Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV

Cummins, Nathan W.; Badley, Andrew D.

doi:10.1007/s00018-012-1239-3

Cited by 28 publications

(32 citation statements)

References 73 publications

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“…HIV-1 replication and spread is closely connected with the induction of cell death and can be modulated by its onset (Cummins and Badley, 2013;Wang et al, 2011Wang et al, , 2016. While the general apoptosis due to toxicity of latency reversing agents is not desirable, elimination of the infected cells is a goal of all approaches aiming at curing HIV-1.…”

Section: Discussionmentioning

confidence: 99%

Effects of heme degradation products on reactivation of latent HIV-1

Shankaran¹,

Madlenakova²,

Hajkova³

et al. 2017

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Human immunodeficiency virus (HIV-1) infection can be currently controlled by combined antiretroviral therapy, but a sterilizing cure is not achievable as this therapy does not target persistent HIV-1 in latent reservoirs. Therefore, different latency reversal agents are intensively explored in various models. We have previously observed that heme arginate, a drug approved for human use, reveals a strong synergism with PKC inducers in reactivation of the latent provirus. Heme is physiologically decomposed by heme oxygenases into 3 degradation products: iron (Fe2+), carbon monoxide (CO) and biliverdin which is further converted to bilirubin by biliverdin reductase. In this paper, we have studied the effects of individual heme-degradation products on latent HIV-1 reactivation in ACH-2 cells harboring integrated HIV-1 provirus and in H12 clone of Jurkat cells harboring HIV-minivirus expressing EGFP. We employed addition of ascorbate to generate Fe2+, resulting in increased expression of both HIV-1 p24 Ag and EGFP in PMA-stimulated ACH-2 and H12 cells, respectively, as characterized on RNA and protein levels. On the other hand, addition of a CO-donor or bilirubin decreased the p24 expression. The reactivation of latent HIV-1 by iron or heme arginate was inhibited by antioxidant N-acetyl cysteine, or by an iron chelator desferrioxamine, suggesting that the effects were mediated by iron- or heme-induced redox stress. Finally, we demonstrated the stimulatory effects of heme arginate and PMA on HIV-1 expression in peripheral blood mononuclear cells of HIV-infected patients cultured ex vivo. These results may constitute a new direction in the latent HIV-1 reactivation and therapy.

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Section: Discussionmentioning

confidence: 99%

Effects of heme degradation products on reactivation of latent HIV-1

Shankaran¹,

Madlenakova²,

Hajkova³

et al. 2017

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“…However, failures in these therapies due to the development of mutant viral strains, does not always lead to an increase in apoptosis [221]. This is observed in the use of enfuvirtide to inhibit gp41 fusion activity.…”

Section: Therapeutic Targets: Targeting Apoptotic Pathwaysmentioning

confidence: 99%

Human Immunodeficiency Virus-1 (HIV-1)-Mediated Apoptosis: New Therapeutic Targets

Mbita

Hull

Dlamini

2014

Viruses

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HIV has posed a significant challenge due to the ability of the virus to both impair and evade the host’s immune system. One of the most important mechanisms it has employed to do so is the modulation of the host’s native apoptotic pathways and mechanisms. Viral proteins alter normal apoptotic signaling resulting in increased viral load and the formation of viral reservoirs which ultimately increase infectivity. Both the host’s pro- and anti-apoptotic responses are regulated by the interactions of viral proteins with cell surface receptors or apoptotic pathway components. This dynamic has led to the development of therapies aimed at altering the ability of the virus to modulate apoptotic pathways. These therapies are aimed at preventing or inhibiting viral infection, or treating viral associated pathologies. These drugs target both the viral proteins and the apoptotic pathways of the host. This review will examine the cell types targeted by HIV, the surface receptors exploited by the virus and the mechanisms whereby HIV encoded proteins influence the apoptotic pathways. The viral manipulation of the hosts’ cell type to evade the immune system, establish viral reservoirs and enhance viral proliferation will be reviewed. The pathologies associated with the ability of HIV to alter apoptotic signaling and the drugs and therapies currently under development that target the ability of apoptotic signaling within HIV infection will also be discussed.

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“…The progressive loss of CD4+ T cells is so reliable that it is used as a marker of HIV-1 disease progression. Intriguingly, macrophages are also permissive to HIV-1 infection but are largely spared the cytopathic effects of replicating virus, suggesting a selective impairment of the apoptotic response in these specific host cells ( Cummins and Badley, 2013). S everal viruses, including HIV-1, have been shown to prevent TRAIL-induced apoptosis in macrophages via the control of certain host cytokines (Swingler et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Viral apoptosis evasion via the MAPK pathway by use of a host long noncoding RNA

Barichievy

Naidoo

Boullé³

et al. 2017

Preprint

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SUMMARYAn emerging realisation of infectious disease is the high incidence of genetic instability resulting from pathogen-induced DNA lesions, often leading to classical hallmarks of cancer such as evasion of apoptosis. The Human Immunodeficiency Virus type 1 (HIV-1) induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages, thereby leading to long-term dissemination of the pathogen specifically by these host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21, in a complex with its protein binding partners HuR and hnRNP-K. Here, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Notably, this pro-survival cascade is unavailable for similar viral manipulation in CD4+ T cells. The introduction of MAP2K1, ERK2 or HDM2 inhibitors in HIV-infected macrophages results in apoptosis providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and hnRNP-K. These results reveal pathogenic control of apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.

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Anti-apoptotic mechanisms of HIV: lessons and novel approaches to curing HIV

Cited by 28 publications

References 73 publications

Effects of heme degradation products on reactivation of latent HIV-1

Effects of heme degradation products on reactivation of latent HIV-1

Human Immunodeficiency Virus-1 (HIV-1)-Mediated Apoptosis: New Therapeutic Targets

Viral apoptosis evasion via the MAPK pathway by use of a host long noncoding RNA

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