Macrophages sustain HIV replication in vivo independently of T cells

Honeycutt, Jenna B.; Wahl, Angela; Baker, Caroline; Spagnuolo, Rae Ann; Foster, John L.; Zakharova, Oksana; Wietgrefe, Stephen W.; Caro-Vegas, Carolina; Madden, Victoria J.; Sharpe, Garrett C; Haase, Ashley T.; Eron, Joseph J.; García, J. Víctor

doi:10.1172/jci84456

Cited by 220 publications

(240 citation statements)

References 72 publications

(108 reference statements)

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“…As is discussed below, recovery only fails when the size of the latent reservoir is substantially reduced (44, 109–111). Controversy remains over the question of whether other cell types including macrophages serve as stable HIV-1 reservoirs (112–123). To date, long term persistence of replication-competent HIV-1 in the setting of optimal ART has only been demonstrated for resting CD4 + T cells (124).…”

Section: Evidence For Latent Infection Of Resting Memory Cd4+ T Cellsmentioning

confidence: 99%

“…This may in part reflect the difficulty of sampling tissue macrophages, particularly in sites such as the central nervous system. Persistence in tissue macrophages can in principle be studied in novel humanized mouse models (123) and in the SIV model, but only through the use of animals on fully suppressive, long term ART and with the caveat that restriction by SAMHD1 is counteracted by SIV Vpx (68, 69). …”

Section: Evidence For Latent Infection Of Resting Memory Cd4+ T Cellsmentioning

confidence: 99%

See 1 more Smart Citation

The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

Murray

Kwon

Farber

et al. 2016

The Journal of Immunology

126

113

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Combination antiretroviral therapy (ART) for HIV-1 infection reduces plasma virus levels to below the limit of detection of clinical assays. However, even with prolonged suppression of viral replication with ART, viremia rebounds rapidly after treatment interruption. Thus ART is not curative. The principal barrier to cure is a remarkably stable reservoir of latent HIV-1 in resting memory CD4+ T cells. Here we consider explanations for the remarkable stability of the latent reservoir. Stability does not appear to reflect replenishment from new infection events but rather normal physiologic processes that provide for immunologic memory. Of particular importance are proliferative processes that drive clonal expansion of infected cells. Recent evidence suggests that in some infected cells, proliferation is a consequence of proviral integration into host genes associated with cell growth. Efforts to cure HIV-1 infection by targeting the latent reservoir may need to consider the potential of latently infected cells to proliferate.

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Section: Evidence For Latent Infection Of Resting Memory Cd4+ T Cellsmentioning

confidence: 99%

Section: Evidence For Latent Infection Of Resting Memory Cd4+ T Cellsmentioning

confidence: 99%

The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

Murray

Kwon

Farber

et al. 2016

The Journal of Immunology

126

113

View full text Add to dashboard Cite

show abstract

“…Moreover, in patients exposed to antiretroviral therapies, HIV-1-infected macrophages may maintain a constant viral production due in part to the low doses of antiviral drugs that reach the tissues (7). In addition, macrophages are now recognized as able to sustain viral replication, transmission, and persistence even in the absence of CD4 ϩ T cells in vivo (8) and under antiretroviral therapy (9). Thus, macrophages represent an important viral reservoir even in patients under antiretroviral therapy (3).…”

mentioning

confidence: 99%

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

Decalf

Desdouits

Rodrigues

et al. 2017

J Virol

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Along with CD4 ϩ T lymphocytes, macrophages are a major cellular source of HIV-1 replication and a potential viral reservoir. Following entry and reverse transcription in macrophages, cloaking of the viral cDNA by the HIV-1 capsid limits its cytosolic detection, enabling efficient replication. However, whether incoming HIV-1 particles are sensed by macrophages prior to reverse transcription remains unclear. Here, we show that HIV-1 triggers a broad expression of interferon (IFN)-stimulated genes (ISG) in monocyte-derived macrophages within a few hours after infection. This response does not require viral reverse transcription or the presence of HIV-1 RNA within particles, but viral fusion is essential. This response is elicited by viruses carrying different envelope proteins and thus different receptors to proceed for viral entry. Expression of ISG in response to viral entry requires TBK1 activity and type I IFNs signaling. Remarkably, the ISG response is transient but affects subsequent viral spread. Together, our results shed light on an early step of HIV-1 sensing by macrophages at the level of entry, which confers an early protection through type I IFN signaling and has potential implications in controlling the infection.IMPORTANCE HIV infection is restricted to T lymphocytes and macrophages. HIV-1-infected macrophages are found in many tissues of infected patients, even under antiretroviral therapy, and are considered a viral reservoir. How HIV-1 is detected and what type of responses are elicited upon sensing remain in great part elusive. The kinetics and localization of the production of cytokines such as interferons in response to HIV is of critical importance to understanding how the infection and the immune response are established. Our study provides evidence that macrophages can detect HIV-1 as soon as it enters the cell. Interestingly, this sensing is independent of the presence of viral nucleic acids within the particles but requires their fusion with the macrophages. This triggers a low interferon response, which activates an antiviral program protecting cells against further viral challenge and thus potentially limiting the spread of the infection. KEYWORDS human immunodeficiency virus, innate immunity, interferons, macrophages, virus entry M acrophages are present in most tissues and endowed with many functions, including sensing and clearing of pathogens. However, pathogens frequently exploit macrophages as a privileged niche for their replication (1). This is the case for HIV-1, which mainly targets two cell types for replication: macrophages and CD4 ϩ T cells (2). Infected macrophages are considered to play an important role from the onset of infection to the development of the pathogenesis (3). The HIV-1 cycle in macrophages possesses specific features compared to T cells: macrophages are resistant to

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“…Monocytes that express CD16 are more prone to infection with HIV-1 in vitro, and some studies have found very low levels of viral DNA within these cells after flow cytometric sorting from peripheral blood of HIV-infected individuals (80,81). However, other groups have reported that viral DNA is not detectable in peripheral blood monocytes from HIV-infected individuals (82,83).…”

Section: Evidence That Macrophages Support Viral Replicationmentioning

confidence: 99%

“…In this model, immunodeficient mice were reconstituted with fetal, human, hematopoietic cells that developed into myeloid cells but not T cells. These particular "humanized" mice, termed myeloid-only mice (MoM), could subsequently be infected with macrophage-tropic strains of HIV in vivo and support viral replication (83). Interestingly, very few CCR5-tropic viruses were able to replicate in MoM, suggesting this might be a very rare event in vivo.…”

Section: Animal Models Of Macrophage Infection In Vivomentioning

confidence: 99%

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

DiNapoli

Hirsch

Brenchley

2016

J Virol

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The cells that are targeted by primate lentiviruses (HIV and simian immunodeficiency virus [SIV]) are of intense interest given the renewed effort to identify potential cures for HIV. These viruses have been reported to infect multiple cell lineages of hematopoietic origin, including all phenotypic and functional CD4 T cell subsets. The two most commonly reported cell types that become infected in vivo are memory CD4 T cells and tissue-resident macrophages. Though viral infection of CD4 T cells is routinely detected in both HIV-infected humans and SIV-infected Asian macaques, significant viral infection of macrophages is only routinely observed in animal models wherein CD4 T cells are almost entirely depleted. Here we review the roles of macrophages in lentiviral disease progression, the evidence that macrophages support viral replication in vivo, the animal models where macrophage-mediated replication of SIV is thought to occur, how the virus can interact with macrophages in vivo, pathologies thought to be attributed to viral replication within macrophages, how viral replication in macrophages might contribute to the asymptomatic phase of HIV/SIV infection, and whether macrophages represent a long-lived reservoir for the virus. Macrophages are a diverse and functionally important component of the immune system. Evolutionarily conserved in almost all species of the phylum Chordata, macrophages are one of the "oldest" leukocyte lineages and have the highest degree of plasticity across leukocyte subsets (1). Macrophages differentiate from the yolk sac, fetal liver, and peripheral blood monocytes that developed from bone marrow-derived hematopoietic stem cells. With their phenotypic and functional plasticity and presence in disparate tissues, macrophages play supportive roles in multiple aspects of physiology. Their function often depends upon their anatomical location, their individual ontogeny, and extracellular cues. For example, macrophages derived from the yolk sac or fetal liver reside in organs such as the brain (as microglia cells), pancreas, spleen, liver (as Kuppfer cells), and kidney. For many years, yolk sac-and fetal liver-derived macrophages were thought to be very long-lived, perhaps for the life span of the host. Indeed, after differentiating during fetal development, these macrophages can populate tissues for the duration of the host's life. However, recent data suggest that these cells can also divide in vivo to maintain homeostasis (1-3) and are able to rapidly repopulate after chemotherapeutic depletion (in the case of brain-resident microglia cells [4]). Our understanding of macrophage longevity and factors important for their homeostatic proliferation in vivo is incomplete and more data are required. FUNCTIONS OF MACROPHAGES IN HEALTHThough macrophage longevity is not fully understood, many studies have demonstrated that tissue-resident macrophages have critically important functions in tissue immunity and repair, antigen presentation, and tissue homeostasis. Indeed, the importance of their fu...

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Macrophages sustain HIV replication in vivo independently of T cells

Cited by 220 publications

References 72 publications

The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

Sensing of HIV-1 Entry Triggers a Type I Interferon Response in Human Primary Macrophages

Macrophages in Progressive Human Immunodeficiency Virus/Simian Immunodeficiency Virus Infections

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