High-level Viremia Research Articles

Measles Virus Selectively Blind to Signaling Lymphocytic Activation Molecule (SLAM; CD150) Is Attenuated and Induces Strong Adaptive Immune Responses in Rhesus Monkeys

The signaling lymphocytic activation molecule (SLAM; CD150) is the immune cell receptor for measles virus (MV). To assess the importance of the SLAM-MV interactions for virus spread and pathogenesis, we generated a wild-type IC-B MV selectively unable to recognize human SLAM (SLAM-blind). This virus differs from the fully virulent wild-type IC-B strain by a single arginine-to-alanine substitution at amino acid 533 of the attachment protein hemagglutinin and infects cells through SLAM about 40 times less efficiently than the isogenic wild-type strain. Ex vivo, this virus infects primary lymphocytes at low levels regardless of SLAM expression. When a group of six rhesus monkeys (Macaca mulatta) was inoculated intranasally with the SLAM-blind virus, no clinical symptoms were documented. Only one monkey had low-level viremia early after infection, whereas all the hosts in the control group had high viremia levels. Despite minimal, if any, viremia, all six hosts generated neutralizing antibody titers close to those of the control monkeys while MV-directed cellular immunity reached levels at least as high as in wild-type-infected monkeys. These findings prove formally that efficient SLAM recognition is necessary for MV virulence and pathogenesis. They also suggest that the selectively SLAM-blind wild-type MV can be developed into a vaccine vector.

Improved Detection of Acute HIV Infection in New York City

Acute HIV infection (AHI) is generally associated with high levels of viremia and, consequently, increased risk of HIV transmission. Diagnosis remains

Perturbation of the natural killer cell compartment during primary human immunodeficiency virus 1 infection primarily involving the CD56bright subset

We investigated the distribution of natural killer (NK) cell subsets, their activating and inhibitory receptors, and their cytolytic potential, in primary human immunodeficiency virus (HIV)-infected (PHI) individuals at baseline and during 1 year of follow-up with or without antiretroviral therapy, and compared the results with those obtained in treatment-naïve, chronically HIV-infected (CHI) individuals, and HIV-seronegative (HN) healthy individuals. The proportion of the CD56(dim) and CD56(bright) subsets decreased with disease progression, whereas that of the CD56(-) CD16(+) subset increased. In the CD56(dim) subset, the proportion of cells with natural cytotoxicity receptors (NCRs) decreased with disease progression, and their cytolytic potential was reduced. Conversely, the CD56(bright) subset was characterized by a high proportion of NCR-positive, killer cell immunoglobulin-like receptor (KIR)-positive NKG2A(+) cells in both CHI and PHI individuals, which was associated with an increase in their cytolytic potential. During the 1 year of follow-up, the PHI individuals with high viraemia levels and low CD4(+) T-cell counts who received highly active antiretroviral therapy (HAART) had a similar proportion of NK subsets to CHI individuals, while patients with low viraemia levels and high CD4(+) T-cell counts who remained untreated had values similar to those of the HN individuals. Our results indicate a marked perturbation of the NK cell compartment during HIV-1 infection that is multifaceted, starts early and is progressive, primarily involves the CD56(bright) subset, and is partially corrected by effective HAART.

Pregnancy and chronic hepatitis B virus infection

The combination of chronic hepatitis B virus (HBV) infection and pregnancy presents unique management questions. Aspects of care that need to be considered include effects of hepatitis B on pregnancy, effects of pregnancy itself on the course of hepatitis B infection, treatment of hepatitis B during pregnancy and prevention of mother-to-infant transmission. Chronic HBV infection is usually mild in pregnant women, but may flare shortly after delivery. Effect of HBV infection on pregnancy outcomes are generally favorable, but may depend on severity of liver disease. Mother-to-infant transmission can be minimized by current immunoprophylaxis strategies, however, high levels of viremia in mothers may be a factor in the small but reproducible failure rate of current immunoprophylaxis strategies. Use of antivirals during pregnancy needs to be individualized. Careful planning and management of pregnancy must be done among patients with chronic HBV infection.

Effect of newer oral antiviral agents on future therapy of chronic hepatitis B

Long-term therapy with oral nucleoside/nucleotide analogues (NAs) is a favoured approach to the treatment of patients with chronic hepatitis B (CHB); however, all oral agents currently approved for the treatment of such patients are associated with some risk for drug resistance. This can lead to a rebound in HBV levels and, eventually, progressive liver disease. Combination therapy is one strategy that has the potential for enhanced antiviral effects and diminished or delayed resistance. The disadvantages of combination therapy include increased cost, the potential for drug interactions and increased toxicity. Additional therapeutic efficacy from combination therapy has not been demonstrated in clinical trials of HBV, and this approach might be less relevant now that potent NAs with excellent drug resistance profiles are available. However, it might be possible to identify subsets of patients (for example, those with extremely high viraemia or low baseline alanine aminotransferase levels) who derive added benefit from combination therapy. This review examines efficacy and resistance data for new low resistance oral NAs and clinical experience to date with de novo combination therapy in patients with CHB. The application of combination therapy in select populations of patients with CHB is also discussed.

High-Level Human Herpesvirus-6 Viremia Associated With Onset of Stevens-Johnson Syndrome: Report of Two Cases:

High-Level Human Herpesvirus-6 Viremia Associated With Onset of Stevens-Johnson Syndrome: Report of Two Cases:

BK Virus in Solid Organ Transplant Recipients

The human polyomavirus BK (BKV) is linked to two ma-jor complications in transplant recipients, polyomavirus-associated nephropathy (PyVAN) (1–4) and polyomavirus-associated hemorrhagic cystitis (PyVHC) (5,6). PyVAN andPyVHC have been encountered in a variety of immunod-eficient patients (7,8), but most cases of PyVAN arise inkidney transplant patients at rates of 1–10%, while PyVHCpreferentially affects allogeneic hematopoietic stem celltransplant patients at rates of 5–15% (7,9). BKV hasbeen less frequently associated with other pathologies,such as ureteric stenosis, pneumonitis, hemophagocyticsyndrome, encephalitis, retinitis, multiorgan failure andpolyomavirus-associated multifocal leukoencephalopathy(PyVML) (10–12), a complication of the central nervoussystem mostly caused by the closely related polyomavirusJC (JCV) (13). The objective of this section is to updateprevious recommendations (14) regarding diagnosis andmanagement of BKV replication and PyVAN in solid organtransplantation (SOT) using the grading proposed by Grosset al. (15).BKV belongs to the family Polyomaviridaetogether withfive other polyomaviruses detected in human specimens,that is JCV, KI virus, WU virus, Merkel cell carcinoma virusand Simian virus 40 (16,17). The virions are nonenvelopedparticles of 42 nm diameter and fairly resistant to envi-ronmental inactivation (18). The circular double-strandedDNA genome of

The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer–cell subsets associated with high levels of HIV-1 viremia

AbstractHIV-1 has developed several strategies to evade natural killer (NK)–cell antiviral functions. One of these mechanisms is the HIV-1–induced expansion of highly dysfunctional NK-cell subsets. Here, we analyze a large cohort of HIV-1–infected patients in early or chronic phases of infection, both cross-sectionally and longitudinally. We demonstrate that a striking decrease in the surface expression of sialic acid–binding immunoglobulin-like lectin 7 (Siglec-7) represents the earliest marker of the aberrant NK-cell dysregulation, which precedes the down-modulation of CD56 mostly occurring in patients with chronic HIV-1 viremia. The combined detection of Siglec-7 and CD56 allows the identification of 2 new pathologic NK-cell subsets expanded preferentially in early (Siglec-7−/CD56+) or chronic (Siglec-7−/CD56−) stages of HIV-1 infection. Remarkably, these phenotypic abnormalities were directly associated with progressive and distinct impairments of NK-cell functions. The aforementioned NK-cell aberrancies could be observed only in the presence of high levels of viral replication and not in patients with low or undetectable HIV-1 viremia, such as long-term nonprogressors or patients having undergone antiretroviral therapy. High frequencies of Siglec-7−/CD56+ and Siglec-7−/CD56− pathologic NK cells reflect the immune and clinical status of HIV-1 infection and can also track the effectiveness of therapy.

Chikungunya Fever: An Epidemiological Review of a Re‐Emerging Infectious Disease

Chikungunya fever is an acute febrile illness associated with severe, often debilitating polyarthralgias. The disease is caused by Chikungunya virus (CHIKV), an arthropod-borne virus that is transmitted to humans primarily via the bite of an infected mosquito. Since a re-emergence of CHIKV in 2004, the virus has spread into novel locations, such as Europe, and has led to millions of cases of disease throughout countries in and around the Indian Ocean. The risk of importation of CHIKV into new areas is ever present because of the high attack rates associated with the recurring epidemics, the high levels of viremia in infected humans, and the worldwide distribution of the vectors responsible for transmitting CHIKV. In this review, we will characterize the epidemiology and global expansion of CHIKV, describe the clinical features and laboratory testing for the disease, and discuss priorities for further studies needed for effective disease control and prevention.

Rate of Sustained Virologic Response in Relation to Baseline Hepatitis C Virus (HCV) RNA Level and Rapid Virologic Clearance in Persons with Acute HCV Infection

Treatment of acute hepatitis C virus (HCV) infection leads to a sustained virologic response (SVR) in the vast majority of patients, although the clinical predictors of these favorable responses are not well understood. In chronic infection, the most potent predictor of a SVR is complete viral suppression after 4 weeks of treatment, also known as a rapid virologic response (RVR). However, few patients with HCV genotype 1 infection and high-level viremia ever achieve this benchmark. In 2 separate cohorts of patients with acute HCV infection, we demonstrate that rapid virologic clearance and low-level viremia (HCV RNA level, <400,000 IU/mL) are highly prevalent, regardless of HCV genotype.

Mouse APOBEC3 affects the production of virus-neutralizing antibodies by restricting early retroviral replication, not by altering the B-cell repertoire

Recent genetic analyses have indicated that polymorphisms in the mouse APOBEC3 locus constitute the Rfv3 gene that influences the production of virus-neutralizing antibodies in mice infected with Friend leukemia retrovirus [1,2]. Mice of the resistant genotype preferentially express the exon 5-lacking transcript in higher levels, while susceptible mice express the full-length transcript in lower levels [2,3]. Mouse APOBEC3 expressed in the resistant strains restricts the replication of mouse retroviruses in vitro through a mechanism independent of its deaminase activity [2]. However, the mechanisms through which mouse APOBEC3 affects the production of virus-neutralizing antibodies remain unclear. To address this question, we analyzed retroviral replication and the production of virus-neutralizing antibodies in mice of different APOBEC3 genotypes and those lacking its expression. Strain A mice with the susceptible APOBEC3 genotype nevertheless produced high levels of virus-neutralizing antibodies when they possessed the H-2b haplotype, and class-switching to IgG was observed in the presence of virus-specific T helper cells. Further, APOBEC3-deficient mice produced virus-neutralizing antibodies when their T helper cells had been primed with the viral antigen. Friend virus-induced derangements in the hematopoiesis and resultant splenomegaly are not directly responsible for the delayed antibody responses, because higher levels of viremia and lower antibody responses were observed upon infection with nonpathogenic Friend murine leukemia helper virus in the absence of APOBEC3. In mice of the resistance-associated APOBEC3 genotype lower levels of viremia were observed even before the detection of virus-neutalizing antibodies in the blood, indicating that the polymorphisms in the APOBEC3 locus affect the production of neutralizing antibodies as a result of restricted retroviral replication.

Human immunodeficiency virus type 1-specific CD8+ T-cell responses during primary infection are major determinants of the viral set point and loss of CD4+ T cells.

Primary HIV-1 infection (PHI) is marked by a flu-like syndrome and high levels of viremia that decrease to a viral set point with the first emergence of virus-specific CD8+ T-cell responses. Here, we investigated in a large cohort of 527 subjects the immunodominance pattern of the first virus-specific cytotoxic T-lymphocyte (CTL) responses developed during PHI in comparison to CTL responses in chronic infection and demonstrated a distinct relationship between the early virus-specific CTL responses and the viral set point, as well as the slope of CD4+ T-cell decline. CTL responses during PHI followed clear hierarchical immunodominance patterns that were lost during the transition to chronic infection. Importantly, the immunodominance patterns of human immunodeficiency virus type 1 (HIV-1)-specific CTL responses detected in primary, but not in chronic, HIV-1 infection were significantly associated with the subsequent set point of viral replication. Moreover, the preservation of the initial CD8+ T-cell immunodominance patterns from the acute into the chronic phase of infection was significantly associated with slower CD4+ T-cell decline. Taken together, these data show that the specificity of the initial CTL response to HIV is critical for the subsequent control of viremia and have important implications for the rational selection of antigens for future HIV-1 vaccines.

Chikungunya Outbreak, Singapore, 2008

Chikungunya Outbreak, Singapore, 2008

Development of Infectious Clones for Virulent and Avirulent Pichinde Viruses: a Model Virus To Study Arenavirus-Induced Hemorrhagic Fevers

Several arenaviruses can cause hemorrhagic fever diseases (VHFs) in humans, the pathogenic mechanism of which is poorly understood due to their virulent nature and the lack of molecular clones. A safe, convenient, and economical small animal model of arenavirus hemorrhagic fever is based on guinea pigs infected by the arenavirus Pichinde (PICV). PICV does not cause disease in humans, but an adapted strain of PICV (P18) causes a disease in guinea pigs that mimics arenavirus hemorrhagic fever in humans in many aspects, while a low-passaged strain (P2) remains avirulent in infected animals. In order to identify the virulence determinants within the PICV genome, we developed the molecular clones for both the avirulent P2 and virulent P18 viruses. Recombinant viruses were generated by transfecting plasmids that contain the antigenomic L and S RNA segments of PICV under the control of the T7 promoter into BSRT7-5 cells, which constitutively express T7 RNA polymerase. By analyzing viral growth kinetics in vitro and virulence in vivo, we show that the recombinant viruses accurately recapitulate the replication and virulence natures of their respective parental viruses. Both parental and recombinant virulent viruses led to high levels of viremia and titers in different organs of the infected animals, whereas the avirulent viruses were effectively controlled and cleared by the hosts. These novel infectious clones for the PICV provide essential tools to identify the virulence factors that are responsible for the severe VHF-like disease in infected animals.

The natural history of chronic HBV infection

Chronic hepatitis B (CHB) is a disease of worldwide importance that carries considerable morbidity and mortality. The natural course of CHB is characterized by an initial hepatitis B e antigen (HBeAg)-positive phase marked by immunologic tolerance, high-level viremia, and histologic quiescence, followed by an immune elimination phase of variable duration that is associated with less viremia but increased disease activity, usually resulting in HBeAg clearance. The ensuing HBeAg-negative phase is characterized by even lower or undetectable viremia with biochemical and histologic quiescence. This inactive carrier state may be of short or lifelong duration and occasionally results in hepatitis B surface antigen clearance. Alternatively, the HBeAg-negative phase may demonstrate intermittent or continuous disease activity, resulting in progressive liver fibrosis, leading to cirrhosis and portal hypertension. Compensated or decompensated cirrhosis is associated with considerable mortality due to complications of portal hypertension and, most importantly, with the development of hepatocellular carcinoma, which is frequent in patients with CHB.

Early decline of the HCV core antigen can predict SVR in patients with HCV treated by Pegylated interferon plus ribavirin combination therapy

Pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy is now a popular treatment for patients with chronic hepatitis C; however, the reported sustained virologic response (SVR) rate remains at nearly 50% in genotype 1b infected patients. Therefore, it is of clinical benefit to be able to predict the effect of combination therapy on individual patients earlier in the treatment. We estimated the predictive serum HCV core antigen levels for SVR in the early therapeutic stage of combination therapy. The HCV core antigen in patients with high-level HCV viremia, in whom standard PEG-IFNalpha2b plus RBV combination therapy had been completed, was measured at baseline and at 3, 7, 14, 28 and 84 days of treatment, and their SVR was determined at 24 weeks after treatment. Sixty genotype 1b- and 30 genotype 2-infected patients were included. Thirty (50%) genotype 1b and 27 (90%) genotype 2 patients achieved a SVR. In genotype 1b patients the decline of HCV core antigen levels was statistically different between the SVR and non-SVR groups. When we defined a separation level at 500 fmol/L, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for SVR at day 7 was 79.4%, 88.5%, 90%, 76.7%, and 83.3%, respectively. In genotype 2 patients, there was no significant difference in the HCV core antigen values between the SVR and non-SVR groups. In genotype 1b patients, 500 fmol/L of HCV core antigen level at day 7 was the best predictor for therapeutic response in the early stage of treatment.

Hepatitis B and pregnancy: an underestimated issue

Hepatitis B infection during pregnancy presents a unique set of management issues. Aspects of care that must be considered include maternal and fetal effects of hepatitis B, effects of pregnancy itself on the course of hepatitis B infection and its complications, treatment of hepatitis B during pregnancy and prevention of perinatal infection. There are insufficient studies to date regarding these concerns; most are from the Far East, and many have important limitations, but some have yielded valuable data. Pregnant women with acute hepatitis B virus (HBV) infection typically have a course not very different from that in the general adult population, but the risk of transmission of HBV to neonates increases the later in gestation the acute infection occurs. Chronic HBV infection is usually mild in pregnant women, but may flare shortly after delivery. The risk of perinatal transmission is highest in women with high levels of viraemia; this may be a factor in the small but reproducible failure rate of current immunoprophylaxis strategies. Obstetrical policies must be assessed with respect to detection of maternal infection and liver disease, as well as with respect to perinatal transmission risk. In addition to the usual issues of drug efficacy and safety in the affected individuals, effects on the developing fetus must be considered. This paper reviews the current experience in each of these areas, and highlights the need for further investigation into this critical but often underestimated topic.

Immunity in natural SIV infections

In stark contrast to human immunodeficiency virus (HIV)-infected individuals who, if left untreated, almost invariably progress to acquired immunodeficiency syndrome (AIDS), natural hosts for the simian immunodeficiency viruses (SIV) remain asymptomatic throughout the course of infection. This observation represents one of the main unresolved puzzles of AIDS research, particularly if one considers that natural SIV infections are characterized by chronically high levels of viraemia as well as intrinsic virus cytopathicity comparable with that of HIV. In this review, I discuss the basic immunological features of natural, nonpathogenic SIV infections, the evidence suggesting that attenuated, rather than extraordinarily strong, immune responses to the virus may favour their benign course, and the implications of these findings in terms of HIV therapy and vaccines.

Evaluation of the Efficacy of a Recombinant Subunit West Nile Vaccine in Syrian Golden Hamsters

The efficacy of a recombinant subunit West Nile (WN) vaccine candidate was determined in a hamster model of encephalitis. Animals included young, aged, and immunocompromised animals in an effort to simulate key groups at risk of WN virus-induced disease. Groups of aged (12 month old), weanling, and adult hamsters rendered leukopenic after immunization were immunized subcutaneously with a WN virus recombinant envelope protein (WN-80E) with or without WN virus non-structural protein 1 (NS1) mixed with adjuvant or adjuvant alone. A challenge dose of wild-type WN virus was administered to produce 40-100% mortality in the control hamsters. The recombinant antigen preparations containing WN-80E with or without WN NS1 gave similar results. Hamsters in both groups had a strong antibody response after immunization, and none of the aged or weanling animals became ill or developed detectable viremia after challenge with WN virus at 2 weeks after booster vaccination. However, mortality among the control animals (administered adjuvant without antigen) at 2 weeks after booster challenge was 40-60%. In hamsters rendered leukopenic after immunization, survival rates up to 80% were observed, and a low-level viremia was detected in the vaccinated and challenged hamsters. The survival rate was significantly (P<0.05) higher in animals vaccinated with a higher dose of WN-80E than a lower dose. The addition of NS1 did not significantly affect survival after challenge. In contrast, all of the control animals that received adjuvant only developed a very high level of viremia, and the mortality rate was 100%. These findings indicate that the recombinant WN vaccines induced antibody in and afforded protection to young and aged hamsters and immunosuppressed hamsters.

Cellular Gene Expression Profiles in Rhesus Macaques Challenged Mucosally with a Pathogenic R5 Tropic Simian Human Immunodeficiency Virus Isolate

Insights into the host factors that contribute to an effective antiviral immune response may be obtained by examining global gene expression in simian human immunodeficiency virus (SHIV)-infected nonhuman primates that exhibit different virological outcomes. Immune responses and gene expression profiles in peripheral blood mononuclear cells (PBMCs) were compared between animals that controlled or did not control viremia after infection. Rectal inoculation of eight rhesus macaques with R5-tropic SHIV(SF162P3) resulted in a high level of plasma viremia during the acute phase of infection. The viremia was controlled to below levels of detection in six of these animals at the set point (controllers), whereas two animals had persistent viremia throughout the 140 wk that the animals were monitored (non-controllers). CD4(+) T-cell counts declined slightly in both controllers and non-controllers in the acute phase of infection, but CD4(+) T-cell counts continued to decline only in the non-controllers. Neutralizing antibodies to the challenge virus were variable and could not account for the control of viremia. However, analysis of the cellular gene expression profiles in the PBMCs from both groups of animals revealed distinctive gene expression patterns between controllers and non-controllers. Using the paired LPE test, 59 genes with p values <0.01 were identified and specific differences in the gene expression profiles in PBMCs from controllers versus non-controllers were detected.