Alison Webster

CYTOMEGALOVIRUS INFECTION AND PROGRESSION TOWARDS AIDS IN HAEMOPHILIACS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION

To examine whether cytomegalovirus (CMV) infection could accelerate progression of human immunodeficiency virus (HIV) infection to AIDS, serological studies were done on 108 HIV-infected haemophiliacs. In the 1.3-9 years from time of first recognised HIV seroconversion, the age-adjusted risk of CDC group IV disease in CMV-seropositive patients was 2.5 times that in CMV-seronegative patients. CMV-seropositive patients were also more likely to have detectable p24 antigenaemia. Survival analysis showed that CMV-seropositive patients were at greater risk of HIV disease than CMV-seronegative patients from about 2 years after HIV seroconversion. Thus CMV infection is associated with a more rapid progression to HIV disease.

NON-A, NON-B HEPATITIS OCCURRING IN AGAMMAGLOBULINAEMIC PATIENTS AFTER INTRAVENOUS IMMUNOGLOBULIN

Acute non-A, non-B hepatitis developed in twelve patients with primary hypogammaglobulinaemia during treatment with intravenous gammaglobulin prepared by Cohn fractionation of pooled plasma. The illness was clinically and histologically identical to the short-incubation non-A, non-B, hepatitis observed in haemophilic patients receiving factor VIII concentrates. Most of the patients were symptomless, but 10 months after onset ten of the twelve still had abnormal liver function. The occurrence of non-A, non-B hepatitis in agammaglobulinaemics indicates that humoral mechanisms are not essential for production of hepatocyte necrosis in this infection. This outbreak emphasises the need for a screening test to identify the agent in blood products, and shows that Cohn fractionation of plasma does not always inactivate the agent. Furthermore, the finding that the virus can be transmitted in IgG concentrates suggests either that the general population has a very low level of antibodies to the putative virus or that such antibodies are not virus-neutralising.

ALPHA-INTERFERON THERAPY FOR NON-A, NON-B HEPATITIS TRANSMITTED BY GAMMAGLOBULIN REPLACEMENT THERAPY

Three hypogammaglobulinaemic patients with non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy were treated with lymphoblastoid alpha-interferon. All showed a striking improvement in serum aminotransferases after the start of each course of treatment.

Population dynamics of Hiv within an individual after treatment with zidovudine

A new mechanism is proposed for the apparent breakthrough of HIV that occurs approximately 6 months after the commencement of therapy with zidovudine (AZT). Using a simple mathematical model of the interacting population dynamics of HIV and its major host cell in the circulation (the CD4+ lymphocyte), predicted patterns of HIV plasma viraemia in the weeks following treatment with zidovudine are generated. These are in close agreement with observed patterns despite the fact that the model contains no mechanisms for the development of drug-resistant strains of virus. It is suggested that the patterns of viral abundance observed during the first 6 months after treatment may be the result of non-linearities in the interactions between HIV and CD4+ cells, and that it is only after the first post-treatment burst of viral production that drug resistance plays an important role.

The T cell response to persistent herpes virus infections in common variable immunodeficiency.

We show that at least half of patients with common variable immunodeficiency (CVID) have circulating CD8+ T cells specific for epitopes derived from cytomegalovirus (CMV) and/or the Epstein–Barr virus (EBV). Compared to healthy age‐matched subjects, more CD8+ T cells in CVID patients were committed to CMV. Despite previous reports of defects in antigen presentation and cellular immunity in CVID, specific CD4+ and CD8+ T cells produced interferon (IFN)‐γ after stimulation with CMV peptides, and peripheral blood mononuclear cells secreted perforin in response to these antigens. In CVID patients we found an association between a high percentage of circulating CD8+ CD57+ T cells containing perforin, CMV infection and a low CD4/CD8 ratio, suggesting that CMV may have a major role in the T cell abnormalities described previously in this disease. We also show preliminary evidence that CMV contributes to the previously unexplained severe enteropathy that occurs in about 5% of patients.

Eliminating PCR contamination: is UV irradiation the answer?

The sensitivity of the polymerase chain reaction (PCR) can mean that even very low levels of contamination with the target DNA will result in a positive signal. At present this aspect is a major limitation in the use of PCR as a routine diagnostic method. By exposing PCR reagents to UV light, contaminating DNA can be inactivated, thus providing an opportunity to eradicate false positive reactions. UV irradiation was applied to PCR systems used for the detection of human cytomegalovirus (CMV) and human immunodeficiency virus (HIV) and shown to be effective in eradicating both laboratory encountered contamination and plasmid DNA (below 100 pg) added to PCR systems prior to UV exposure. The sensitivity of a PCR system to amplify the long terminal repeat (LTR) sequence of HIV-1 was not affected by the irradiation procedure; however, the ultimate sensitivity of a PCR system for the amplification of an early gene promotor sequence of the CMV genome was reduced 1000-fold. UV irradiation did not affect the size of the PCR product as determined by strand separating polyacrylamide gel electrophoresis of a 32P-labelled amplimer. Thus, a simple pre-exposure to UV light would seem a worthwhile step to incorporate into PCR protocols provided that the effects on sensitivity have been determined empirically for each PCR system.

Defective maturation of dendritic cells in common variable immunodeficiency

Monocyte‐derived dendritic cells (MdDCs) from many patients with common variable immunodeficiency (CVID) have been shown recently to have reduced expression of surface molecules associated with maturity. Using flow cytometry and confocal microscopy, we now show that this is due to a partial failure to fix Class II DR molecules on the surface during procedures that induce full maturation in vitro in cells from normal subjects. Major histocompatibility complex (MHC) class I, CD86 and CD83 expression were expressed normally, but CD40 was reduced. These abnormalities are unlikely to be due to prior in vivo exposure of monocytes to lipopolysaccharide (LPS), as addition of LPS to monocytes from normal subjects in vitro caused a different pattern of changes. CVID MdDCs retained Class II DR in the cytoplasm during maturation, showed increased internalization of cross‐linked Class II DR surface molecules and were unable to polarize DR within a lipid raft at contact sites with autologous lymphocytes. These cells retained some features of monocytes, such as the ability to phagocytose large numbers of fixed yeast and fluorescent carboxylated microspheres and expression of surface CD14. These abnormalities, if reflected in vivo, could compromise antigen presentation and may be a fundamental defect in the mechanism of the antibody deficiency in a substantial subset of CVID patients.

RISK-FACTORS FOR VIRAL REACTIVATION FOLLOWING BONE-MARROW TRANSPLANTATION

SummaryThe identification of risk factors for viral reactivation following transplantation is essential in order that antiviral prophylactic regimes may be allocated rationally. In the pretransplant period qualitative serological assessment of recipient and donor is informative with regard to the risk of post-transplant reactivation and disease. In addition, the quantitative level of herpes simplex virus (HSV) IgG in the pretransplant recipient is predictive of post-transplant HSV excretion, although this relationship does not exist for other viruses of the herpes group. We discuss the value of surveillance cultures for cytomegalovirus in the post-transplant period in predicting the development of CMV disease, and how this may allow effective intervention to prevent what is a major cause of morbidity and mortality in the transplant population.

Human immunodeficiency virus infection in women.

Heterosexual transmission is the leading route of transmission worldwide of human immunodeficiency virus (HIV) infection, although the cumulative rate of infection is significantly higher among female partners of infected intravenous drug abusers and men from central African countries than among female partners of bisexual men or blood product recipients. Factors associated with an increased risk of heterosexual transmission are currently under investigation, but number of sexual partners and the presence of genital ulceration appear to be significant. The natural history and clinical manifestations of acquired immunodeficiency syndrome (AIDS) are the same in men and women. Despite initial reports to the contrary, it appears that pregnancy does not have an adverse effect on the course of HIV infection. However, there is clear evidence that HIV is transmitted to the fetus during pregnancy and lactation. A transmission rate of 25-35% has been recorded in follow-up studies of infants born to mothers infected with the AIDS virus. Pregnancy termination should thus be suggested to pregnant AIDS patients, and asymptomatic seropositive women should be advised to delay pregnancy until more is known about the natural history of their infection. The most feasible approach, however, is to identify women at high risk of AIDS before they become pregnant and offer antenatal blood screening.