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A hunter virus that targets both infected cells and HIV free virions: implications for therapy.

ABSTRACT: The design of 'hunter' viruses aimed at destroying human immunodeficiency virus (HIV) infected cells is an active area of research that has produced promising results in vitro. Hunters are designed to target exposed viral envelope proteins in the membranes of infected cells, but there is evidence that the hunter may also target envelope proteins of free HIV, inducing virus-virus fusion. In order to predict the effects of this fusion on therapy outcomes and determine whether fusion ability is advantageous for hunter virus design, we have constructed a model to account for the possibility of hunter-HIV fusion. The study was based on a target cell-limited model of HIV infection and it examined the hunter therapeutic effect on recovering the HIV main target cells, the activated CD4(+) T lymphocytes. These cells assist in setting up an immune response to opportunistic infections. The study analyzed the hunter dual mechanisms to control infection and because of diverse estimates for viral production and clearance of HIV, simulations were examined at rates spanning an order of magnitude. Results indicate that without hunter-HIV fusion ability, hunters that kill HIV-infected cells lead to a substantial recovery of healthy cell population at both low and high HIV turnover rates. When hunter-HIV fusion is included, cell recovery was particularly enhanced at lower HIV turnover rates. This study shows that the fusion ability, in addition to hunter infection ability, could be a favorable attribute for improving the efficacy of hunter-viral therapy. These results provide support for the potential use of engineered viruses to control HIV and other viral infections.

SUBMITTER: Greer C

PROVIDER: S-EPMC3551785 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Enteric viruses are shed in fecal material by humans and other animals and are common contaminants in wastewater and surface water. Wastewater treatment plants often disinfect this effluent with low-pressure and medium-pressure UV lamps, which emit 254-nm and 220- to 280-nm irradiation, respectively. It is not known whether this treatment is efficacious against enteric viruses or how such treatments may inactivate these enteric viruses. This study examined UV disinfection for two enteric viruses: rotavirus (RV) (strain OSU with double-stranded RNA and a three-layer capsid) and Tulane virus (TV) (a cultivable surrogate for human norovirus with single-stranded RNA and a single-layer capsid). Viruses were treated with UV irradiation at 220 or 254 nm under conditions relevant to wastewater stabilization ponds, whose water is often used for irrigation. TV was susceptible to 220- or 254-nm UV at similar levels. It appears that UV irradiation inactivated TV by mutagenizing both its genome and capsid binding proteins. RV was more susceptible to UV at 220 nm than to UV at 254 nm. UV irradiation of RV at either 220 or 254 nm resulted in a virus that retained its ability to bind to its host cell receptor. After 220-nm treatment, the VP7 segment of the RV genome could not be amplified by PCR, suggesting that this treatment mutagenized the viral genome. However, this correlation was not observed when UV at 254 nm was used. Thus, RV and TV, with different genome and capsid contents, are targeted by UV irradiation in different ways.IMPORTANCE UV irradiation is becoming common for disinfection in water treatment plants, but little is known about the effectiveness of this treatment for enteric RNA viruses. Here, we observed that 220-nm UV irradiation was efficacious against rotavirus (RV) and Tulane virus (TV). UV irradiation at 254 nm inactivated TV to a greater extent than RV. Additional assays showed that UV irradiation compromised different portions of the RV and TV life cycles. UV irradiation decreased the binding of TV to its host receptor and mutagenized the TV genome. UV irradiation at 220 nm appeared to allow RV-host receptor interaction but halted RV genome replication. These findings provide knowledge about the disinfection of waterborne viruses, information that is important for the safe reuse or release of treated wastewater.

Project description:BackgroundGeneration of new reagents that can be used to screen or monitor HIV-1-specific responses constituted an interesting field in the development of HIV vaccines to improve their efficacy.MethodsWe have evaluated the specific T cell response against different types of NL4-3 virions (including NL4-3 aldrithiol-2 treated, NL4-3/?RT and R5 envelopes: NL4-3/?RT/?Env[AC10] and NL4-3/?RT/?Env[Bal]) and against pools of overlapping peptides (15 mer) encompassing the HIV-1 Gag and Nef regions. Cryopreserved PBMC from a subset of 69 chronic asymptomatic HIV positive individuals have been employed using different techniques including IFN-? ELISPOT assay, surface activation markers and intracellular cytokine staining (ICS) by flow cytometry.ResultsThe differential response obtained against NL4-3 aldrithiol-2 treated and NL4-3/?RT virions (25% vs 55%, respectively) allow us to divide the population in three groups: "full-responders" (positive response against both viral particles), "partial-responders" (positive response only against NL4-3/?RT virions) and "non-responders" (negative responses). There was no difference between X4 and R5 envelopes. The magnitude of the total responses was higher against NL4-3/?RT and was positively correlated with gender and inverse correlated with viral load. On the contrary CD4+ T cell count was not associated with this response. In any case responses to the viruses tended to be lower in magnitude than those detected by the overlapping peptides tested. Finally we have found an increased frequency of HLA-B27 allele (23% vs 9%) and a significant reduction in some activation markers (CD69 and CD38) on T cells surface in responders vs non-responders individuals.ConclusionsIn summary these virions could be considered as alternative and useful reagents for screening HIV-1-specific T cell responses in HIV exposed uninfected people, HIV infected patients and to assess immunogenicity of new prototypes both in vitro and in vaccine trials, by a feasible, simply, effective and low cost assay.

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A hunter virus that targets both infected cells and HIV free virions: implications for therapy.

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