Management Of Viral Infections Research Articles

HIV type-1 infection of the cotton rat (Sigmodon fulviventer and S. hispidus).

Cotton rats (Sigmodon hispidus and S. fulviventer) are susceptible to many viruses that infect humans (e.g., poliovirus, respiratory syncytial virus, influenza virus, adenovirus, and parainfluenza virus) and have been influential in developing therapeutic clinical intervention strategies for many viral infections of man. This study set out to determine whether cotton rats are susceptible to infection with HIV type 1 (HIV-1). Results indicate that HIV-1 does infect the cotton rat and S. fulviventer is more susceptible than S. hispidus. The virus was passaged from animal to animal for a total of three serial passages; but HIV replicated poorly in vivo, was only detectable as proviral DNA, and never exceeded one provirus per 1.8 x 10(5) cotton rat peripheral blood mononuclear cells. Infection induced a distinct and characteristic anti-HIV antibody response that, in some animals, included neutralizing antibodies, recognized all of the major HIV-1 antigens and the antibodies lasted out to 52 wk post-infection. Neonate S. fulviventer were not more susceptible to infection than adults. In vitro culture studies produced indirect evidence of viral replication by detection of viral gag gene RNA in reverse transcriptase-PCR assays on viral culture supernatants. Collectively, these results indicate that HIV-1 can replicate in a nontransgenic rodent and that this system may have potential as an animal model for HIV-1 infection if viral replication rates can be improved in vivo.

Influenza virus resistance to neuraminidase inhibitors

The recent reports from Hong Kong of an avian influenza virus which caused the death of six people has served to remind us of the constant threat of pandemics posed by influenza. Recently, structure-based drug design has resulted in the discovery of a new class of antiviral agents which specifically target the influenza virus neuraminidase. Two neuraminidase inhibitors are currently undergoing clinical evaluation for the prevention and treatment of influenza virus infection in man. Here we review the results of in vitro and in vivo studies relating to the potential development of resistance to this new class of compounds.

Recent advances in the management of viral infections.

The immunocompromised cancer patient is vulnerable to a wide spectrum of viral pathogens (Table 1). There has been increasing recognition of viruses as clinically important pathogens in cancer patients during the past decade. In part this is attributable to improved diagnostic techniques to better recognize viral pathogens as causes of illnesses not earlier recognized to be virally caused. In part this is also due to the increasing dose intensity of cytoreductive regimens used to control cancer, the increasing use of bone marrow transplantation (BMT) in the treatment of neoplastic diseases, and improvements in supportive care that permit patients to survive bacterial and fungal infections that in the past might have led to death before viral illness became manifest. Thus, there are greater numbers of highly immunosuppressed patients with severe compromise in cell-mediated immunity, the major host defense against most viral pathogens.

An Immunosuppressed Mouse Model of Lethal Murine Gammaherpesvirus 68 Infection for Studying Potential Treatment of Epstein—Barr Virus Infection in Man

Murine gammaherpesvirus 68 (MHV-68) is a rodent virus related to human Epstein—Barr virus (EBV). MHV-68 infection and its treatment were studied in a novel lethal immunosuppression model in BALB/c ...

Evaluation of potential treatments for Epstein-Barr virus infections in man using a murine gammaherpesvirus-68 infection model: Donald F. Smee, K.W. Bailey, and R.W. Sidwell. Inst. for Antiviral Research, Utah State Univ., Logan, UT 84322-5600

Evaluation of potential treatments for Epstein-Barr virus infections in man using a murine gammaherpesvirus-68 infection model: Donald F. Smee, K.W. Bailey, and R.W. Sidwell. Inst. for Antiviral Research, Utah State Univ., Logan, UT 84322-5600

Management of Viral Infections in Bone Marrow Transplant Recipients

Following bone marrow transplantation (BMT), patients are at risk of viral infections because of prolonged and often profound immunosuppression. Specific viral pathogens that have been identified include members of the Herpesvirus family such as herpes simplex virus (HSV), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus-6 (HHV-6) and adenovirus, as well as respiratory viruses including respiratory syncytial virus (RSV), influenza and parainfluenza.

Haemorrhagic fever with renal syndrome: an emerging disease

Summary: Worldwide about 150 000 people are hospitalized with haemorrhagic fever with renal syndrome (HRFS; 3–15% fatality) each year. the aetiologic agents of hantavirus infections are Hantaan, Belgrade, Seoul, Puumala and Sin Nombre virus of the genus Hantavirus, family Bunyaviridae. A severe form of HFRS caused by Hantaan and Belgrade virus occurs in Asian and Balcan countries. A new clinical form with 70% fatality, Hantavirus pulmonary syndrome, caused by novel hantaviruses occurs in Americas. A moderate form caused by Seoul virus occurs in Asia and in Europe and a mild form caused by Puumala virus occurs in Europe. Recently, Puumala virus infections in man and field mice were found in Siberia, in Korea and in Japan. the reservoirs of hantaviruses are rodents and other small mammals including bats and birds and mode of transmission is aerosol. Serologic and PCR studies of 72 hantaviruses isolated from patients and from animals throughout the world indicated that there are eight or more serotypes. Many hantavirus patients have been misdiagnosed as influenza, interstitial nephritis, leptospirosis, scrub typhus, dengue, hepatitis and pneumonia. Recently, we developed simple serologic differential diagnostic kits (HDPA test) for Hantaan, Seoul and Puumala virus infections. an inactivated Hantaan virus vaccine against HFRS is available. In the 1990s, it is highly possible to identify new hantavirus illness in parts of the world where the disease is not known because of the availability of diagnostic tools.

Laboratory indicators for monitoring HIV disease.

Immunological monitoring of disease progression following HIV infection and seroconversion illness, latency and AIDS, not only helps in the basic investigation of the natural history of the viral infection in man, but also can assist in prognosis and treatment of AIDS-defining illnesses. However, outside clinical trials, these tests should be selected and used in clinical practice only if they are validated as relevant and effective. The absolute CD4+ T-helper lymphocyte count, measured by flow cytometry, has emerged as the best available investigation, but needs care in sampling due to diurnal and circadian rhythms, effects of age, pregnancy, therapy, intercurrent infections and technique. Sampling should provide a baseline and trends-monthly intervals initially, then quarterly in uncomplicated cases. Thresholds may be given for counts (e.g. 200/microliter) below which prophylaxis against pneumocystis pneumonia should be administered, and repeating persistently low counts (e.g. below 50/microliter) is seldom helpful in practice. Serum levels of beta-2 microglobulin, neopterin and immunoglobulins rarely add information. Physicians and laboratories should have testing guidelines based on clinical audit of best practice, based in turn on scientific understanding of the immunological processes involved.

Hepatitis E virus infection in individuals at high risk of transmission of non-A, non-B hepatitis and sexually transmitted diseases.

The aim of the study was to determine the prevalence of hepatitis E virus (HEV) infection among individuals at high risk of transmission of non-A, non-B hepatitis or sexually transmitted diseases (STDs), and to evaluate whether they have an increased risk of exposure to HEV. Serum samples from 125 thalassemia patients, 300 intravenous drug users, 420 hemodialysis patients, 263 individuals with STDs, 47 human immunodeficiency virus (HIV) infected homosexual men, and 316 healthy volunteers were tested for immunoglobulin G (IgG) and M (IgM) antibodies to HEV (anti-HEV) by enzyme immunoassays (EIAs) following a predetermined algorithm (Abbott Labs). Anti-HEV IgG was confirmed in 3/125 (2.4%) thalassemia patients, 5/300 (1.7%) intravenous drug users, 27/420 (6.4%) hemodialysis patients, 4/263 (1.5%) STD patients, 1/47 (2.1%) homosexual men, and 7/316 (2.2%) of the reference group. No patient was found positive for anti-HEV IgM. The higher prevalence which was observed in hemodialysis group was due to the confounding effect of age, as multivariate analysis showed. The anti-HEV prevalence increased significantly with age (p = 10(-4)). No significant association was found between anti-HEV, anti-HCV, and anti-HBc. In conclusion, individuals at high risk of non-A, non-B hepatitis and STDs have no increased risk of exposure to HEV and the higher prevalence of anti-HEV IgG among older subjects may be due to an epidemic form of HEV infection which occurred some decades ago, when the sanitary conditions in our country were poor.

Research strategies in 'slow' infections in psychiatry.

The research processes in the elucidation of the causes of general paresis, the first slow infection in psychiatry, and of Kuru, the first slow virus infection in man, were considered. The errors and difficulties encountered may contribute to the formulation of research strategies for contemporary work on possible persistent infections with unknown viruses as a cause of psychiatric disorders. Clinical obsservation, bold hypotheses and methodological advances appear more valuable than diagnostic categorization in etiological research into psychiatric disorders. The low heuristic value of diagnosis is due to the lack of specificity of psychiatric symptoms and syndromes, especially in low grade organic disturbances.

Risk behavior and correlates of risk for HIV infection in the Dallas County Household HIV survey.

The Dallas County study of a proposed national household seroprevalence survey was designed to assess the feasibility of conducting a national survey and to estimate the prevalence of human immunodeficiency virus (HIV) and hepatitis B virus infection for Dallas County. Risk behavior data were collected and correlated with HIV infection. Participants in this survey represented a probability sample of the county. A self-administered questionnaire on demographic characteristics and HIV risk behavior was completed and a blood sample was obtained. Of the 1724 adults eligible for the survey, 1446 completed the questionnaire and 1374 provided a blood sample. The prevalence estimates were 0.4% for HIV and 7.3% for hepatitis B virus. A strong relationship was observed between HIV and hepatitis B status and risk behavior. In this study population, receptive anal intercourse and increasing numbers of male partners had the strongest correlation with the prevalence of HIV and hepatitis B virus infection in men. The high level of risk reporting for individuals positive for HIV or hepatitis B suggests that survey participants who engage in risk behaviors were willing to report those behaviors.

Antibodies to dsDNA are produced during primary BK virus infection in man, indicating that anti-dsDNA antibodies may be related to virus replication in vivo.

Experimental immunizations with both the Polyomavirus BK and with the isolated viral genomic dsDNA regularly induce antibodies with a relative affinity for BK virus dsDNA. In the present study we demonstrate that the anti-dsDNA responses to BK virus in experimental animals also appear during natural BK virus infection in man. Fifty-nine children were examined over time for serological signs of primary BK virus infection. Of eight children found to undergo primary infection with BK virus, anti-BK dsDNA antibodies appeared in all. In 4 of the 8 patients the antibodies cross-reacted significantly with mammalian dsDNA, and weak cross-reactions were also noted in at least three other patients. The antibodies resembled those induced in the experimental model with regard to their relative affinity for BK dsDNA. In contrast, most, but not all, anti-dsDNA antibodies from 10 SLE patients cross-reacted extensively with dsDNA from viral and mammalian origin. Thus, a dsDNA virus like BK virus may provoke immunological intolerance to dsDNA, but, with qualities different from those produced during SLE. The present observations demonstrate that induction of anti-dsDNA antibodies is not restricted to experimental immunization of animals, but does also take place in humans during naturally acquired BK virus infection. The relevance of this model for the spontaneous production of anti-dsDNA antibodies is discussed.

Natural history of chronic hepatitis B virus infection: new light on an old story.

Chronic hepatitis B virus (HBV) infection is one of the most common persistent virus infection in man. It causes significant morbidity and mortality, and therefore is important. Extensive studies on clinicopathologic studies and long-term follow up on hepatitis B surface antigen (HBsAg) carriers have largely disclosed the natural history of chronic HBV infection. The infection easily becomes chronic when contracted in early infancy. As high as 90% of babies born to HBV carrier mothers will also become HBsAg carriers. Once chronic infection is established, it is refractory, and HBsAg carriage usually persists for life. However, the chronic infection is not monotonous, it actually evolves from an HBV replicative phase to a non-replicative phase. The host responds differently and with more complexity in different phases. The virus-host interactions, divided into three phases, virus tolerance, virus clearance and residual HBV integrated phases, result in a heterogeneous variety of hepatic lesions. The first two phases occur when HBV is actively replicating, and the last corresponds to the non-replicative phase. The high HBV level (and hence HBV gene products) renders the host's immune system tolerant to the virus, and the infected host does not exert an effort to get rid of the virus. At this stage, the liver is nearly normal, and the host is asymptomatic. However, later in the replicative phase, the HBV replication begins to wane, and the immune tolerance is no longer maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

Rabies virus selectively alters 5-HT 1 receptors subtypes in rat brain

Rabies virus infection in man induces a series of clinical symptoms, some suggesting involvement of the central serotonergic system. The results of the present study show that, 5 days after rabies virus infection in rat, the total reversible high-affinity binding of [ 3H]5-HT in the hippocampus is not affected, suggesting that 5-HT 1A binding is not altered. 5-HT 1B sites identified by [ 125I]cyanopindolol binding are not affected in the cortex 3 and 5 days after the infection. Accordingly, the cellular inhibitory effect of trifluoromethylphenylpiperazine (TFMPP) on the [ 3H]acetylcholine-evoked release, presumably related to 5-HT 1B receptor activity, is not modified 3 days after infection. In contrast, [ 3H]5-HT binding determined in the presence of drugs masking 5-HT 1A, 5-HT 1B and 5-HT 1C receptors, is markedly (50%) reduced 3 days after the viral infection. These results suggest that 5-HT 1D-like receptor subtypes may be affected specifically and at an early stage after rabies viral infection.

Increased de novo hepatic lipogenesis in human immunodeficiency virus infection.

We measured de novo lipogenesis in human immunodeficiency virus (HIV) infected men using a newly developed stable isotope method. HIV-infected subjects with a history of weight loss (n = 17, mean weight loss 14.9 +/- 3.2 kg), asymptomatic HIV-seropositive subjects with normal CD4 T-cell counts (n = 7) and healthy HIV seronegative controls (n = 11) were studied. Hepatic lipogenesis was determined by infusion of [2-13C]-acetate, using the recently described xenobiotic probe technique with mass isotopomer analysis. Hepatic acetyl-coenzyme A enrichment was measured by high performance liquid chromatography/mass spectrometry of secreted sulfamethoxazole-acetate, with measurement of incorporation into very low density lipoprotein-fatty acids by gas chromatography-mass spectrometry. Circulating tumor necrosis factor (TNF), interleukin-1 (IL-1), interferon alpha (IFN alpha), insulin, and triglycerides were measured concurrently, and 7-day weighed food records were performed. De novo hepatic lipogenesis was increased 3- to 4-fold in HIV-infected subjects with weight loss compared to normal controls (P < 0.05 for palmitate and stearate in both overnight-fasted and fed states), and was also significantly increased in asymptomatic HIV seropositive subjects. Circulating TNF and IL-1 were not measurable in any subject (detection limit 2 pg/ml for IL-1 and 20 pg/ml for TNF). Serum IFN alpha was measurable in 11 out of 17 subjects with wasting and correlated significantly with de novo lipogenesis in overnight-fasted but not fed states. Serum IFN alpha was unmeasurable in asymptomatic HIV-infected subjects despite elevated lipogenic rates. Serum triglyceride concentrations were elevated in subjects with weight loss (2.09 +/- 0.28 mmol/L) and asymptomatic HIV-positives (1.34 +/- 0.34 mmol/L) in comparison to controls (0.67 +/- 0.08 mmol/L), and correlated with lipogenesis. Food intake correlated inversely with lipogenesis in the overnight-fasted state. We conclude that HIV infection is characterized by abnormal fat anabolism. This applies to subjects with reduced lean body mass and to asymptomatic HIV-positive subjects with normal T-cell counts. The former observation may have implications for the pathophysiology and treatment of the wasting syndrome. The latter observation is consistent with activation of the immune response and a state of viral nonlatency in early HIV disease.

Circadian rhythms of circulating NK cells in healthy and human immunodeficiency virus-infected men.

Antiviral immunity involves NK cells, which circulate rhythmically every 24 hours. We have investigated circadian and 12-hour rhythms in the peripheral count of circulating NK cells in 15 men infected with human immunodeficiency virus (HIV) and 13 healthy controls. We analyzed three phenotypes using double-labeling with monoclonal antibodies and flow cytometry assessment: CD3- CD16+, CD3-CD57+, and CD2+CD3-. A statistical validation of time-dependent differences was achieved if significance (p < 0.05) was validated both with analysis of variance and cosinor. The circadian rhythm had a similar asymmetric waveform for the three phenotypes and is homogeneous on an individual basis. The circulating NK cell count peaked in the early morning and was low at night. A circadian rhythm and a circahemidian harmonic characterized all phenotypes in healthy subjects. We considered two groups of HIV-infected men: those who were asymptomatic (eight) and those with acquired immune deficiency syndrome (AIDS) (seven). Circadian changes in NK cell count were similar in both subgroups and in healthy controls. The circadian pattern was also consistent among individual patients. Asymptomatic HIV-infected men (early-stage disease) exhibited more pronounced 12-hour rhythmicity than did patients with AIDS or controls. The circulation of NK cells does not appear to share the same synchronizer(s) as other circulating T- or B-lymphocyte subsets. Thus, HIV infection gradually abolished circadian rhythmicity in circulating T and B cells, whereas it did not disturb that in NK cells.

The Impact of Human T-Lymphotrophic Virus Type I/II Infection on the Prognosis of Sexually Acquired Cases of Acquired Immunodeficiency Syndrome

Twenty (18%) of 111 Peruvian men with sexually acquired human immunodeficiency virus infection were found also to be infected with human T-lymphotrophic virus type I or II in a retrospective study. At the time of data evaluation, 75 patients had reached Centers for Disease Control stage IV (clinical acquired immunodeficiency syndrome) and had not received antiviral medication; mortality in this group was 63.3% (38/60) among patients infected with human immunodeficiency virus alone and 80% (12/15) in the dually infected group. Of the 50 patients who had died, survival time from onset of stage IV to death was shorter in the dually infected group (5.02 +/- 3.27 months) than in those with human immunodeficiency virus infection alone (10.07 +/- 4.42 months). In Peru, sexually acquired human immunodeficiency virus infection in men is often accompanied by human T-lymphotrophic virus type I/II infection, and dual retrovirus infection is associated with a shorter survival after onset of clinical acquired immunodeficiency syndrome.

Decreased Serum Dehydroepiandrosterone Is Associated with an Increased Progression of Human Immunodeficiency Virus Infection in Men with CD4 Cell Counts of 200-499

Dehydroepiandrosterone (DHEA) and its interconvertible sulfate derivative (DHEA-S) are human androgenic steroids that have been reported to inhibit viral expression and have been associated with a decreased risk of cancer. The relationship between serum DHEA and DHEA-S levels and subsequent progression to AIDS was investigated in a sample of human immunodeficiency virus (HIV)-infected men from the San Francisco Men's Health Study followed prospectively since 1984. Among 108 men seropositive for HIV at study entry and with CD4 lymphocyte counts of 200-499 microliters 24 months later, serum DHEA levels below the lower limit of normal (less than 180 ng/dl) at this later date were predictive of subsequent progression to AIDS (relative hazard = 2.34; 95% confidence interval = 1.18-4.63; P = .01) after controlling for hematocrit, age, and log absolute CD4 cell number in a Cox proportional hazards model. This is the first large prospective cohort in which an endocrinologic variable has been observed to independently predict progression to AIDS. These observations, in addition to recent in vitro data, suggest that DHEA might have a protective effect in HIV infection.

Management of viral infections during pregnancy

Management of viral infections during pregnancy

Detection of Defective Genomes in Hepatitis A Virus Particles Present in Clinical Specimens

Hepatitis A virus (HAV) particles harbouring a physically defective RNA genome have been reported to occur in all HAV-infected cell culture systems analysed so far. The most prominent defects consist of three distinct overlapping deletions in the region of the HAV genome encoding the structural proteins. By probing for the endpoints of these deletions in RNA samples using S1 nuclease and exonuclease VII mapping, we obtained suggestive evidence for the existence also of defective genomes in HAV particles present in faecal specimens, in viraemic blood collected in the course of hepatitis A virus infection in man, as well as in the liver of an experimentally infected marmoset monkey. The deletions identified extend from nucleotide (nt) 1200 to nt 3820 and from nt 1200 to nt 3240 of the HAV genome. They are compatible with two of the deletions detected in particles grown in vitro in cell cultures and shown to interfere with the replication of standard hepatitis A virions.