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South London Specialist Virology Centre, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom Virus Reference Department, Microbiology Services Colindale, 61 Colindale Avenue, London NW9 5HT, United Kingdom Department of Histopathology, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom Department of HIV/Genitourinary Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom

A community survey of human T cell lymphotropic virus type I (HTLV-I) in Montserrat, West Indies, identified 22 instances in which 2 HTLV-I-seropositive adults lived within 60 m of each other (close pairs), compared with 7.8 expected (P < .001). Five of these close pairs were mother-offspring or husband-wife. The remaining 17 pairs were of unrelated members in separate households. The percentages of male-female (41%), female-female (41%), and male-male (18%) types in these 17 pairs were very similar to those among the 1377 similarly defined pairs in which neither or only 1 member was seropositive, affording no support for extramarital heterosexual activity as an explanation for the clustering observed. Thus, the demography of HTLV-I was not accounted for completely by sexual and mother-to-offspring transmission. The predominance of clustering of unrelated HTLV-I-seropositive individuals in locations with high mosquito infestation raised the possibility of sporadic transmission of HTLV-I by hematophagous insects.

SUMMARYBetween March and June 2008, 12 cases of hepatitis A were notified in Winchester. Cases were from a primary school and a nursery school with no direct linkage. Hepatitis A virus (HAV) RNA sequenced from nine cases confirmed the strain in both schools to be identical. The outbreak could have affected three other schools and a maternity unit and was controlled by immunization and screening of neonates in the maternity unit by dried blood spots. No neonates were infected and no further cases were reported until 5 months later when the index case's mother became infected with same strain of virus associated with the outbreak despite vaccination. Neither the source of the outbreak or the subsequent infection of the index case's mother was identified; however, with the timing of the cases continued transmission in the community by children with asymptomatic infection or a recurrent source cannot be ruled out.

SUMMARYThe cross-reaction of HHV6 antibody with that to the other herpesviruses was studied in 96 blood donors whose sera were tested for IgG antibody to human herpesvirus type 6 (HHV6), cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella zostervirus (VZV) and herpes simplex virus (HSV). No correlation was found between IgG antibody to HHV6 and that to any of the other herpesviruses in these individuals. Antibodies to HHV6 and CMV were measured in patients undergoing documented serological responses to HHV6. Eleven cases of primary HHV6 infection associated with roseola infantum in babies, 1 of whom suffered from gastroenteritis as well as pyrexia and rash, are reported. Three cases of HHV6 reactivation, 1 in a 3-year-old child and 2 in adults, 1 of whom simultaneously underwent a primary CMV infection are also reported. Our results suggest that indirect immunofluorescence is a specific way of measuring HHV6 antibody, that HHV6 IgG and IgM can be detected in the absence of antibody to CMV and that HHV6 IgM is present both in primary HHV6 infections and in reactivations.

Pre-emptive treatment strategies based on sensitive screening for cytomegalovirus (CMV) infection up to day +100 after allogeneic transplantation have been shown to reduce the incidence of CMV disease during the period of surveillance. However, the use of ganciclovir has been associated with delays in immune reconstitution and an increased incidence of late CMV disease after day +100. In the present study, 81 patients undergoing allogeneic transplantation received polymerase chain reaction (PCR)-guided pre-emptive therapy based on detection of CMV DNA by PCR on 2 consecutive weeks up to day +180. Thirty-three of the 52 high-risk patients (CMV-seropositive donor or recipient) received a total of 45 treatment episodes up to day +100. Three of these patients (5.7%) developed CMV disease, with one fatality. Twelve of the surviving 44 high-risk patients (27%) required pre-emptive treatment between days +101 and +192, but none of these patients developed late CMV disease with a median follow-up of 402 d (range 117-952 d). Antiviral therapy was stopped after a single negative PCR result with no subsequent episodes of CMV disease while patients remained off antiviral treatment. As all initial episodes of CMV DNA detection occurred within 60 d of transplantation, it may be possible to discontinue monitoring beyond day +100 in patients who have remained CMV PCR negative before this. Thus, we have confirmed that PCR-guided pre-emptive therapy results in a low incidence of CMV disease before day +100 and that discontinuing treatment on the basis of viral clearance as determined by CMV PCR appears to be safe practice. In addition, we have observed no episodes of late CMV disease with an extension of surveillance to 26 weeks.

Ideally HIV antibody tests have to be both extremely sensitive and able to recognize all known HIV subtypes. Three patients whose sera failed to react with a synthetic oligopeptide-based HIV antibody test are described in this report. The patients were a Pakistani male infected recently, an Australian male infected for several years, and a Ugandan woman with AIDS. The presence of anti-HIV antibodies was confirmed by means of a standard algorithm with different assay formats. All three sera failed to react in one antiglobulin enzyme-linked immunosorbent assay (ELISA) (Bioelisa HIV-1+2, Biokit SA). No single underlying reason could be identified for the assay failure in the three cases. The first patient, probably infected recently when first tested, was strongly positive by the same assay a year later, confirming the relative insensitivity of oligopeptide assays reported previously for detecting the early antibody response. The other two patients appear to have been infected for several years. Although unlikely to have been infected with a non-clade B virus, the sample from patient 2 lacked detectable antibody to the transmembrane glycoprotein (gp41), the site of the synthetic oligopeptides. Patient 3, of Ugandan origin, was found to be infected with a non-clade B virus. Although her serum reacted strongly to subtype B gp41 in Western blot, it failed to react in the antiglobulin ELISA. Since there appears to be no single common explanation for these three failures there is little opportunity to identify prospectively those situations where testing using assays employing synthetic oligopeptides on the solid phase is likely to fail.

Replication of HIV introduces errors into the genome which are responsible for conferring a growth advantage over wildtype virus when drugs such as zidovudine (ZDV) exert a selective pressure. The molecular basis for HIV-1 resistance to ZDV has been mapped to codons 41, 67, 70, 215 and 219 of the reverse transcriptase gene both in vitro and in clinical samples of blood. This study has investigated the relationship between the quantitative prevalence of ZDV resistance in multiple organs of the same individual. Proviral HIV-1 load was measured by quantitative-competitive PCR in 90 samples from organs of 11 patients dying with AIDS. Nine of these patients had been prescribed zidovudine. The distribution of wildtype and mutant sequences at the positions 41, 67, 70, 215 and 219 of the reverse transcriptase was assessed using a point mutation assay. The results showed that the highest proviral loads were predominately found in lymph node, spleen and lung and there was a significant association between viral load and resistance to ZDV (P=0.008). Inter-organ distribution of wildtype and mutant sequences at codons 41, 67, 70, 215 and 219 was frequently not uniform and in some patients differed markedly between the lymphoreticular system and other organs. These results demonstrate that treatment of HIV-1 infection with zidovudine does not exert uniform selective pressures in multiple organs. These findings have implications for the interpretation of resistance data and design of treatment strategies for HIV, arguing in particular that alterations in therapeutic regimens should consider the likelihood of different resistance patterns being present in multiple sites within the same individual.

In a series of fourteen patients with adult T-cell lymphoma-leukaemia (ATLL) in Brazil the main features were lymphadenopathy, hepatosplenomegaly, hypercalcaemia, and high leucocyte counts, with abnormal lymphoid cells which had irregular nuclei. The series included the youngest patient with ATLL so far (18 months). Analysis with monoclonal antibodies showed a mature T-cell phenotype (CD4+, CD8-). Antibodies to HTLV-I and/or integration of HTLV-I proviral DNA were found in eleven patients. In the other three HTLV-I DNA could not be demonstrated even by means of the polymerase chain reaction; they therefore had HTLV-I-negative ATLL. This report of ATLL in Brazil corroborates serological reports that HTLV-I may be endemic in some parts of that country. Follow-up studies are required to identify precisely the main route of transmission of HTLV-I in South America and the risk factors for the development of ATLL in carriers.

The expression of hepatitis B virus antigens was studied by double staining liver tissue with appropriate antisera and correlated with serum hepatitis B viral DNA and histology in 28 patients with disease related to chronic hepatitis B virus infection. The cellular localization of hepatitis B core and hepatitis B e antigens generally coincided, but there were important differences at a subcellular level. Thus, hepatitis B e antigen was detected in nuclei and/or cytoplasm but strong cytoplasmic hepatitis B e antigen was associated with a high serum hepatitis B viral DNA (P = 0.0017) but not with active liver disease. Hepatitis B core antigen could also be detected in nuclei and/or cytoplasm, but strong cytoplasmic hepatitis B core antigen expression, exceeding that of hepatitis B e antigen, was associated with active liver disease (P = 0.041) and not with serum hepatitis B virus DNA. The proportion of hepatocytes expressing hepatitis B surface antigen correlated inversely with the serum titer (P = 0.0017), whereas hepatitis B surface and nucleocapsid antigens were usually expressed independently. The data support the hypothesis that cytoplasmic hepatitis B core antigen and not hepatitis B e antigen is the target for immune system-mediated cytolysis of hepatocytes. Cytoplasmic hepatitis B e antigen is not associated with liver damage but is instead associated with high levels of hepatitis B virus replication.

The sensitivity of nine commercial assays, Western blot, and a newly developed monoclonal antibody-based assay for antibody to human T lymphotropic virus type III/lymphoadenopathy associated virus (anti-HTLV III/LAV) were evaluated using a panel of mainly weak-positive sera. In tests on 20 sera three commercial assays and a monoclonal-based assay, representing two different solid-phase methodologies, were found to be more sensitive than Western blot. Our findings suggest that Western blot cannot be depended upon as the sole confirmatory test for anti-HTLV III/LAV. The continued use of the more sensitive enzyme-linked immunosorbent assays (ELISAs), particularly those of dissimilar methodology, would be a more valid approach to confirmatory testing.

SUMMARYEight sera from 125 cases of infectious mononucleosis (IM) were reactive for rubella-specific IgM in an M-antibody capture radioimmunoassay. The reactivity of individual sera varied depending upon the source of the rubella antigen used in the assay. One serum gave strongly positive results with some rubella haemagglutinating antigens but negative results with others and may have contained an IgM antibody which was capable of distinguishing between strains of rubella virus.If the diagnosis of rubella is based solely on detection in solid-phase immunoassay of rubella-specific IgM, IM should be excluded.

Summary Studies in animals have determined the importance of specific receptors to the action of many hormones and drugs. In man, a non-invasive external counting technique has been used and absence of receptor function has been demonstrated in a patient with nephrogenic diabetes insipidus using radioactively labelled arginine vasopressin. This is in contrast to the findings in a patient with pituitary diabetes insipidus and a normal control. These results suggest a model for the study of hormone and drug kinetics in man avoiding multiple samplings of biological fluids.

Exposure to ionizing radiation produces several systemic and local reactions which could be mediated by prostaglandins. Prostaglandin levels were therefore studied in blood and tissues of mice which had been exposed to x-rays. Significant increases were found in spleens after 200 to 700 R, and in lungs after 600 to 700 R. These changes were most pronounced 4-7 days after irradiation. Ionizing radiation promptly and potently reduced the activity of prostaglandin dehydrogenase in the spleen, whereas prostaglandin synthesis was less affected. Evidence was obtained for the activation and consumption of haemolytic complement in serum in the course of heart-lung operations involving extracorporeal circulation. Activation involved primarily the classical pathway, and only slightly the alternate pathway.

The aetiology of acute anterior uveitis (AAU) in the great majority of cases is unclear. Various infective agents have been postulated, however, as playing a direct or indirect part in the disease process, possibly via an immune-complex vasculitis. In an earlier study we concluded that, contrary to a previous report, hepatitis B virus (HBV) played only a small role, if any, in the pathogenesis of uveitis in Great Britain. Since we did not look for other markers of HBV infection other than hepatitis B surface antigen (HBsAg), it is possible that some cases of recent HBV infection may have been missed. In the present study 49 patients with AAU were tested for markers of hepatitis B infection. Sera from all patients tested were found to be negative for HBsAg and for antibody to the HBV core (anti-HBc), excluding HBV as a significant cause of AAU in this country. Since the quest for an infective agent in AAU may remain unproductive, future research on the aetiopathogenesis of AAU should include the study of tissue 'vulnerability' and the local and systemic immunoregulatory factors which modulate inflammatory responses.

A renal transplant patient was infected by a transfusion of blood from a chronic carrier of hepatitis B and he also became a symptomless carrier. Stored sera enabled detailed retrospective measurement of the rate of decline of passively transferred HBsAg, anti-HBc, and anti-HBe. Active HBsAg production was detected after two months and anti-HBc after six months; neither HBe nor anti-HBe was actively produced although there were many 42 nm HBV particles in the patient's serum.

An anti-HIV 1 competitive ELISA was developed using a monoclonal anti-HIV 1 gag to capture viral antigen to the solid phase. This format of assay was compared with a competitive ELISA where a polyclonal human anti-HIV 1 was used, to capture the viral antigen. Several benefits were observed using the monoclonal-antibody form of the assay. Firstly, less viral antigen was needed on solid phase to give an equivalent test in terms of positive and negative optical density 450 nm values. Secondly, a slight increase in sensitivity was also gained without any loss of specificity and finally, as a result of the murine nature of the antibody on the solid phase, no cross-reaction with the labelled human antibody in the test conjugate was observed. Such cross-linking has been observed with the polyclonal form of the assay and can lead to false-negative reactions.

By November 7, 1983, 24 cases of AIDS in the United Kingdom had been reported to the Communicable Disease Surveillance Centre. At the same time an increasing number of homosexual men with unexplained lymphadenopathy syndrome (LAS) have been seen in our department. Between December 1982 and July 1983, 14 homosexual men with LAS and 11 healthy homosexual men were studied. Patients with LAS had a high number of lifetime episodes of sexually transmitted diseases, a history of recent sexual activity in the United States (9 of 14), sexual contact with British AIDS patients or other persons with LAS (7 of 14), and hypergammaglobulinemia. Low T-helper/T-suppressor ratios (less than 0.8), due mainly to a decrease in T-helper cells, were found in both groups. Lymph node biopsies showed follicular hyperplasia and hypocellular pattern. All 25 patients studied had antibodies to Epstein-Barr virus capsid antigen (anti-VCA) and 11 had antibodies to early antigen (anti-EA); 13 of 17 were excreting the virus; and two showed no Epstein-Barr-virus-specific regression. Peripheral blood immunoglobulin-producing B-cells from six patients with hypergammaglobulinemia were negative for the Epstein-Barr virus nuclear antigen (EBNA). Five lymph node biopsies showed no EBNA-positive cells. Epstein-Barr virus reactivation is common in the patients with LAS and healthy homosexual men in London, but would not seem to be the cause of the polyclonal B-cell activation or lymphadenopathy.

Serological markers for hepatitis B virus infection have been examined in 34 patients with acute hepatitis B, 17 of whom developed fulminant hepatic failure. Hepatitis B surface antigen concentrations were significantly lower and hepatitis Be antigen was less frequently detectable in patients with fulminant hepatic failure compared with those with acute hepatitis (median 0.64 micrograms, range 16-0 and median 32 micrograms and range 100-4 micrograms respectively, p less than 0.001; HBeAg detected in 12% and 88% respectively, p less than 0.001). The IgM component of hepatitis B core antibody was significantly higher in the patients with fulminant hepatic failure with median values of 500 IU/ml compared with those with uncomplicated hepatitis (median 202 IU/ml, p less than 0.05 Wilcoxon's rank test). Three patients who developed a fulminant course had detectable levels of either anti-HBs or anti-HBe. These results are consistent with enhanced antibody responses to all three hepatitis B virus antigens and more rapid clearance of the latter during fulminant hepatic failure.