HIV-1 is rarely detected in blood and colon myeloid cells during viral-suppressive antiretroviral therapy

Cattin, Amélie; Salinas, Tomas Raul Wiche; Gosselin, Annie; Planas, Delphine; Shacklett, Barbara L.; Cohen, Éric A.; Ghali, Maged P.; Routy, Jean Pierre; Ancuța, Petronela

doi:10.1097/qad.0000000000002195

Cited by 30 publications

(51 citation statements)

References 74 publications

(139 reference statements)

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“…First, as we previously described for the CD4-targeting miR-221 (24), miR-103/107 and p53 mRNA were greatly upregulated in colon macrophages (3 donors) ( Fig. 8A), thus potentially contributing to the resistance of these cells to HIV-1 infection (22,23). In alveolar macrophages, which were isolated as described in the legend of Fig.…”

Section: Resultsmentioning

confidence: 55%

“…Myeloid cells from either peripheral blood or sigmoid colon biopsy specimens were isolated from 3 adult HIV-negative donors, as previously described ( 23 , 24 ). Cells stained with a cocktail of Abs were suspended in phosphate-buffered saline (PBS) with 5% fetal bovine serum (FBS) and 25 mmol/liter HEPES buffer, and the myeloid cell-enriched fraction with a CD326 − CD8 − CD19 − CD66b − CD3 − HLA-DR high phenotype was sorted on a BD-FACS Aria III instrument (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…While HIV-1 infection has been demonstrated in lymphoid as well as nonlymphoid tissues, tissue-resident macrophages display different susceptibilities to productive HIV-1 infection ( 14 ). For instance, whereas productive infection has been observed in vaginal ( 15 ), penile urethral ( 16 , 17 ), and, to a weaker degree, lung alveolar ( 18 – 21 ) macrophages, intestinal macrophages reveal significant resistance to HIV-1 infection ( 22 , 23 ), thus indicating that the origin and activation status of tissue-resident macrophages as well as local environmental signals influence their susceptibility to HIV-1 infection. Indeed, the nonpermissiveness of intestinal macrophages is in part due to reduced expression levels of CD4 and CCR5 ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…In individuals receiving cART, the extent of in vivo infection of monocytes and macrophages is more contentious, and evidence is limited. Monocytes have host-cell restriction mechanisms which limit HIV infection, including the restriction factors SAMHD1 and APOBEC3, and cellular microRNAs (97–102); however, several groups have detected HIV in blood monocytes in PLWH with defined cART status including virologically suppressed individuals (Table 1) (39, 103–116). In addition to the studies summarized in Table 1, other groups have detected HIV in monocytes of suppressed individuals (117–121) but have not been included in Table 1 due to insufficient information to determine the virological status of participants.…”

Section: Monocyte/macrophage Hiv Reservoirs In Hiv+ Individualsmentioning

confidence: 99%

The HIV Reservoir in Monocytes and Macrophages

Jaworowski²,

2019

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In people living with HIV (PLWH) who are failing or unable to access combination antiretroviral therapy (cART), monocytes and macrophages are important drivers of pathogenesis and progression to AIDS. The relevance of the monocyte/macrophage reservoir in PLWH receiving cART is debatable as in vivo evidence for infected cells is limited and suggests the reservoir is small. Macrophages were assumed to have a moderate life span and lack self-renewing potential, but recent discoveries challenge this dogma and suggest a potentially important role of these cells as long-lived HIV reservoirs. This, combined with new HIV infection animal models, has led to a resurgence of interest in monocyte/macrophage reservoirs. Infection of non-human primates with myeloid-tropic SIV implicates monocyte/macrophage activation and infection in the brain with neurocognitive disorders, and infection of myeloid-only humanized mouse models are consistent with the potential of the monocyte/macrophage reservoir to sustain infection and be a source of rebound viremia following cART cessation. An increased resistance to HIV-induced cytopathic effects and a reduced susceptibility to some antiretroviral drugs implies macrophages may be relevant to residual replication under cART and to rebound viremia. With a reappraisal of monocyte circulation dynamics, and the development of techniques to differentiate between self-renewing tissue-resident, and monocyte-derived macrophages in different tissues, a new framework exists to contextualize and evaluate the significance and relevance of the monocyte/macrophage HIV reservoir. In this review, we discuss recent developments in monocyte and macrophage biology and appraise current and emerging techniques to quantify the reservoir. We discuss how this knowledge influences our evaluation of the myeloid HIV reservoir, the implications for HIV pathogenesis in both viremic and virologically-suppressed PLWH and the need to address the myeloid reservoir in future treatment and cure strategies.

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“…A major effect of HIV-1 (herein called HIV) infections is the loss of CD4 T cells, the primary target of direct HIV infection. While HIV does not significantly infect mDC in vivo (11), mDCs are altered in function (12) and decreased in number (13)(14)(15)(16)(17) in the blood in untreated people living with HIV (PLWH) and simian immunodeficiency virus (SIV)-infected macaques (18,19). Increased HIV RNA viral loads and disease progression are associated with loss of blood mDC (13)(14)(15)(16)18).…”

Section: Introductionmentioning

confidence: 99%

Myeloid Cells Enriched for a Dendritic Cell Population From People Living With HIV Have Altered Gene Expression Not Restored by Antiretroviral Therapy

et al. 2020

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Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infections has been designed to optimize CD4 T-cell survival and limit HIV replication. Cell types other than CD4 T cells such as monocytes/macrophage, dendritic cells, and granulocytes (collectively known as myeloid cells), are generally not considered in the development of ART protocols. Myeloid dendritic cells (mDCs) are the most potent inducers of CD4 T-cell activation and central to the regulation of immune responses. mDCs in the blood are decreased in number, altered in function, and implicated in promoting HIV latency in people living with HIV (PLWH). We found that cells enriched for mDC in PLWH had transcriptional changes compared to mDC from HIV uninfected individuals, some of which were not completely restored by ART. In contrast, other mDC functions such as interleukin-1 signaling and type I interferon pathways were restored by ART. Some of the transcriptional changes in mDC not completely reversed by ART were enriched in genes that are classically associated with cells of the monocyte/macrophage lineage, but new single-cell RNA sequencing studies show that they are also expressed by a subset of mDC. A cellular enzyme, acyloxyacyl hydrolase (AOAH), important for lipopolysaccharide (LPS) detoxification, had increased transcription in mDC of PLWH, not restored by ART. It is possible that one reason ART is not completely successful in PLWH is the failure to phenotypically change the mDCs. Thus, inability of ART to be completely effective might involve myeloid cells and the failure to restore mDC function as measured by gene transcription. We suggest that mDC and myeloid cells should be considered in future combination ART development.

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HIV-1 is rarely detected in blood and colon myeloid cells during viral-suppressive antiretroviral therapy

Cited by 30 publications

References 74 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 HIV Reservoir in Monocytes and Macrophages

Myeloid Cells Enriched for a Dendritic Cell Population From People Living With HIV Have Altered Gene Expression Not Restored by Antiretroviral Therapy

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