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Review
. 2015 Mar;12(2):128-38.
doi: 10.1038/cmi.2014.75. Epub 2014 Aug 18.

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

Mark R Wills, Emma Poole, Betty Lau, Ben Krishna, John H Sinclair
Review

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

Mark R Wills et al. Cell Mol Immunol. 2015 Mar.

Abstract

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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Figures

Figure 1
Figure 1
Following primary infection, HCMV replicates and disseminates during which time the host generates an effective immune response which includes natural killer cells, neutralizing antibodies and a high frequency of CD4+ and CD8+ T cells. This eventually controls viral replication and resolves the primary infection. HCMV, human cytomegalovirus.
Figure 2
Figure 2
HCMV replicates and disseminates leading to infection of myeloid progenitors and the establishment of latent infection in e.g., CD34+ bone marrow progenitor cells. Reactivation of virus from these sites followed by new virus replication and productive replication induces secondary immune responses. HCMV, human cytomegalovirus.
Figure 3
Figure 3
During lytic infection, HCMV expresses numerous viral proteins which mediate immune evasion. These include viral genes which interfere with host interferon responses, natural killer cell recognition (e.g. UL16, 18, 40, 141,142, US18, US20) as well as CD4+ and CD8+ T-cell recognition by preventing MHC Class I and II antigen processing and presentation (e.g. US2 US11). Other viral genes, such as the viral IL-10 homologue (UL111a), as well as viral proteins that act as receptor sinks for host inflammatory cytokines (US28), aid in general suppression of the host immune responses. HCMV, human cytomegalovirus.
Figure 4
Figure 4
HCMV can establish latency in CD34+ myeloid progenitor cells and is carried down the myeloid lineage. In latently infected CD34+ cells and CD14+ monocytes, there is a targeted suppression of lytic viral gene expression and generally undetectable levels of major IE proteins. However, expression of a number of latency-associated genes is detectable. These include transcripts from the major IE region (UL122–123 CLTs), UL81–82ast (LUNA), UL138, UL111a, UL144 and US28, although, more recently, other RNAs have been identified. Differentiation of these cells to macrophages and mDCs causes the derepression of the MIEP and allows initiation of the lytic transcription programme which involves a temporal cascade of viral gene transcription and translation (consisting of immediate early, early and late gene products), allowing viral DNA replication and reactivation of de novo virus production. HCMV, human cytomegalovirus; mDC, mature dendritic cell; MIEP, major immediate early promoter.
Figure 5
Figure 5
Latently infected CD34+ cells produce a secretome high in immunosuppressive cytokines such as cIL-10 and TGF-β which act to inhibit anti-viral CD4+ cytokine and cytotoxicity (Th1) cell effector function. Uninfected bystander CD34+ cells are also induced to secrete cIL-10 and TGF-β further enhancing the immunosuppressive microenvironment. Antigen-specific CD4+ regulatory T cells also recognize latent viral proteins and secrete their own cIL-10 and TGF-β which also generates an immunosuppressive microenvironment, so helping to prevent clearance of latently infected cells. cIL-10, cellular IL-10.
Figure 6
Figure 6
Neutralization of the immunosuppressive cytokines cIL-10 and TGF-β and/or depletion of regulatory T cells could allow latent viral proteins to be recognized by anti-viral CD4+ (Th1) effector cells. Treatment of latently infected cells with HDAC inhibitors could also allow transient expression of viral IE proteins which, after processing and presentation by Class I MHC, would be predicted to allow IE-specific CD8+ cytotoxic T cells (CTLs) to now recognize cells containing latent virus. cIL-10, cellular IL-10; HDAC, histone deacetylase.
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References

    1. 1Rubin RH. Cytomegalovirus in solid organ transplantation. Transpl Infect Dis 2001; 3(Suppl 2): 1–5. - PubMed
    1. 2Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J Gen Virol 2006; 87: 1763–1779. - PubMed
    1. 3Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res 2011; 157: 151–160. - PubMed
    1. 4Powers C, DeFilippis V, Malouli D, Fruh K. Cytomegalovirus immune evasion. Curr Top Microbiol Immunol 2008; 325: 333–359. - PubMed
    1. 5Amsler L, Verweij MC, DeFilippis VR. The tiers and dimensions of evasion of the type I interferon response by human cytomegalovirus. J Mol Biol 2013; 425: 4857–4871. - PMC - PubMed

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