The search for an HIV cure: tackling latent infection

Kent, Stephen J.; Reece, Jeanette C.; Petravic, Janka; Martyushev, Alexey; Kramski, Marit; Rose, Robert De; Cooper, David A.; Kelleher, Anthony D.; Emery, Sean; Cameron, Paul; Lewin, Sharon R.; Davenport, Miles P.

doi:10.1016/s1473-3099(13)70043-4

Cited by 57 publications

(41 citation statements)

References 88 publications

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“…It is worth noting that similar approaches are currently being tested in cell populations latently infected with HIV-1 to promote 'reawakening' of latent HIV gene expression to allow these cells to be recognized and eliminated by HIV-specific T cells. [95][96][97] There is a very clear rational behind reducing the latent load within an individual person to limit viral reactivation; however, this clearly needs to be balanced by the risks that such an intervention may carry with it. In the case of particular clinical settings, such as immunosuppression in transplantation, we would suggest that this balance is in favour of using chemotherapeutic and/or immunological techniques to reduce the latent reservoir.…”

Section: Induction Of Immunogenic Lytic Genes In the Absence Of Immunmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Section: Induction Of Immunogenic Lytic Genes In the Absence Of Immunmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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“…Although the introduction of effective antiretroviral therapy (ART) has resulted in huge reductions in rates of human immunodeficiency virus type 1 (HIV-1) illness, HIV-1 infection remains incurable. In addition, ART encounters a number of challenges, including a persistent latent viral reservoir, the requirement for lifelong adherence, and the potential development of drug resistance and toxicity (Chun et al, 2008;Corbeau & Reynes, 2011;Kent et al, 2013;Richman et al, 2009;Sendagire et al, 2009). Thus the development of novel therapeutic methods that may enhance current therapeutic options and even lead to curative approaches would significantly expand our portfolio of strategies to counteract HIV-1/AIDS.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Guan

et al. 2015

Journal of General Virology

179

136

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CCR5 serves as an essential coreceptor for human immunodeficiency virus type 1 (HIV-1) entry, and individuals with a CCR5 D32 variant appear to be healthy, making CCR5 an attractive target for control of HIV-1 infection. The CRISPR/Cas9, which functions as a naturally existing adaptive immune system in prokaryotes, has been recently harnessed as a novel nuclease system for genome editing in mammalian cells. Although CRISPR/Cas9 can be readily delivered into cell lines, due to the large size of the Cas9 protein, efficient delivery of CCR5-targeting CRISPR/Cas9 components into primary cells, including CD4 + T-cells, the primary target for HIV-1 infection in vivo, remains a challenge. In the current study, following design of a panel of top-ranked single-guided RNAs (sgRNAs) targeting the ORF of CCR5, we demonstrate that CRISPR/Cas9 can efficiently mediate the editing of the CCR5 locus in cell lines, resulting in the knockout of CCR5 expression on the cell surface. Next-generation sequencing revealed that various mutations were introduced around the predicted cleavage site of CCR5. For each of the three most effective sgRNAs that we analysed, no significant off-target effects were detected at the 15 top-scoring potential sites. More importantly, by constructing chimeric Ad5F35 adenoviruses carrying CRISPR/Cas9 components, we efficiently transduced primary CD4 + Tlymphocytes and disrupted CCR5 expression, and the positively transduced cells were conferred with HIV-1 resistance. To our knowledge, this is the first study establishing HIV-1 resistance in primary CD4 + T-cells utilizing adenovirus-delivered CRISPR/Cas9.

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“…The Journal of Immunology, 2014, 192: 308-315. A n urgent need exists for novel prophylactic vaccine constructs against HIV, as well as immunotherapeutic interventions to target reactivated latent viral reservoirs. There is increased interest in using NK cell-mediated Abdependent cellular cytotoxicity (ADCC) for such prophylactic and therapeutic purposes (1)(2)(3). Interest in ADCC has been stimulated by a series of observations implying the involvement of this immune response in the control and prevention of HIV infection.…”

mentioning

confidence: 99%

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

Parsons

Tang

Jegaskanda

et al. 2014

The Journal of Immunology

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There is much interest in the potential of Ab-dependent cellular cytotoxicity (ADCC) to slow disease progression following HIV infection. Despite several studies demonstrating a positive association between ADCC and slower disease progression, it is possible that continued stimulation of NK cells by ADCC during chronic HIV infection could render these cells dysfunctional. Indeed, activation of NK cells by ADCC results in matrix metalloproteinase–induced reductions in CD16 expression and activation refractory periods. In addition, ex vivo analyses of NK cells from HIV-infected individuals revealed other alterations in phenotype, such as decreased expression of the activating NKp46 receptor that is essential for NK-mediated antitumor responses and immunity from infection. Because NKp46 shares a signaling pathway with CD16, we hypothesized that activation-induced downregulation of both receptors could be controlled by a common mechanism. We found that activation of NK cells by anti-HIV or anti-CD16 Abs resulted in NKp46 downregulation. The addition of a matrix metalloproteinase inhibitor attenuated NKp46 downregulation following NK cell activation by anti-HIV Abs. Consequently, these results suggest that continued stimulation through CD16 has the potential to impair natural cytotoxicity via attenuation of NKp46-dependent signals.

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The search for an HIV cure: tackling latent infection

Cited by 57 publications

References 88 publications

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Anti-HIV Antibody–Dependent Activation of NK Cells Impairs NKp46 Expression

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