size of the reservoirs. There is an overlap between the risk factors for HIV and opioid abuse. Opiates have been recognized as prominent co-morbidities in HIV-infected populations. People infected with HIV also abusing opioids have immune modulatory effects and more severe neurological disease. However, the impact of opioid abuse on HIV reservoirs remains unclear. In this study, we used morphine dependent SIVmac251 infected rhesus macaque (RM) model to study the impact of opioids on HIV reservoirs. Our studies suggested that people with HIV who abuse opioids had higher reservoirs in CNS than the lymphoid system. Extrapolating the macaque findings in humans suggests that such differential modulation of HIV reservoirs among people living with HIV abusing opioids could be considered for future HIV cure research efforts.

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NF-κB Duplications in the Promoter-Variant HIV-1C LTR Impact Inflammation Without Altering Viral Replication in the Context of Simian Human Immunodeficiency Viruses and Opioid-Exposure

Cited by 10 publications

References 35 publications

An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins

An additional NF-κB site allows HIV-1 subtype C to evade restriction by nuclear PYHIN proteins

Autonomic balance determines the severity of COVID-19 courses

Chronic Morphine Administration Differentially Modulates Viral Reservoirs in a Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaque Model

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