Poliovirus mutants excreted by a chronically infected hypogammaglobulinemic patient establish persistent infections in human intestinal cells

Abstract

Immunodeficient patients whose gut is chronically infected by vaccine-derived poliovirus (VDPV) may excrete large amounts of virus for years. To investigate how poliovirus (PV) establishes chronic infections in the gut, we tested whether it is possible to establish persistent VDPV infections in human intestinal Caco-2 cells. Four type 3 VDPV mutants, representative of the viral evolution in the gut of a hypogammaglobulinemic patient over almost 2 years [J. Virol. 74 (2000) 3001], were used to infect both undifferentiated, dividing cells, and differentiated, polarized enterocytes. A VDPV mutant excreted 36 days postvaccination by the patient was lytic in both types of intestinal cell cultures, like the parental Sabin 3 (S3) strain. In contrast, three VDPVs excreted 136, 442, and 637 days postvaccination, established persistent infections both in undifferentiated cells and in enterocytes. Thus, viral determinants selected between day 36 and 136 conferred on VDPV mutants the capacity to infect intestinal cells persistently. The percentage of persistently VDPV-infected cultures was higher in enterocytes than in undifferentiated cells, implicating cellular determinants involved in the differentiation of enterocytes in persistent VDPV infections. The establishment of persistent infections in enterocytes was not due to poor replication of VDPVs in these cells, but was associated with reduced viral adsorption to the cell surface.

Universal use of inactivated polio vaccine

“…A falta de cobertura vacinal da população favorece a disseminação dos vírus (caso de Hispaniola, em que a cobertura girava em torno de 30 a 60% em 2000 44 ), daí a não ocorrência de surto nos EUA, pelo menos até o presente momento. É importante salientar que, nos EUA, o esquema vacinal contra poliomielite utiliza exclusivamente a IPV desde 2000, não tendo havido desde essa ocasião nenhum caso de VAPP 46 .…”

“…Falhas na cobertura vacinal são fatores críticos determinantes da ocorrência dos surtos de cVDPV 38 . Note-se que, conforme as recentes publicações da OMS 8 Outro problema a ser enfrentado é a manutenção dos poliovírus nos imunossuprimidos (iVDPV), como reservatórios potenciais, com excreção permanente dos vírus (podendo chegar a mais de 6 meses em pessoa com imunodeficiência primária severa) 46 . Teoricamente, os iVDPV podem reintroduzir os poliovírus na população geral.…”

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

“…However, many viral and some cellular mRNAs have evolved a capindependent mechanism of translation initiation t h a t u s e s a h i g h l y s t r u c t u r e d i n t e r n a l ribosome-entry site (IRES) sequence located in the 5' untranslated region (5'UTR) of their mRNA (Holcik & Sonenberg, 2005). The IRES was first discovered in poliovirus (a typical member of picornaviruses) and later in other viruses such as hepatitis C virus (HCV), HIV, Herpesviruses, etc., and also in many cellular mRNAs (Jang, et al, 1988, Labadie, et al, 2004, Locker, et al, 2011, Pelletier & Sonenberg, 1988. Cellular physiological conditions dictate when a given mRNA uses cap-dependent or IRES-dependent translation initiation.…”

Enhanced Gene Silencing in Cells Cured of Persistent Virus Infection by RNA Interference

“…However, virus clearance from cells and the complete cure of persistent virus infections have only rarely been reported (24, 25). We have developed several models of persistent virus infection by using poliovirus (PV), a positive-strand RNA virus of the Picornaviridae family (5,7,16,21). We previously studied the effects of antiviral siRNAs applied months after the infection of HEp-2 cells with a persistent PV mutant (7, 25).…”

“…Treated and mock-treated cells were infected 16 h posttransfection with PV strain Sabin 3, at a multiplicity of infection (MOI) of 1 50% infectious dose (ID 50 ) per cell. The viral progeny was titrated 24 h postinfection, as previously described (16). HEp-Q4 and HEp-Q5 were permissive to PV infection, although viral yields were about 1 log lower in these cells than in HEp-2 cells (Fig.…”