Significant Viremia Research Articles

Use of well-defined HIV-derived epitopes to evaluate CD4(+) and CD8(+) T cell responses in patients with chronic HIV-1 infection treated with HAART.

Highly active antiretroviral therapy (HAART) is associated with a dramatic clinical benefit to HIV-infected patients through significant plasma viremia reduction and CD4(+) T cells increase. In previous reports, HIV-specific CD4(+) and/or CD8(+) T cell responses have been studied separately during HAART; therefore the relationship between these two virus-specific populations is currently not well understood. In this study, both HIV-specific CD4(+) and CD8(+) T cell responses were investigated using a large panel of well-defined T cell epitope peptides in 24 HIV-1-infected patients undergoing HAART, with undetectable viral load and CD4(+) T cell count >/= 350/mm(3). One-third of the patients had CD4(+) T cells able to proliferate when exposed to HIV-1 protein fragments but only two patients displayed polyclonal responses. In addition the majority (78%) of HAART-treated patients displayed no or monospecific CD8(+) T cell responses and the phenotypic analysis of these HIV-specific CD8(+) T cells demonstrated the absence of terminally differentiated effectors. In conclusion, the experimental approach used in this study shows that CD4(+) T cell responses may persist during HAART but are not associated with strong CD8(+) T cell responses

Relationship between the development of precore and core promoter mutations and hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus.

Chinese patients with chronic hepatitis B virus (332 with and 44 without cirrhosis-related complications) were studied. Fifty percent of patients <30 years old had precore mutations. The prevalence of precore mutations among hepatitis B e antigen (HBeAg)-positive patients, although lower than that among anti-HBe-positive patients (P=.031), was already high (44.2%). Median HBV DNA level in anti-HBe-positive patients was 1.5 x 10(6)-1.55 x 10(6) copies/mL, irrespective of the presence or absence of precore mutations. There was no difference in the prevalence of precore mutations between patients with and without complications (P, not significant). However the prevalence of core promoter mutations was higher among patients with complications than among those without complications (90.5% vs. 69.3%, respectively; P=.003). In conclusion, precore mutations occurred in a large proportion of Chinese patients with chronic hepatitis B virus before HBeAg seroconversion. The development of complications was not related to precore mutations but was probably due to the persistence of significant viremia after HBeAg seroconversion.

Specific Restrictions in the Progression of Venezuelan Equine Encephalitis Virus-Induced Disease Resulting from Single Amino Acid Changes in the Glycoproteins

The pathogenesis of Venezuelan equine encephalitis virus (VEE) was examined in the mouse model using V3000, a virus derived from a molecular clone of the Trinidad donkey strain of VEE. These results were compared in parallel experiments with avirulent mutants of VEE derived by site-directed mutagenesis of the clone. Adult mice, inoculated subcutaneously in their left rear footpad with V3000, were followed in a time course study for 6 days in which 15 organs were tested for histopathological changes, for the presence of viral antigen by immunohistochemical staining, for the presence of viral nucleic acid by in situ hybridization analysis, and for content of viable virus. Virus was detected in the footpad inoculation site, but until 12 hr postinoculation (pi), the level of virus did not suggest early viral replication. By 4 hr pi, however, replication of V3000 was evident in the draining popliteal lymph node. At this early time point, no virus could be isolated from any other organ examined. At 12 hr, a significant serum viremia was observed, and virus was detected at a low level in a number of well vascularized organs, including spleen, heart, lung, liver, kidney, and adrenal gland. By 18 hr, high virus titers were present in serum and all the lymphoid organs examined, and these tissues appeared to be the major peripheral sites of V3000 replication. Virus in serum and peripheral organs was cleared by 3-4 days pi. In a second phase of the infection, V3000 invaded the central nervous system (CNS), replicated predominantly in neurons, and persisted in the brain until death by encephalitis. Pathologic findings as well as the results of immunocytochemical and in situ hybridization examination were generally coordinate with virus titration. A site-directed mutant of V3000, V3010, contained a mutation in the gene for the E2 glycoprotein at codon 76 (Glu to Lys) which rendered it avirulent after footpad inoculation. Detection of V3010 replication in the draining lymph node was sporadic and was sometimes delayed to as long as 3 days pi. Infrequent and/or delayed virus spread to other sites also was observed. Analogous experiments were performed with other mutants which were avirulent by the footpad inoculation route: V3014, a mutant differing from V3000 at three loci (E2 Lys 209, E1 Thr 272, and E2 Asn 239), as well as single-site mutants V3032 (E2 Lys 209) and V3034 (E1 Thr 272). The mutations in V3014 prevented spread beyond the draining lymph node. The single-site E2 Lys 209 mutation allowed spread to the draining lymph node and to other lymphoid organs without significant serum viremia or invasion of the CNS, and E1 Thr 272 was characterized by near normal peripheral replication, but only sporadic replication in the CNS. These results suggest that VEE-induced disease results from a sequence of events which can be defined by interdicting the pathogenic pathway with specific mutations in the VEE genome.

Human Retroviruses and Neoplastic Disease

Human retroviral infections result in significant neoplastic disease. Human T cell lymphotropic virus I (HTLV-I), the first human retrovirus to be discovered, is associated with the development of acute T cell leukemia with characteristic hypercalcemia and skin lesions after many years of chronic infection of CD4+ cells. HTLV-I also produces myelopathy. A minor T cell immunodeficiency occurs in HTLV-I acute T cell leukemia with associated strongyloidiasis and Pneumocystis carinii pneumonia. Human T cell lymphotropic virus II (HTLV-II) is found to be endemic in Amerindians and intravenous drug users (IVDUs) and has been linked to some cases of hairy-cell leukemia. HTLV-II infects the CD8+ population, with significant cell-associated viremia. Clinical neurological disease is rare, with one patient with myelopathy having been described. Immunodeficiency does not seem to occur. Human immunodeficiency virus 1 (HIV-1) produces aggressive large cell and Burkitt's lymphoma in as many as 10% of HIV-1-infected patients. More than 20% of homosexual men infected with HIV-1 develop Kaposi's sarcoma (KS). The pathogenesis of KS is better understood through studying KS-like cell lines that induce angiogenic factors. In some patients HIV-1 and HTLV-I or HTLV-II infections occur concomitantly. HIV-1 accelerates the tumorigenesis of HTLV-I and produces unusual skin diseases when combined with HTLV-II. Immunodeficiency occurs in all HIV-1-infected patients.

Differential alterations in host peripheral polymorphonuclear leukocyte chemiluminescence during the course of bacterial and viral infections.

Previous studies have shown that stimulation of the oxidative metabolism in polymorphonuclear leukocytes (PMN) by in vitro phagocytosis of various microorganisms results in photon emission, termed chemiluminescence (CL). Studies were conducted to determine whether bacterial and viral infections induce enhanced basal endogenous host peripheral PMN CL in the absence of in vitro phagocytic stimulation. Nonimmune rats and guinea pigs as well as immune rats were inoculated with various doses (10(5) to 10(7)) of live vaccine strain Francisella tularensis (per 100 g of body weight). In addition, nonimmune guinea pigs were inoculated with 40,000 plaque-forming units of Pichinde virus. Luminol-assisted endogenous PMN CL was measured at various time intervals after inoculation of microorganisms. Enhanced endogenous PMN CL was detected as early as the appearance of fever (12 h) in nonimmune animals infected with F. tularensis. Addition of sodium azide, N-ethylmaleimide, superoxide dismutase, or catalase to the CL reaction mixture containing PMN from infected animals significantly decreased the CL response. Immune rats challenged with F. tularensis exhibited resistance to infection and a decreased PMN CL compared with nonimmune rats 24 and 48 h after inoculation. However, the CL response from immune rats was significantly elevated, compared with control values. In contrast to the results obtained with the model bacterial infection, PMN isolated from guinea pigs inoculated with Pichinde virus failed to exhibit enhanced CL, compared with controls, despite significant viremia and fever. Results suggest that enhanced endogenous CL during bacterial infection occurs through mechanisms involving increased PMN oxidative metabolism and the subsequent generation of microbicidal forms of oxygen. Further, measurement of endogenous PMN CL may have diagnostic and prognostic value in infectious diseases.

Discordant e Antigen, DNA Polymerase Activity, and Dane Particle Responses in Two Patients Representing an Index Case-Contact Case Pair with Hepatitis B Virus Infection

Discordant results for e antigen, DNA polymerase activity, and Dane particle frequency were noted in the sera of two patients representing an index case-contact case pair with chronic aggressive hepatitis B. The lack of correlation between presence of e antigen and the infecting viral strain, as well as the strong relationship of e antigen to persistent and significant viremia, emphasize the role of the host's immune response in the expression of this antigen.

A study of the possible basis of age-dependent resistance of mice to poxvirus diseases.

SummaryThe age‐dependent resistance of mice to cowpox virus has been studied. The young mice were more susceptible to the lethal effects of the virus inoculated by various routes, and adult levels of resistance were attained between 2 and 3 weeks of age.Subcutancously inoculated cowpox virus infected adult and young mice equally. Virus titrations and immunofluorescence studies showed that significant viraemia and infection of viscera occurred only in young mice. There was no particular target organ in young mice, and the degree of infection and the extent of histological damage seen in the liver were slight compared to that seen in fatal mousepox. Circulating free virus was found to infect the livers of young mice more easily.The adult mice had a superior neutralizing antibody response and this could have been an important factor in preventing the infection of internal organs. The evidence did not suggest that interferon or macrophages were important, factors in age‐dependent resistance to poxviruses. Death in young mice from viral infection did not appear to be due to any greater sensitivity to bacterial endotoxin. It was also found that young mice from a low pathogen colony were more resistant than mice of the same age from the regular colony.

Studies of Live Attenuated Japanese Encephalitis Vaccine in Swine

Summary Colostrum-deprived pigs were found to be highly susceptable to Japanese encephalitis (JE) virus even by subcutaneous inoculation. Such animals represent the most suitable host for assaying the virulence of JE virus in swine. When a small dose (10 LD50) of a virulent strain was injected subcutaneously in colostrum-deprived pigs, they showed significant viremia and clinical signs, including nervous symptoms. On the other hand, an attenuated mutant (m) strain of JE virus produced no detectable viremia and no clinical symptoms even when more than 107 TCD50 of the virus was inoculated. The m virus was able to evoke both hemagglutination-inhibiting (HI) and neutralizing antibodies in colostrum-deprived pigs after a single subcutaneous injection. The same antibody responses were also observed after one injection of m virus in young adult pigs with HI antibody titers less than 1:10, and the antibody levels persisted for at least 80 days.

The susceptibility of Arvicanthis abyssinicus (Rüppell) to infection with various arboviruses

The susceptibility of Arvicanthis abyssinicus (Rüppell) to 19 African arboviruses and one other virus not now thought to be an arbovirus was investigated. Very few of the viruses tested produced significant viraemia but, of the total surviving Arvicanthis, 58% developed neutralizing antibody. The findings are compared with those described by other authors, and the results suggest that Arvicanthis might play a role in the epidemiology of arbovirus diseases.