HIV-1 Induces Telomerase Activity in Monocyte-Derived Macrophages, Possibly Safeguarding One of Its Reservoirs

Reynoso, Rita; Wieser, Matthias; Ojeda, Diego S.; Bönisch, Maximilian; Kühnel, Harald; Bolcic, Federico; Quendler, Heribert; Grillari, Johannes; Grillari‐Voglauer, Regina; Quarleri, Jorge

doi:10.1128/jvi.01495-12

Cited by 38 publications

(39 citation statements)

References 81 publications

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“…[69][70][71][72] In the case of latently infected cells, the modulation of DDR by HIV-1 may involve viral proteins expressed at a very low level (e.g. reservoirs established in macrophages).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells. These results indicate a DDR defect even though the virus is latent. DDR-inducing agents, specifically high doses of nucleoside RT inhibitors (NRTIs), caused greater increases in gamma-H2AX levels in latently infected cells. Additionally, latently infected cells are more susceptible to long-term exposure to G-quadruplex stabilizing agents, and this effect is enhanced when the agent is combined with an inhibitor targeting DNA-PK, which is crucial for DSB repair and telomere maintenance. Moreover, exposing these cells to the cancer drug etoposide resulted in formation of DSBs at a higher rate than in un-infected cells. Similar effects of etoposide were also observed in population of primary memory T cells infected with latent HIV-1. Sensitivity to these agents highlights a unique vulnerability of latently infected cells, a new feature that could potentially be used in developing therapies to eliminate HIV-1 reservoirs.

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Section: Discussionmentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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“…On the other hand, HIV-1 envelope glycoprotein has been shown to disrupt Fas and TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and regulate the induction of the prosurvival cytokine macrophage colony-stimulating factor (M-CSF) (52), whereas HIV Nef has been shown to prevent apoptosis in macrophages by inactivating the proapoptotic Bad protein (53). Others have shown that HIV infection induces noncanonical telomerase activity in macrophages that protects them from oxidative stress and DNA damage (54). Another study showed that SIV-specific CD8 ϩ T cells were unable to suppress viral replication in SIV-infected macrophages (55).…”

Section: The Gut Macrophage Reservoir In Hiv Infectionmentioning

confidence: 99%

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Brown¹,

Mattapallil²

2014

Clin. Vaccine Immunol.

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The gastrointestinal tract (GIT) is a primary site for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection, replication, and dissemination. After an initial explosive phase of infection, HIV establishes latency. In addition to CD4 T cells, macrophages are readily infected, which can persist for long periods of time. Though macrophages at various systemic sites are infected, those present in the GIT constitute a major cellular reservoir due to the abundance of these cells at mucosal sites. Here, we review some of the important findings regarding what is known about the macrophage reservoir in the gut and explore potential approaches being pursued in the field to reduce this reservoir. The development of strategies that can lead to a functional cure will need to incorporate approaches that can eradicate the macrophage reservoir in the GIT. Macrophages are one of the most abundant immune cells in the gut (1, 2). Morphologically, gut macrophages are similar to most resident tissue macrophages, with a mononuclear shape and a granular cytoplasm, and they are highly phagocytic and microbicidal (3-5). They express major histocompatibility complex (MHC) class II, CD36, CD68, CD163 (6, 7), and CD209 (7) but have low levels of CD80, CD86, and CD40 (8-11). Unlike monocytes in peripheral blood that are largely CD14 ϩ , human mucosal macrophages in the gut have been shown to express aϪ phenotype (12, 13). The expression of CD4 and CCR5/CXCR4 key receptors for human immunodeficiency virus (HIV) infection, on macrophage populations has been shown to differ based on the sites the cells reside in. Shen et al. (14) showed that vaginal macrophages expressed CD4 and CCR5/CXCR4 similarly to blood monocytes, whereas intestinal macrophages expressed little or no detectable CD4 and CCR5/CXCR4 (15-17).Interestingly, under normal conditions or in response to Tolllike receptor (TLR) ligands, gut macrophages constitutively secrete anti-inflammatory cytokines, such as interleukin-10 (IL-10), rather than proinflammatory mediators, such as IL-12, IL-23, tumor necrosis factor alpha (TNF-␣), IL-1, IL-6, and interferoninducible protein 10 (IP-10) (18)(19)(20)(21)(22), suggesting that intestinal macrophages may be critical for maintaining immune homeostasis in the gastrointestinal tract (6). Smythies et al. (23) reported that intestinal macrophages displayed significant inflammation anergy even though they had avid phagocytic and bactericidal activity. Depletion of mucosal macrophages was shown to be associated with increased susceptibility to colitis and graft-versus-host disease in mice (24-26). Likewise, altering the phenotype of macrophages to that of a proinflammatory phenotype as seen during HIV replication was associated with increased inflammation and tissue damage (27).In addition to their role in maintaining mucosal immune homeostasis, gut macrophages, like dendritic cells (DC), have been shown to sample microbes directly from the intestinal lumen and transfer these antigens to DC for processing or tran...

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“…The nondividing status of terminally differentiated macrophages and low deoxynucleoside triphosphate (dNTP) levels have to be accommodated in order for primate lentiviruses to establish a productive infection (5,6). Additionally, macrophages are resistant to the cytopathic effects of viral replication in comparison to the sensitivity of activated CD4 ϩ T cells (2,(7)(8)(9), and HIV-1 has evolved mechanisms to prolong the life span of infected macrophages (9,10). HIV-1 can also be detected in individuals on suppressive antiretroviral therapy (ART), raising the possibility that these cells serve as a viral reservoir (11).…”

mentioning

confidence: 99%

Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8 ⁺ T Cell Killing

Rainho

Martins

Cunyat

et al. 2015

J Virol

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Simian immunodeficiency virus (SIV)-specific CD8؉ T cells kill SIV-infected CD4 ؉ T cells in an major histocompatibility complex class I (MHC-I)-dependent manner. However, they are reportedly less efficient at killing SIV-infected macrophages. Since the viral accessory protein Nef has been shown to downregulate MHC-I molecules and enhance cytotoxic T lymphocyte (CTL) evasion in human immunodeficiency virus type 1 (HIV-1)-infected CD4؉ T cells, we examined whether Nef played a role in protecting SIV-infected macrophages from killing by SIV-specific CD8 ؉ T cells. To explore the role of Nef in CD8 ؉ T cell evasion, we compared the ability of freshly sorted SIV-specific CD8 ؉ T cells to readily suppress viral replication or eliminate CD4 ؉ T cells or monocyte-derived macrophages infected with SIV variants containing wild-type (WT) or mutated nef genes. As expected, SIVspecific CD8؉ T cells suppressed viral replication and eliminated the majority of SIV-infected CD4 ؉ T cells, and this killing was enhanced in CD4؉ T cells infected with the nef variants. However, macrophages infected with nef variants that disrupt MHC-I downregulation did not promote rapid killing by freshly isolated CD8 ؉ T cells. These results suggest that mechanisms other than Nef-mediated MHC-I downregulation govern the resistance of SIV-infected macrophages to CD8؉ T cell-mediated killing. This study has implications for viral persistence and suggests that macrophages may afford primate lentiviruses some degree of protection from immune surveillance. Macrophages may play an important role in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) pathogenesis. Infection of microglia and perivascular macrophages actively mediates entry of HIV-1 into the central nervous system (CNS), resulting in HIV-associated dementia, encephalitis, cognitive disorder, and peripheral neuropathy (1). Accumulating data suggest that tissue macrophages are an important reservoir of virus. Infection of rhesus macaques with a highly pathogenic hybrid simian-human immunodeficiency virus (SHIV) resulted in the rapid depletion of CD4 ϩ T cells such that macrophages were the principal reservoir that sustained high viral loads in the SHIV-infected animals (2). In another study, rhesus macaques depleted of CD4 ϩ T cells exhibited higher viral loads than nondepleted animals, and in situ staining performed on gut tissue revealed that macrophages were the primary source of viral replication (3). It has also been suggested that the level of monocyte turnover is responsible for disease progression in the macaque model of AIDS (4).Macrophages present unique obstacles to infection by primate lentiviruses. The nondividing status of terminally differentiated macrophages and low deoxynucleoside triphosphate (dNTP) levels have to be accommodated in order for primate lentiviruses to establish a productive infection (5, 6). Additionally, macrophages are resistant to the cytopathic effects of viral replication in comparison to the sensitivity of activated ...

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HIV-1 Induces Telomerase Activity in Monocyte-Derived Macrophages, Possibly Safeguarding One of Its Reservoirs

Cited by 38 publications

References 81 publications

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8 ⁺ T Cell Killing

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HIV-1 Induces Telomerase Activity in Monocyte-Derived Macrophages, Possibly Safeguarding One of Its Reservoirs

Cited by 38 publications

References 81 publications

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

Gastrointestinal Tract and the Mucosal Macrophage Reservoir in HIV Infection

Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8 + T Cell Killing

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Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8 ⁺ T Cell Killing