Poliomyelitis in intraspinally inoculated poliovirus receptor transgenic mice

Mice transgenic with the human poliovirus receptor gene develop clinical signs and neuropathology similar to those of human poliomyelitis when neurovirulent polioviruses are inoculated into the central nervous system (CNS). Factors contributing to disease severity and the frequencies of paralysis and mortality include the poliovirus strain, dose, and gender of the mouse inoculated. The more neurovirulent the virus, as defined by monkey challenge results, the higher the rate of paralysis, mortality, and severity of disease. Also, the time to disease onset is shorter for more neurovirulent viruses. Male mice are more susceptible to polioviruses than females. TGM-PRG-3 mice have a 10-fold higher transgene copy number and produce 3-fold more receptor RNA and protein levels in the CNS than TGM-PRG-1 mice. CNS inoculations with type III polioviruses differing in relative neurovirulence show that these mouse lines are similar in disease frequency and severity, demonstrating that differences in receptor gene dosage and concomitant receptor abundance do not affect susceptibility to infection. However, there is a difference in the rate of accumulation of clinical signs. The time to onset of disease is shorter for TGM-PRG-3 than TGM-PRG-1 mice. Thus, receptor dosage affects the rate of appearance of poliomyelitis in these mice.     

Characterization of mutations in the VP(1) region of Sabin strain type 1 polioviruses isolated from vaccine-associated paralytic poliomyelitis cases in Iran.

BACKGROUND: The live-attenuated oral polio vaccine used to interrupt poliovirus transmission is genetically unstable. Reversion of some attenuating mutations, which normally occurs during vaccine strain replication in some recipients, and can rarely cause vaccine-associated paralytic poliomyelitis (VAPP). The poliovirus eradication program designed by the World Health Organization (WHO) includes immunization with OPV in addition to careful surveillance of all acute-flaccid paralysis (AFP) cases. OBJECTIVES: In Iran we last isolated imported wild poliovirus in 2000 and the immunization coverage was 100% in 2002. During 2001, there were three AFP cases with residual paralysis from which Sabin-like type 1 polioviruses were isolated in our national polio laboratory. STUDY DESIGN: The complete VP(1) region of the three isolates was sequenced and amino acid substitutions associated with these neurovirulent isolates were recorded. RESULTS: These isolates had either 4, 2 or 1 nucleotide substitution(s) in the VP(1) region, corresponding to amino acid change in the VP(1) of isolate 1 of either (H-[149]->Y), (T-[106]->A) or (I-[90]->L), respectively. CONCLUSIONS: Surveillance of the VAPP cases in countries where endemic transmission has recently ceased increases our understanding of the important neurovirulent mutations in vaccine-strain isolates and assists in planning the next step in the eradication program in these countries.     

A comparison of the neurotropism of Theiler's virus and poliovirus in CBA mice

Theiler's murine encephalomyelitis virus (TMEV) and poliovirus infect the central nervous system (CNS) and cause neurological damage. The exact route by which TMEV and polioviruses enter the CNS remains, for the most part, unknown, although the neural and/or the hematogenous pathway have both been postulated. To explore these hypotheses, this research focuses on both the site of entry and the pathway used to invade the CNS. Following different inoculation sites of the GDVII strain of Theiler's virus or Lansing Type 2 poliovirus in CBA mice, the incidence of paralysis and/or encephalitis was evaluated on the basis of clinical signs and histopathology. The forms of paralysis displayed corresponded to the site of viral inoculation. Following intramuscular (i.m.), intraperitoneal (i.p.), and footpad routes of injection, bilateral and or contralateral paralyses were observed for both TMEV and poliovirus. In mice injected intratongue and in the hypoglossal nerve, tongue paralysis or paralysis of the forelimb, which progressed to bilateral forelimb paralysis, was observed, additionally the penis of most infected males was protruded. Intracranial (i.c.) injections with type II poliovirus strain resulted in forelimb paralysis. Intravenous (i.v.), injections with TMEV also resulted in forelimb paralysis. Thus Lansing Type II poliovirus and TMEV infections of CBA mice, result in similar incidence of paralysis and histopathological findings.     

Construction and properties of intertypic poliovirus recombinants: first approximation mapping of the major determinants of neurovirulence

An attempt was made to map, in a general way, the region of the poliovirus genome that is responsible for the neurovirulent and attenuated phenotypes of different virus strains. A set of four recombinants was investigated, one described previously (E. A. Tolskaya, L. I. Romanova, M. S. Kolesnikova, and V. I. Agol, 1983, Virology 124, 121-132) and three obtained in the present work with the following genetic structure: a 5' end-adjacent segment of the genome derived from either a virulent strain (452/62 3D), or from an attenuated strain (Leon-2) of poliovirus type 3, the remaining RNA sequences being derived from either a virulent strain (Mgr), or an attenuated strain (LSc-gr3) of poliovirus type 1. The crossover points in the recombinant genomes were centrally located, somewhere between the gene(s) that determines antigenic specificity of the virus and the locus that determines resistance of virus multiplication to low doses of guanidine. The recombinant nature of the newly selected clones was definitively established by mapping RNase T1 oligonucleotides of their genome. The recombinants were characterized with respect to their ability to produce infectious progeny and synthesize viral RNA at an elevated temperature. Neurovirulence of the recombinants was assayed by intracerebral inoculation of monkeys. Irrespective of the origin of the 3' end-adjacent segment of the genome, the recombinants that inherited the 5' end-adjacent segment from the neurovirulent parent were neurovirulent, whereas the recombinants with the 5' end-adjacent segment derived from the attenuated parent were not. The results suggest that the major determinants of neurovirulence of these recombinants (and by inference, of their parental viruses) reside in the 5' end-adjacent segment of poliovirus genome, known to code for capsid proteins.     

Vector competence of mosquitoes (Diptera: Culicidae) from Maroochy Shire, Australia, for Barmah Forest virus

Mosquitoes were collected in light traps from Maroochy Shire and fed on blood containing the sympatric BF1611 strain of Barmah Forest virus (BF). Saltmarsh Aedes vigilax (Skuse) and freshwater Aedes procax (Skuse) were highly susceptible to infection, with ID50s of 10(1.7) and 10(1.5) African green monkey kidney (Vero) cell culture infectious dose, 50% endpoint (CCID50) per mosquito, respectively, followed by Aedes multiplex (Theobald) and Aedes funereus (Theobald) with 10(2.5) and 10(3.2) CCID50 per mosquito, respectively. Culex australicus Dobrotworsky & Drummond and Mansonia uniformis (Theobald) that were fed 10(3.6) CCID50 (Vero) BF per mosquito had infection rates of 28 and 60%, respectively. Only 8% of freshwater Culex annulirostris Skuse fed the same viral dose were infected. Evidence of virus transmission to mice was found with Ae. vigilax and Ae. procax, with transmission rates of 65 and 88% at 11-12 d after infection, respectively. Based on adult abundance, susceptibility to infection, and efficiency of virus transmission, Ae. vigilax would appear to be the most important vector of BF in Maroochy Shire.     

Neurovirulence of herpes simplex virus types 1 and 2 isolates in diseases of the central nervous system

Herpes simplex virus (HSV) isolates derived from the central nervous system of ten patients with HSV-1-induced encephalitis, one patient with multiple sclerosis, and 14 patients with HSV-2-induced meningitis were investigated for neurovirulence by assaying the LD₅₀ after nose and intracerebral (i.c.) inoculation of mice. HSV-1 encephalitis strains were significantly more virulent after nose inoculation (i.e. neuroinvasive) when compared with HSV-1 isolates from patients with oral lesions only, whereas HSV-2 meningitis strains were significantly more virulent after i.c. inoculation when compared with HSV-2 isolates from patients with genital lesions only. No correlation between high neurovirulence (defined as low LD₅₀ for both routes of infection) and replication in cell cultures of neuronal and non-neuronal cell lines was found, but the weakly neurovirulent HSV-1 strain isolated from a patient with multiple sclerosis gave low replication yields. After nose inoculation, a highly neuroinvasive HSV-1 laboratory reference strain replicated to high titers in nose tissue, the trigeminal ganglia and brainstem, while a strain with low neuroinvasiveness but high i.c. virulence replicated less well in the brainstem. Neuroinvasiveness of the virus strain might be one factor of relevance in the pathogenesis of HSV-1 encephalitis in man.     

A single chimpanzee-human neutralizing monoclonal antibody provides post-exposure protection against type 1 and type 2 polioviruses

BackgroundDevelopment of anti-poliovirus therapies to complement vaccination is an urgent priority. A number of antiviral drugs are in development. Recently we have developed human monoclonal antibodies that could be used for treatment of chronically infected individuals and emergency response to potential reappearance of polioviruses after eradication.ObjectiveThe aim of this study was to characterize neutralizing activity of anti-poliovirus monoclonal antibody A12 against wild type, vaccine-derived, and drug-resistant poliovirus strains, evaluate in vivo pre- and post-exposure protective properties of the antibody against polioviruses of serotypes 1 and 2, and to determine whether it interferes with response to immunization with poliovirus vaccine.Study designImmunogenicity studies were performed in CD1 mice. Poliovirus neutralizing titers were determined in poliovirus microneutralization assay. Poliovirus immunization-challenge experiments were performed in poliovirus-susceptible TgPVR21 mice.ResultsWe show that monoclonal antibody A12 effectively neutralizes in vitro a broad range of type 1 and type 2 wild and vaccine-derived polioviruses, provides effective pre- and post-exposure protection of TgPVR21 mice from challenge with a lethal dose of poliovirus. Treatment of animals with the antibody concurrent with IPV immunization does not prevent immune response to the vaccine.ConclusionsAnti-poliovirus antibody A12 effectively neutralizes a range of wild and VDPV strains and protectstransgenic mice susceptible to poliovirus against lethal challenge upon pre- and post-exposure administration. This suggests that the antibodies could be used in combination with drugs and/or vaccine to improve their efficacy and prevent emergence of resistant variants, and provides a justification for initiating their clinical evaluation.     

Comparative evaluation of four large-volume RNA extraction kits in the isolation of viral RNA from water samples

The quality of the RNA extraction system plays a crucial role for the detection of viruses in water or environmental samples. In the present study we investigated the detection limit, the efficiency and the presence of eventually co-extracted inhibitors by comparing four commercially available large scale (>or=1 ml) viral RNA extraction methods (QIAamp Viral RNA Mini Kit in combination with preconcentration by Centricon YM-100 [Centricon-QIAamp], QIAamp UltraSens Virus Kit, NucliSens Isolation Kit and NucleoSpin RNA Virus F). A 1 ml 50 mM glycine (pH 8.0) containing 1% beef extract was spiked with different concentrations of poliovirus vaccine strains, extracted by the four methods and analysed by RT-nested PCR or RT-quantitative LightCycler PCR. Eight replicates were analysed for each concentration on different days. The positive cut-off point was determined to be at 0.25 CCID(50) per ml (Centricon-QIAamp), 1.46 CCID(50) per ml (UltraSens), 0.4 CCID(50) per ml (NucliSens) and 3.03 CCID(50) per ml (NucleoSpin). Quantitative analysis (LightCycler) of a high-titer sample showed significant differences between the efficiencies of the four extraction methods examined. The efficiencies of the extraction methods were normalized to the NucliSens method as follows: (71% Centricon-QIAamp, 18% UltraSens, 100% NucliSens and 23% NucleoSpin). In addition, spiked negative controls did show significant differences, indicating a co-extraction of inhibitors. Compared with the non-inhibited positive control the inhibitions were 21, 37, 27 and 68% for the Centricon-QIAamp, UltraSens, NucliSens and NucleoSpin methods, respectively. Taken together, these findings indicate that of the four evaluated extraction methods both the NucliSens and Centricon-QIAamp are best suited to extract viral RNA from water samples previously concentrated and have shown to be very sensitive, efficient and robust methods.     

Herpes simplex virus neurovirulence and productive infection of neural cells is associated with a function which maps between 0.82 and 0.832 map units on the HSV genome

A herpes simplex virus (HSV) intertypic recombinant (RE6) has been shown to be completely and specifically non-neurovirulent in mice. Direct intracranial inoculation of 10(8) PFU of RE6 does not result in a lethal encephalitis. Neurovirulent recombinant viruses were generated by cotransfection of RE6 DNA with DNA fragments cloned from the pathogenic HSV-1 strain 17 syn+. It was found that a 1.6-kb fragment mapping between 0.82-0.832 m.u. could restore the neurovirulent phenotype. Recombinants which incorporated at least part of this fragment were at least 100,000-fold more neurovirulent than RE6. The recombinants displayed a greatly enhanced capacity to replicate in mouse brain in vivo, but did not display enhanced replication over that of RE6 in cultured mouse cells at 38.5 degrees. Immunohistochemical analysis of infected mouse brain tissue revealed that the permissive host cell range of the recombinants was dramatically altered from that of RE6. While antigen positive cells were extremely rare in mouse brain tissue infected with RE6, the neurovirulent recombinants produced antigens in many cell types including neurons. Thus, wild-type HSV-1 sequences mapping between 0.82-0.832 m.u. can donate a highly neurovirulent phenotype to RE6.     

Early pathogenesis in chicks of infection with a trypsin-sensitive avian reovirus

Experiments are described which show how the sensitivity to trypsin of avian reovirus strain TR1 restricts its replication in the intestine of the chicken in comparison with a trypsin-resistant strain R2. Following oral infection with a high dose (5.3 log10 TCID50), the trypsin-sensitive virus generally showed lower titres than the resistant one in all tissues examined. Infection of chicks with strain TR1 via the respiratory route enabled the virus to spread throughout the body and localize in the hock joint, an important target site for reoviruses. Trypsin-sensitive reoviruses might be transmitted via the respiratory route, even though TR1 caused little damage to the respiratory epithelium. Dose-response studies showed that TR1 injected via the footpad can localize in the hock joint after very low doses, but high oral doses (4-5 log10) are necessary for such localization. Intranasal infection was intermediate in effect.     

Minimal infective dose of rotavirus

Summary We studied the minimal infective dose of the gastroenteritis virus, rotavirus. Increasingly lower doses [10⁴, 10³, 10¹, 1, 10^–2 plaque forming units (PFU)] of the OSU strain of porcine rotavirus were administered to highly susceptible (colostrum deprived, cesarean derived) newborn miniature swine piglets.In vitro studies showed that virus infectivity was inactivated in piglet gastric juice, both by low pH and by pH- and concentration-dependent factor(s). These factors remain unidentified, but to prevent intragastric viral inactivation, sodium bicarbonate was administered prior to oral virus inoculation of piglets with virulent (non-tissue culture passaged) virus. The lowest dose of virus to induce clinical illness or to demonstrate viral replication by recovery of significantly more infectious virus than was administered, or both, was 1 PFU. These results should help establish standards for virus contamination of water and recommendations for evaluating disinfection procedures for rotaviruses.     

Correlation of mutations and recombination with growth kinetics of poliovirus vaccine strains

Attenuated strains of Sabin poliovirus vaccine replicate in the human gut and, in rare cases, may cause vaccine-associated paralytic poliomyelitis (VAPP). The genetic instability of Sabin strains constitutes one of the main causes of VAPP, a disease that is most frequently associated with type 3 and type 2 Sabin strains, and more rarely with type 1 Sabin strains. In the present study, the growth phenotype of eight oral poliovirus vaccine (OPV) isolates (two non-recombinants and six recombinants), as well as of Sabin vaccine strains, was evaluated using two different assays, the reproductive capacity at different temperatures (Rct) test and the one-step growth curve test in Hep-2 cells at two different temperatures (37°C and 40°C). The growth phenotype of isolates was correlated with genomic modifications in order to identify the determinants and mechanisms of reversion towards neurovirulence. All of the recombinant OPV isolates showed a thermoresistant phenotype in the Rct test. Moreover, both recombinant Sabin-3 isolates showed significantly higher viral yield than Sabin 3 vaccine strain at 37°C and 40°C in the one-step growth curve test. All of the OPV isolates displayed mutations at specific sites of the viral genome, which are associated with the attenuated and temperature-sensitive phenotype of Sabin strains. The results showed that both mutations and recombination events could affect the phenotype traits of Sabin derivatives and may lead to the reversion of vaccinal strains to neurovirulent ones. The use of phenotypic markers along with the genomic analysis may shed additional light on the molecular determinants of the reversed neurovirulent phenotype of Sabin derivatives.     

Local Antibody Response to Experimental Poliovirus Infection in the Central Nervous System of Rhesus Monkeys

By employing the techniques of immunofluorescence and radioimmunodiffusion using (32)P-labeled poliovirus as the antigen, the immunoglobulin response to poliovirus in serum, nasopharynx, spinal fluid, and in different segments of the central nervous system (CNS) was studied after intramuscular, oral, intranasal, and intrathalamic administration of inactivated (Salk), live attenuated (Sabin), or live virulent (Mahoney) type I poliovirus. Spinal fluid gammaG antibody was detected after immunization with Sabin or Mahoney virus and intramuscular administration of Salk vaccine. The response in the CNS was characterized by the appearance of gammaG antibody after oral or intrathalamic administration of Mahoney virus and rarely after intrathalamic inoculation of Sabin vaccine. The antibody activity in CNS was limited to the areas of poliovirus replication. Intrathalamic immunization with Mahoney virus resulted in local gammaG antibody production in the CNS in the absence of any detectable response in serum. Discrete foci of gammaG-containing cells were observed in those areas of CNS which contained poliovirus antibody. No immunoglobulin-containing cells or poliovirus antibody was seen in the CNS of monkeys immunized with intramuscularly or orally administered Sabin or Salk vaccine and in sham-immunized control monkeys. It is suggested that the CNS, when stimulated locally with a potent replicating viral antigen, may manifest a specific local antibody response, which is independent of the response in serum.     

Isolation of recombinant type 2 vaccine-derived poliovirus (VDPV) from a Nigerian child

A type 2 vaccine-derived poliovirus (VDPV), differing from Sabin 2 at 2.5% (22/903) of VP1 nucleotide (nt) positions, was isolated from an incompletely immunized 21-month-old Nigerian child who developed acute flaccid paralysis in 2002. Sequences upstream of nt position 620 (within the 5'-untranslated region [5'-UTR]) and downstream of nt position 5840 (in the 3C(pro) region) were derived from species C enteroviruses unrelated to the oral poliovirus vaccine (OPV) strains. The two substitutions associated with the attenuated phenotype had either recombined out (A(481)-->G in the 5'-UTR) or reverted (Ile(143)-->Thr in VP1). The VDPV isolate had lost the temperature sensitive phenotype of Sabin 2 and it was antigenically distinct from the parental OPV strain, having amino acid substitutions in or near neutralizing antigenic sites 1 and 3. The date of the initiating OPV dose, calculated from the number of synonymous substitutions in the capsid region, was estimated to be approximately 16 to 18 months before onset of paralysis, a finding inconsistent with the most recent mass OPV campaign (conducted 12 days before onset of paralysis) as being the source of infection. Although no related type 2 VDPVs were detected in Nigeria or elsewhere, the VDPV was found in an area where conditions favor VDPV emergence and spread.     

Mouse neuropathogenic poliovirus strains cause damage in the central nervous system distinct from poliomyelitis

Poliomyelitis as a consequence of poliovirus infection is observed only in primates. Despitea host range restricted to primates, experimental infection of rodents with certain genetically well defined poliovirus strains produces neurological disease. The outcome of infection of mice with mouse-adapted poliovirus strains has been described previously mainly in terms of paralysis and death, and it was generally assumed that these strains produce the same disease syndromes in normal mice and in mice transgenic for the human poliovirus receptor (hPVR-tg mice). We report a comparison of the clinical course and the histopathological features of neurological disease resulting from intracerebral virus inoculation in normal micewith those of murine poliomyelitis in hPVR-tg mice. The consistent pattern of clinical deficits in poliomyelitic transgenic mice contrasted with highly variable neurologic disease that developed in mice infected with different mouse-adapted polioviruses. Histopathological analysis showed a diffuse encephalomyelitis induced by specific poliovirus serotype 2 isolates in normal mice, that affected neuronal cell populations without discrimination, whereas in hPVR-tg animals, damage was restricted to spinal motor neurons. Mouse neurovirulent strains of poliovirus type 2 differed from mouse neurovirulent poliovirus type 1 derivatives in their ability to induce CNS lesions. Our findings indicate that the characteristic clinical appearance and highly specific histopathological features of poliomyelitis are mediated by the hPVR. Our data lead us to conclude that the tissue tropism of mouse-adapted poliovirus strains in normal mice is fundamentally different from that of poliovirus in hPVR-tg mice and primates, and that this is indicative of an as yet unknown mechanism of adsorption and uptake of the virus into cells of the murine CNS.     

Characterization of encephalitis in adult mice induced by intracerebral inoculation of herpes simplex virus type 1 (KOS) and comparison with mutants showing decreased virulence

The spread of herpes simplex virus type 1 (HSV-1) strain KOS, and two less neurovirulent mutants of the strain was studied in female DBA/2 mice during the 1- to 5-day postinoculation period after intracerebral inoculation. Immunohistopathology showed that wild-type KOS virus first infected the meninges and ependymal cells but did not infect cells at the inoculation sites. The virus continued to spread to some cells directly adjacent to ventricles; however, the most extensive and severe lesions were found in the pyriform lobes and other structures associated with the limbic system. The pattern of spread suggested that direct cell to cell viral spread is important but that retrograde axonal transport to distant sites probably accounts for the more severe lesions associated with the limbic system. Both less neurovirulent mutant viruses multiplied to a much lesser degree in the brain and spread less extensively than the wild type virus when equivalent doses were given; however, when a large dose of the least neurovirulent mar C10.1 mutant virus was inoculated, infection spread rapidly to the same regions of the brain affected by KOS. Studies of mar C10.1 showed that thymidine kinase deficiency, rather than a mutation in the gene coding for glycoprotein C, probably accounted for the decreased neurovirulence of this mutant. This mouse model of HSV-1 virus-induced encephalitis, in combination with appropriate studies of the molecular biology of the HSV-1 KOS strain, should be useful for the study of neurovirulence factors contributing to the pathogenesis of HSV-1.     

Molecular and antigenic characterization of a highly evolved derivative of the type 2 oral poliovaccine strain isolated from sewage in Israel

An unusual, highly diverged derivative of the Sabin type 2 oral poliovaccine (OPV) strain was recovered from environmental samples during routine screening for wild polioviruses. Virus was cultivated in L20B cells and then passaged on BGM cells at 40 degrees C (RCT [reproductive capacity at supraoptimal temperature]-positive marker) to select against most OPV strains. All but 1 of 25 RCT-positive OPV-derived environmental isolates were antigenically and genetically (>99.5% VP1 sequence match) similar to the respective Sabin strains. However, isolate PV2/4568-1/ISR98 (referred to below as 4568-1) escaped neutralization with Sabin 2-specific monoclonal antibodies and cross-adsorbed sera, and had multiple nucleotide substitutions (220 of 2,646; 8.3%) in the P1 capsid region. Fourteen of the 44 associated amino acid substitutions in the capsid mapped to neutralizing antigenic sites. Neutralizing titers in the sera of 50 Israeli children 15 years old were significantly lower to 4568-1 (geometric mean titer [GMT], 47) than to Sabin 2 (GMT, 162) or to the prototype wild strain, PV2/MEF-1/EGY42 (GMT, 108). Two key attenuating sites had also reverted in 4568-1 (A(481) to G in the 5' untranslated region and the VP1 amino acid I(143) to T), and the isolate was highly neurovirulent for transgenic mice expressing the poliovirus receptor (PVR-Tg21 mice). The extensive genetic divergence of 4568-1 from the parental Sabin 2 strain suggested that the virus had replicated in one or more people for approximately 6 years. The presence in the environment of a highly evolved, neurovirulent OPV-derived poliovirus in the absence of polio cases has important implications for strategies for the cessation of immunization with OPV following global polio eradication.     

Outcome of herpes simplex virus type 2 infection in guinea pigs.

Factors that influence the outcome of genital herpes simplex virus (HSV) infection were explored in a guinea pig model. The viral inoculum required to establish infection in 50% of animals (ID50) was similar for inbred (strain 2) and outbred (Hartley) guinea pigs. However, the viral inoculum required to produce clinical disease in 50% of the animals (CD50) was 10 times greater for strain 2 compared to Hartley animals. HSV infection of both inbred and outbred animals was more likely to result in death of weanling than adult animals. The duration and severity of genital disease and the magnitude of vaginal viral replication were similar for strain 2 and Hartley animals in both young and adult animals. The lethal dose for 50% of animals (LD50) was 100-fold greater than the CD50 for Hartley animals, but the LD50 and the CD50 were equal in strain 2 guinea pigs. Viral cultures of homogenized neural tissues from infected animals revealed that HSV ascended to the level of the temporal cortex in strain 2 guinea pigs while virus was never recovered above the lumbar spinal cord in Hartley animals. Endogenous peripheral blood mononuclear cell-mediated cytolytic activity against HSV-infected targets was greater prior to HSV inoculation in survivors compared to animals that died. A fatal outcome of genital HSV-2 may relate to the failure to limit CNS viral replication. Death is more common among guinea pigs that have low endogenous HSV-directed natural killer activity, such as occurs among strain 2 and young animals whether inbred or outbred.     

Vaccine-derived poliomyelitis 12 years after infection in Minnesota

A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin.