HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication

Herskovitz, Jonathan; Gendelman, Howard E.

doi:10.1007/s11481-018-9785-6

Cited by 37 publications

(28 citation statements)

References 165 publications

(179 reference statements)

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“…The great variation in the HIV-1 susceptibility of macrophages is due to their different activation levels, origins, and tissue localizations (63). Indeed, several antiviral restriction factors are enhanced in activated MDMs and target various steps of the viral replicative cycle.…”

Section: Downloaded Frommentioning

confidence: 99%

Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

Lodge

Bellini

Laporte

et al. 2020

mBio

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Macrophages are a target of human immunodeficiency virus type 1 (HIV-1) and may serve as a viral reservoir during antiretroviral therapy (ART). Their susceptibility to HIV-1 infection is subject to variations from permissiveness to resistance depending on their origin, tissue localization, and polarization profile. This is in part due to the expression of regulatory microRNAs. Here, we identify two microRNA paralogs, microRNA 103 (miR-103) and miR-107, as regulators of CCR5 expression that are upregulated in noninfected bystander cells of HIV-1-infected-monocyte-derived macrophage (MDM) cultures. Transfection of microRNA 103 mimics in MDMs reduced CCR5 expression levels and inhibited CCR5-dependent HIV-1 entry, whereas the corresponding antagomirs enhanced virus spread in HIV-infected MDMs. Treatment of MDMs with interleukin-1β (IL-1β) enhanced microRNA 103 expression, a condition that we found contributed to the reduction of CCR5 mRNA in IL-1β-exposed MDMs. Interestingly, we show that the induction of miR-103/107 expression is part of a tumor suppressor p53 response triggered by secreted IL-1β that renders macrophages refractory to HIV-1 entry. In a more physiological context, the levels of microRNAs 103 and 107 were found enriched in tissue-resident colon macrophages of healthy donors and alveolar macrophages of individuals under antiretroviral therapy, conceivably contributing to their relative resistance to HIV-1 infection. Overall, these findings highlight the role of p53 in enforcing proinflammatory antiviral responses in macrophages, at least in part, through miR-103/107-mediated downmodulation of CCR5 expression and HIV-1 entry. IMPORTANCE Macrophages are heterogeneous immune cells that display varying susceptibilities to HIV-1 infection, in part due to the expression of small noncoding microRNAs involved in the posttranscriptional regulation of gene expression and silencing. Here, we identify microRNAs 103 and 107 as important p53-regulated effectors of the antiviral response triggered by the proinflammatory cytokine IL-1β in macrophages. These microRNAs, which are enriched in colon macrophages of healthy donors and alveolar macrophages of HIV-infected individuals under antiretroviral therapy, act as inhibitors of HIV-1 entry through their capacity to downregulate the CCR5 coreceptor. These results highlight the important role played by miR-103/107 in modulating CCR5 expression and HIV-1 entry in macrophages. They further underscore a distinct function of the tumor suppressor p53 in enforcing proinflammatory antiviral responses in macrophages, thus providing insight into a cellular pathway that could be targeted to limit the establishment of viral reservoirs in these cells.

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Section: Downloaded Frommentioning

confidence: 99%

Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

Lodge

Bellini

Laporte

et al. 2020

mBio

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“…Macrophages play a critical role in the pathogenesis of HIV-1 infection due to their resistance to the cytopathic effects that are secondary to viral replication and to their ability to continuously produce virus particles. These cells are important reservoirs of HIV-1 because of their ability to escape from immune system surveillance and produce virions when activated by stimuli derived from the virus itself and the tissue microenvironment ( 7 – 9 ). HIV-1 infection may become latent in macrophages, a condition that allows the formation, maintenance, and cycling of viral reservoirs and that constitutes a major obstacle to the therapeutic control of HIV-1 infection ( 7 – 9 ).…”

Section: Introductionmentioning

confidence: 99%

“…These cells are important reservoirs of HIV-1 because of their ability to escape from immune system surveillance and produce virions when activated by stimuli derived from the virus itself and the tissue microenvironment ( 7 – 9 ). HIV-1 infection may become latent in macrophages, a condition that allows the formation, maintenance, and cycling of viral reservoirs and that constitutes a major obstacle to the therapeutic control of HIV-1 infection ( 7 – 9 ). During viral transcription, the HIV-1 transactivation protein Tat recruits the Cyclin/Cyclin-dependent kinase (CDK) family, eliciting productive transcription of the HIV-1 genome, along with the participation of the transcription factors NF-κB and NFAT ( 10 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

The Neuropeptides Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Control HIV-1 Infection in Macrophages Through Activation of Protein Kinases A and C

Temerozo¹,

Azevedo²,

Insuela³

et al. 2018

Front. Immunol.

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Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are highly similar neuropeptides present in several tissues, endowed with immunoregulatory functions and other systemic effects. We previously reported that both neuropeptides reduce viral production in HIV-1-infected primary macrophages, with the participation of β-chemokines and IL-10, and now we describe molecular mechanisms engaged in this activity. Macrophages exposed to VIP or PACAP before HIV-1 infection showed resistance to viral replication, comparable to that observed when the cells were treated after infection. Also, multiple treatments with a suboptimal dose of VIP or PACAP after macrophage infection resulted in a decline of virus production similar to the inhibition promoted by a single exposure to the optimal inhibitory concentration. Cellular signaling pathways involving cAMP production and activation of protein kinases A and C were critical components of the VIP and PACAP anti-HIV-1 effects. Analysis of the transcription factors and the transcriptional/cell cycle regulators showed that VIP and PACAP induced cAMP response element-binding protein activation, inhibited NF-kB, and reduced Cyclin D1 levels in HIV-1-infected cells. Remarkably, VIP and PACAP promoted G-to-A mutations in the HIV-1 provirus, matching those derived from the activity of the APOBEC family of viral restriction factors, and reduced viral infectivity. In conclusion, our findings strengthen the antiretroviral potential of VIP and PACAP and point to new therapeutic approaches to control the progression of HIV-1 infection.

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“…currently being done to develop long-acting HIV therapy [138][139][140], repurposing drugs to directly target diverse myeloid carriers such as macrophages may not only lower viral loads but also ensure the timely dissemination of pro-drugs into diverse tissues as these cells could act as drug carriers.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Immuno-epidemiology and pathophysiology of coronavirus disease 2019 (COVID-19)

et al. 2020

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Occasional zoonotic viral attacks on immunologically naive populations result in massive death tolls that are capable of threatening human survival. Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent that causes coronavirus disease (COVID-19), has spread from its epicenter in Wuhan China to all parts of the globe. Real-time mapping of new infections across the globe has revealed that variable transmission patterns and pathogenicity are associated with differences in SARS-CoV-2 lineages, clades, and strains. Thus, we reviewed how changes in the SARS-CoV-2 genome and its structural architecture affect viral replication, immune evasion, and transmission within different human populations. We also looked at which immune dominant regions of SARS-CoV-2 and other coronaviruses are recognized by Major Histocompatibility Complex (MHC)/Human Leukocyte Antigens (HLA) genes and how this could impact on subsequent disease pathogenesis. Efforts were also placed on understanding immunological changes that occur when exposed individuals either remain asymptomatic or fail to control the virus and later develop systemic complications. Published autopsy studies that reveal alterations in the lung immune microenvironment, morphological, and pathological changes are also explored within the context of the review. Understanding the true correlates of protection and determining how constant virus evolution impacts on host-pathogen interactions could help identify which populations are at high risk and later inform future vaccine and therapeutic interventions.

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HIV and the Macrophage: From Cell Reservoirs to Drug Delivery to Viral Eradication

Cited by 37 publications

References 165 publications

Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

Interleukin-1β Triggers p53-Mediated Downmodulation of CCR5 and HIV-1 Entry in Macrophages through MicroRNAs 103 and 107

The Neuropeptides Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Control HIV-1 Infection in Macrophages Through Activation of Protein Kinases A and C

Immuno-epidemiology and pathophysiology of coronavirus disease 2019 (COVID-19)

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