Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

Avalos, Claudia R.; Abreu, Celina Monteiro; Queen, Suzanne E.; Li, Ming; Price, Sarah L.; Shirk, Erin N.; Engle, Elizabeth L.; Forsyth, Ellen R.; Bullock, Brandon; Gabhann, Feilim Mac; Wietgrefe, Stephen W.; Haase, Ashley T.; Zink, M. Christine; Mankowski, Joseph L.; Clements, Janice E.; Gama, Lúcio

doi:10.1128/mbio.01186-17

Cited by 140 publications

(150 citation statements)

References 71 publications

(116 reference statements)

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“…Macrophages are inherently resistant to HIV-1 infection due to low levels of the viral receptors CD4 and CCR5, high levels of active SAMHD1, and the ability to detect and respond to infections with a robust innate response. Nevertheless, they represent a natural target cell for HIV-1 in vivo , contributing to the viral reservoir (45), and are perhaps the most elusive targets for drug treatment, residing in difficult to reach regions such as the CNS, in the form of microglia (46). Most studies into HIV-1 infection of macrophages make use of either monocytic cell lines that have altered cell cycle control and loss of SAMHD1 activity, or blood monocyte-derived macrophages differentiated in vitro under various non-physiological conditions, e.g.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand

Owen

Vaughan-Jackson

Nußbaum

et al. 2018

Preprint

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word count: 168 15 Text word count: 5468 16 17 18 2 Abstract 19Retroviral restriction factors are important regulators of viral infection, targeting vulnerable 20 steps of the virus lifecycle; steps that are also targeted by antiviral drugs. It has become clear 21 that the route of cellular infection can alter the sensitivity of HIV-1 to these agents. Using 22 39 3 evolutionary battle between virus and host and show how the virus has co-opted a host protein 40 to protect it from destruction by an antiviral mechanism. These two key findings suggest 41 potential novel treatment strategies that may reduce the viral reservoir and help our natural 42 defences take back control from the virus. 43 44 58 uncoating, proteasomal degradation of the viral capsid, and ultimately inhibition of reverse 59 transcription; however human TRIM5α is inactive against HIV-1 (4). TRIM5α can be saturated 60 4 by large doses of virus e.g. during viral dissemination via virological synapses, and can also be 61 circumvented by alterations in the viral capsid gene that prevent TRIM5α binding (5, 6). The 62 compatibility between the viral capsid sequence and the host species TRIM5 locus is a major 63 determinant of successful infection. In fact, converting a single amino acid to the equivalent in 64 rhesus macaque TRIM5α is sufficient to enable human TRIM5α to restrict HIV-1 (7). The same 65 region of capsid that determines the sensitivity of HIV-1 to TRIM5α is also the binding site for 66 the host peptidyl prolyl isomerase enzyme cyclophilin A (CypA) (8). Binding of CypA to an 67 incoming HIV-1 capsid prevents detection of reverse transcription products by macrophages, 68 and the subsequent production of IFN, but conversely binding of CypA aids restriction by TRIM5 69 of some monkey species (9). This interaction site has been the focus of an evolutionary arms 70 race between the TRIM5 locus and the simian relatives of HIV-1. In several monkey species 71 (e.g. Rhesus macaques and Owl monkeys) multiple retrotransposition events resulted in CypA 72 being inserted into the TRIM5 locus, producing a novel antiviral protein, TRIMCyp (10, 11). 73 Although TRIMCyp does not contain the usual PRYSPRY domain for viral binding, it uses the 74 CypA domain to bind the capsid of sensitive viruses. The species-specific activity of TRIM5 and 75TRIMCyp suggest that they act as cross-species barriers to retrovirus infection (12, 13), and that 76 in consequence, the TRIM5 locus has great potential to act as a target for gene therapy. To that 77 end, it has been shown that overexpression of macaque TRIM5 variants or TRIMCyp in human 78 cells results in protection from HIV-1 infection (14, 15). However, these approaches fail to take 79 account of the role of endogenous TRIM5α as both a target and signaller of the IFN system (16), 80 nor any potentially adverse consequences of overexpression of this potent antiviral element. 81 respective isotype controls (light grey). Stem cells were fixed in 2% paraformaldehyde, followed

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Section: Discussionmentioning

confidence: 99%

HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand

Owen

Vaughan-Jackson

Nußbaum

et al. 2018

Preprint

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“…The horizontal black line represents the median IUPM values. The MΦ QVOA results from SIV-infected animals with and without ART have been reported (85, 94). Significance was determined by Mann-Whitney nonparametric t test; a P of <0.05 was considered significant.…”

Section: Figurementioning

confidence: 96%

“…Antiretroviral drugs have been shown to fully suppress SIV replication in blood (82) and, in limited studies, CSF (83–85) to levels comparable to those in ART-suppressed HIV-infected individuals. SIV-infected macaques carry latently infected CD4+T cells that harbor replication competent virus, as shown by quantitative viral outgrowth assays (QVOA) (86) and by the rapid rebound of SIV in plasma when ART is discontinued (87).…”

Section: Siv Macaque Modelsmentioning

confidence: 99%

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SIV Latency in Macrophages in the CNS

Gama

Abreu

Shirk

et al. 2018

Current Topics in Microbiology and Immunology

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Lentiviruses infect myeloid cells, leading to acute infection followed by persistent/latent infections not cleared by the host immune system. HIV and SIV are lentiviruses that infect CD4+ lymphocytes in addition to myeloid cells in blood and tissues. HIV infection of myeloid cells in brain, lung, and heart causes tissue-specific diseases that are mostly observed during severe immunosuppression, when the number of circulating CD4+ T cells declines to exceeding low levels. Antiretroviral therapy (ART) controls viral replication but does not successfully eliminate latent virus, which leads to viral rebound once ART is interrupted. HIV latency in CD4+ lymphocytes is the main focus of research and concern when HIV eradication efforts are considered. However, myeloid cells in tissues are long-lived and have not been routinely examined as a potential reservoir. Based on a quantitative viral outgrowth assay (QVOA) designed to evaluate latently infected CD4+ lymphocytes, a similar protocol was developed for the assessment of latently infected myeloid cells in blood and tissues. Using an SIV ART model, it was demonstrated that myeloid cells in blood and brain harbor latent SIV that can be reactivated and produce infectious virus in vitro, demonstrating that myeloid cells have the potential to be an additional latent reservoir of HIV that should be considered during HIV eradication strategies.

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“…While several recent studies support that Mφ serve as a major non-T cell HIV reservoir [30][31][32][33][34][35][36][37][38], the role of Mφ in HIV infection and persistence has been conclusively demonstrated by employing humanized BLT and myeloid only mice (MoM mice containing myeloid cells devoid of T cells). Honeycutt et al show that replication competent virus could be recovered from tissue Mφ, and the transfer of infected Mφ into uninfected animals resulted in sustained infection demonstrating that Mφ are genuine targets for HIV infection in vivo [3].…”

Section: Introductionmentioning

confidence: 99%

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Kumar

Reh

Sxm

et al. 2019

Preprint

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Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naïve and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNFα and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

Cited by 140 publications

References 71 publications

HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand

HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand

SIV Latency in Macrophages in the CNS

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

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