Human cytomegalovirus vaccine development: Immune responses to look into vaccine strategy

Lin, Xia; Su, Ruochen; An, Zhiqiang; Fu, Tong Ming; Luo, Wenxin

doi:10.1080/21645515.2017.1391433

Cited by 12 publications

(9 citation statements)

References 126 publications

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“…Though the pentameric complex elicits a high titer of HCMV neutralization activity, the antibodies elicited are protective against HCMV infection of epithelial cells, endothelial cells and monocytes, but not fibroblasts or primary trophoblast progenitor cells [ 46 , 47 , 48 , 49 , 68 , 69 , 70 , 71 ]. It has been suggested that the combination of trimeric gB and pentameric complex proteins may be an optimal prophylactic HCMV vaccine [ 37 , 72 , 73 ]. The effect of gB in combination with pentameric complex has been evaluated using MVA vectored or RNA vaccine that simultaneously express gB and the pentameric complex [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

et al. 2020

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Human cytomegalovirus (HCMV) core fusion machinery proteins gB and gH/gL, and accessory proteins UL128/UL130/UL131A, are the key envelope proteins that mediate HCMV entry into and infection of host cells. To determine whether these HCMV envelope proteins could elicit neutralizing activities synergistically, we immunized rabbits with individual or various combinations of these proteins adsorbed to aluminum hydroxide mixed with CpG-ODN. We then analyzed serum neutralizing activities with multiple HCMV laboratory strains and clinical isolates. HCMV trimeric gB and gH/gL elicited high and moderate titers of HCMV neutralizing activity, respectively. HCMV gB in combination with gH/gL elicited up to 17-fold higher HCMV neutralizing activities compared to the sum of neutralizing activity elicited by the individual proteins analyzed with both fibroblasts and epithelial cells. HCMV gB+gH/gL+UL128/UL130/UL131A in combination increased the neutralizing activity up to 32-fold compared to the sum of neutralizing activities elicited by the individual proteins analyzed with epithelial cells. Adding UL128/UL130/UL131A to gB and gH/gL combination did not increase further the HCMV neutralizing activity analyzed with fibroblasts. These data suggest that the combination of HCMV core fusion machinery envelope proteins gB+gH/gL or the combination of gB and pentameric complex could be ideal vaccine candidates that would induce optimal immune responses against HCMV infection.

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Section: Discussionmentioning

confidence: 99%

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

et al. 2020

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“…Novel approaches for treatment of HCMV infections are areas of great research interest. No vaccines aimed at ameliorating the severity of disease and preventing HCMV infections have so far been successful in achieving durable and protective immunity [85, 86]. Several new promising vaccine strategies against HCMV have been developed and evaluated ex vivo and in animal models [82, 87, 88].…”

Section: Treatment Of Oncogenic Hcmv Infectionsmentioning

confidence: 99%

The emerging role of human cytomegalovirus infection in human carcinogenesis: a review of current evidence and potential therapeutic implications

2019

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It is well-established that infections with viruses harboring oncogenic potential increase the cancer risk. Virus induced oncogenic processes are influenced by a complex and unique combination of host and environmental risk factors that are currently not fully understood. Many of the oncogenic viruses exhibit a prolonged, asymptomatic latency after a primary infection, and cause cancer in only a minority of carriers. From an epidemiologic point of view, it is therefore difficult to determine their role in cancer development. However, recent evidence suggests a neoplastic potential of one additional ubiquitous virus; human Cytomegalovirus (HCMV). Emerging data presents HCMV as a plausible cancer-causing virus by demonstrating its presence in >90% of common tumor types, while being absent in normal tissue surrounding the tumor. HCMV targets many cell types in tumor tissues, and can cause all the ten proposed hallmarks of cancer. This virus exhibits cellular tumor-promoting and immune-evasive strategies, hijacks proangiogenic and anti-apoptotic mechanisms and induces immunosuppressive effects in the tumor micro-environment. Recognizing new cancer-causing mechanisms may increase the therapeutic potential and prophylactic options for virus associated cancer forms. Such approaches could limit viral spread, and promote anti-viral and immune controlling strategies if given as add on to standard therapy to potentially improve the prognosis of cancer patients. This review will focus on HCMV-related onco-viral mechanisms and the potential of HCMV as a new therapeutic target in HCMV positive cancer forms.

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“…Asymptomatic seropositivity has also been linked to increased risk for age-related, chronic inflammatory pathologies, including vascular disease, frailty and immune dysfuntion [7][8][9][10][11] . Currently, there is no vaccine for HCMV, and antivirals fail to eliminate the latent reservoir of virus because the drugs only target actively replicating virus 12,13 .…”

Section: Introductionmentioning

confidence: 99%

Cell Type-Specific Biogenesis of Novel Vesicles Containing Viral Products in Human Cytomegalovirus Infection

Momtaz

Molina

Mlera

et al. 2021

J Virol

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Human cytomegalovirus (HCMV), while highly restricted for the human species, infects an diverse array of cell types in the host. Patterns of infection are dictated by the cell type infected, but cell type-specific factors and how they impact tropism for specific cell types is poorly understood. Previous studies in primary endothelial cells showed that HCMV infection induces large multivesicular-like bodies (MVBs) that incorporate viral products, including dense bodies (DBs) and virions. Here we define the nature of these large vesicles using a recombinant virus where UL32, encoding the pp150 tegument protein, is fused in frame with green fluorescent protein (GFP, TB40/E-UL32-GFP). In fibroblasts, UL32-GFP-positive vesicles were marked with classical markers of MVBs, including CD63 and lysobisphosphatidic acid (LBPA), both classical MVB markers, as well as the clathrin and LAMP1. Unexpectedly, UL32-GFP-positive vesicles in primary human microvascular endothelial cells (HMVECs) were not labeled by CD63, and LBPA was completely lost from infected cells. We defined these UL32-positive vesicles in endothelial cells using markers for the cis-Golgi (GM130), lysosome (LAMP1), and autophagy (LC3B). These findings suggest that UL32-GFP containing MVBs in fibroblasts are derived from the canonical endocytic pathway and takeover classical exosomal release pathway. However, UL32-GFP containing MVBs in HMVECs are derived from the early biosynthetic pathway and exploit a less characterized early Golgi-LAMP1-associated non- canonical secretory autophagy pathway. These results reveal striking cell-type specific membrane trafficking differences in host pathways that are exploited by HCMV, which may reflect distinct pathways for virus egress. Importance Human cytomegalovirus (HCMV) is a herpesvirus that, like all herpesvirus, that establishes a life-long infection. HCMV remains a significant cause of morbidity and mortality in the immunocompromised and HCMV seropositivity is associated with age-related pathology. HCMV infects many cells in the human host and the biology underlying the different patterns of infection in different cell types is poorly understood. Endothelial cells are important target of infection that contribute to hematogenous spread of the virus to tissues. Here we define striking differences in the biogenesis of large vesicles that incorporate virions in fibroblasts and endothelial cells. In fibroblasts, HCMV is incorporated into canonical MVBs derived from an endocytic pathway, whereas HCMV matures through vesicles derived from the biosynthetic pathway in endothelial cells. This work defines basic biological differences between these cell types that may impact how progeny virus is trafficked out of infected cells.

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Human cytomegalovirus vaccine development: Immune responses to look into vaccine strategy

Cited by 12 publications

References 126 publications

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

The emerging role of human cytomegalovirus infection in human carcinogenesis: a review of current evidence and potential therapeutic implications

Cell Type-Specific Biogenesis of Novel Vesicles Containing Viral Products in Human Cytomegalovirus Infection

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