Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells

Gray, Lachlan Robert; On, Hung; Roberts, Emma L.; Lu, Hao K; Moso, Michael A; Raison, Jacqueline A.; Papaioannou, Catherine; Cheng, Wan-Jung; Ellett, Anne; Jacobson, Jonathan; Purcell, Damian F. J.; Wesselingh, Steve; Gorry, Paul R; Lewin, Sharon R.; Churchill, Melissa

doi:10.1007/s13365-015-0413-4

Cited by 29 publications

(39 citation statements)

References 37 publications

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“…These data are in agreement with previous studies showing no increase in HIV‐1 production by LRAs in persistently infected astrocytes (Chauhan, ; Li et al, ). However, other studies reported some reactivation with bryostatin (Diaz et al, ), JQ1 and various HDAC inhibitors (Gray et al, ; Narasipura et al, ). Differences in experimental methodologies may account for the discrepant findings.…”

Section: Discussionmentioning

confidence: 96%

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Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Barat

Proust

Deshière

et al. 2018

Glia

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The "shock and kill" HIV-1 cure strategy proposes eradication of stable cellular reservoirs by clinical treatment with latency-reversing agents (LRAs). Although resting CD4 T cells latently infected with HIV-1 constitute the main reservoir that is targeted by these approaches, their consequences on other reservoirs such as the central nervous system are still unknown and should be taken into consideration. We performed experiments aimed at defining the possible role of astrocytes in HIV-1 persistence in the brain and the effect of LRA treatments on this viral sanctuary. We first demonstrate that the diminished HIV-1 production in a proliferating astrocyte culture is due to a reduced proliferative capacity of virus-infected cells compared with uninfected astrocytes. In contrast, infection of non-proliferating astrocytes led to a robust HIV-1 infection that was sustained for over 60 days. To identify astrocytes latently infected with HIV-1, we designed a new dual-color reporter virus called NL4.3 eGFP-IRES-Crimson that is fully infectious and encodes for all viral proteins. Although we detected a small fraction of astrocytes carrying silent HIV-1 proviruses, we did not observe any reactivation using various LRAs and even strong inducers such as tumor necrosis factor, thus suggesting that these proviruses were either not transcriptionally competent or in a state of deep latency. Our findings imply that astrocytes might not constitute a latent reservoir per se but that relentless virus production by this brain cell population could contribute to the neurological disorders seen in HIV-1-infected persons subjected to combination antiretroviral therapy.

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Section: Discussionmentioning

confidence: 96%

“…In addition, the high concentration of SAHA used in this study (i.e., 10 μM) was toxic when we used it with HFA (data not shown). Gray et al reported that some LRAs promote HIV‐1 transcription in HFA (Gray et al, ). However, they only monitored HIV‐1‐specific RNA levels, which do not necessarily reflect protein expression.…”

Section: Discussionmentioning

confidence: 99%

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Barat

Proust

Deshière

et al. 2018

Glia

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“…Along with CD4 ϩ T cells, macrophages and microglial cells are targets of HIV infection in vivo and are associated with neurocognitive disorders and tissue pathology, especially during the late stages of AIDS, when T cells are depleted (6)(7)(8)(9)(10)(11). Several distinct features of HIV replication in macrophages underscore their key role as potential viral reservoirs (12,13), including (i) relative resistance to the cytopathic effects of HIV compared to T cells (14); (ii) harboring replication-competent virus for up to several weeks (15); (iii) residing within lymphoid tissues, where antiretroviral drug (ARV) penetration is reduced (16)(17)(18); and (iv) viral accumulation within surface-connected compartments (19)(20)(21) that are inaccessible to neutralizing antibodies (6).…”

mentioning

confidence: 99%

HIV Infection Stabilizes Macrophage-T Cell Interactions To Promote Cell-Cell HIV Spread

López

Koh

Hnatiuk

et al. 2019

J Virol

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Macrophages are susceptible to HIV infection and play an important role in viral dissemination through cell-cell contacts with T cells. However, our current understanding of macrophage-to-T cell HIV transmission is derived from studies that do not consider the robust migration and cell-cell interaction dynamics between these cells. Here, we performed live-cell imaging studies in 3-dimensional (3D) collagen that allowed CD4+ T cells to migrate and to locate and engage HIV-infected macrophages, modeling the dynamic aspects of the in situ environment in which these contacts frequently occur. We show that HIV+ macrophages form stable contacts with CD4+ T cells that are facilitated by both gp120-CD4 and LFA-1–ICAM-1 interactions and that prolonged contacts are a prerequisite for efficient viral spread. LFA-1–ICAM-1 adhesive contacts function to restrain highly motile T cells, since their blockade substantially destabilized macrophage-T cell contacts, resulting in abnormal tethering events that reduced cell-cell viral spread. HIV-infected macrophages displayed strikingly elongated podosomal extensions that were dependent on Nef expression but were dispensable for stable cell-cell contact formation. Finally, we observed persistent T cell infection in dynamic monocyte-derived macrophage (MDM)-T cell cocultures in the presence of single high antiretroviral drug concentrations but achieved complete inhibition with combination therapy. Together, our data implicate macrophages as drivers of T cell infection by altering physiological MDM-T cell contact dynamics to access and restrain large numbers of susceptible, motile T cells within lymphoid tissues. IMPORTANCE Once HIV enters the lymphoid organs, exponential viral replication in T cells ensues. Given the densely packed nature of these tissues, where infected and uninfected cells are in nearly constant contact with one another, efficient HIV spread is thought to occur through cell-cell contacts in vivo. However, this has not been formally demonstrated. In this study, we performed live-cell imaging studies within a 3-dimensional space to recapitulate the dynamic aspects of the lymphoid microenvironment and asked whether HIV can alter the morphology, migration capacity, and cell-cell contact behaviors between macrophages and T cells. We show that HIV-infected macrophages can engage T cells in stable contacts through binding of virus- and host-derived adhesive molecules and that stable macrophage-T cell contacts were required for high viral spread. Thus, HIV alters physiological macrophage-T cell interactions in order to access and restrain large numbers of susceptible, motile T cells, thereby playing an important role in HIV progression.

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“…This means it is anatomically able to target any latently infected cells residing within the CNS. However, Gray et al found it did not induce viral transcription in monocyte-derived macrophages, a cellular model for brain perivascular macrophages and microglia, or primary foetal astrocytes [50]. This result is disappointing: if reproducible in vivo, disulfiram may not improve the cognitive decline of HIV patients.…”

Section: Discussionmentioning

confidence: 99%

A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice

Hdj

2017

AIDS Research and Treatment

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Combination antiretroviral therapy (cART) effectively suppresses the replication of human immunodeficiency virus type 1 (HIV-1), improves immune function, and decreases the morbidity of acquired immune deficiency syndrome (AIDS). However, it is unable to eradicate the virus because it does not eliminate latently infected cells. The latent reservoir poses the major barrier to an HIV-1 cure. The “shock and kill” strategy aims to reactivate the virus and destroy latently infected cells. Many latency reversing agents (LRAs) reactivate HIV in vitro, but the absence of damaging side-effects and efficacy in vivo make disulfiram particularly promising. However, in clinical trials to date, disulfiram treatment has not resulted in a reduction in the size of the latent reservoir. In this article I will therefore discuss the evidence for the latency reversing effect of disulfiram, the possible explanations for its inability to reduce the size of the latent reservoir in vivo, and the caveats associated with its use in practice. These considerations will help to inform judgements about the prospect of an HIV cure from disulfiram based treatments.

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Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells

Cited by 29 publications

References 37 publications

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

Astrocytes sustain long‐term productive HIV‐1 infection without establishment of reactivable viral latency

HIV Infection Stabilizes Macrophage-T Cell Interactions To Promote Cell-Cell HIV Spread

A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice

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