Decline In Viremia Research Articles

Clinical implications of hepatitis C viral kinetics

Antiviral treatment of patients with chronic hepatitis C can perturb the steady-state of virus production and clearance. From serial measurements of changes in viremia, kinetic information on the dynamics of hepatitis C virus (HCV) replication can be obtained. After a delay of about 9 h due to interferon-α pharmacokinetics, the decline of viremia in patients treated with interferon-α is characterized by a concave shape. In the first phase (day 1) a rapid dose-dependent decline in viral load is observed. The second phase viral decline (≥day 2) shows a much slower decline with no or less pronounced differences between the applied interferon-α schedules. While a first phase decline can be observed in almost all patients treated with interferon-α, non-responders typically reveal no further decline of viremia during the second phase. Kinetic analysis showed that combination therapy with interferon-α plus ribavirin has no direct synergistic antiviral effect in the initial 4 weeks of treatment of HCV-infected patients with 6 MU IFNα three times per week. Calculations revealed a minimum virus production and clearance per day in patients with chronic hepatitis C of approximately 10 10–10 12 virions per day and an in vivo half-life of the virus in the order of a few hours. The high turnover rates of HCV explain the rapid generation of viral diversity and the opportunity for viral escape from the host immune surveillance and antiviral therapy. The implications derived from HCV kinetics comprise the consideration of more aggressive initial dosing regimens (especially daily doses), the possibility to optimize therapy individually not only according to pretreatment parameters but also according to the initial decline of viral load and the perception that eradication of the virus will rely on the half-life of infected cells.

Cell-associated viral RNA expression during acute infection with HIV type 1.

The mechanism of decline in viremia following acute infection with HIV is unknown. To characterize this process virologically, the expression of viral RNAs was analyzed in samples of peripheral blood mononuclear cells (PBMCs) from a patient who experienced a 100-fold decline in plasma viremia over a 13-day period prior to the initiation of antiretroviral therapy. Cell-associated viral RNA declined in association with the decline in plasma virus. During the initial 7 days of observation, plasma viremia declined more than 10-fold with no change in the ratio of unspliced to multiply spliced mRNAs. The efficiency of viral gene expression did not decline during the study period and varied from 380 to 2800 unspliced RNA copies per productively infected cell. Together, these data indicate no change in the relative proportion of cells in late- and early-stage gene expression during the initial decline and provide evidence against shortening of the viral replication cycle by immune surveillance. However, the prevalence of productively infected cells declined markedly during the 13 days of observation, from 1 in 250 to 1 in 25,000 PBMCs. These data are compatible with depletion of available target cells during the initial decline in viremia. As the level of plasma virus stabilized after 8 days of observation, the ratio of unspliced to multiply spliced mRNAs rose; this rise was due to a relatively greater decline in multiply spliced mRNA. These data suggest the possible onset of a blockade to new infection events (for example, by neutralizing antibody or chemokines), causing an increase in the relative proportion of cells in late-stage gene expression. They may also be explained, however, by the persistence of cell-associated virions together with the near disappearance of productively infected cells from the circulation.

Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus.

The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodominant epitope in gp 160, there was rapid elimination of the transmitted virus strain and selection for a virus population bearing amino acid changes at a single residue within this epitope, which conferred escape from recognition by epitope-specific CTL. The magnitude (> 100-fold), kinetics (30-72 days from onset of symptoms) and genetic pathways of virus escape from CTL pressure were comparable to virus escape from antiretroviral therapy, indicating the biological significance of the CTL response in vivo. One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes.

CD8+ Cells in Human Immunodeficiency Virus Type I Pathogenesis: Cytolytic and Noncytolytic Inhibition of Viral Replication

Publisher Summary This chapter discusses the potential role of CD8 + lymphocytes in the immunopathogenesis of HIV-1 infection. The chapter describes both the cytolytic and noncytolytic activities of CD8 + cells from infected persons. The CD8 + cells from infected persons are able to suppress HIV-1 replication. Most related studies have been performed by coculturing CD8 + cells with infected CD4 + cells and monitoring the viral replication by supernatant reverse transcriptase (RT) activity or HIV-1 p24 antigen concentration. In the acutely infected individuals, the ability of CD8 + cells to mediate antiviral inhibition develops prior to the development of virus-specific neutralizing antibodies and is temporally correlated to the decline of viremia. The role of HIV-l-specific cytotoxic T lymphocytes (CTLs) in viral suppression has been defined in experiments analogous to the functional assays used to study the viral suppression by bulk CD8 + cells. The HIV-1 replication in CD4 + cells transfected with the appropriate restricting MHC class I molecule is heavily suppressed in the presence of virus-specific cytotoxic T-lymphocytes (CTLs), whereas non-transfected CD4 + cells are not inhibited. Thus, human leukocyte antigen (HLA)-restricted and epitope-specific triggering of CTLs results in antiviral suppression by two mechanisms: cytolytic and noncytolytic.

Early suppression of SIV replication by CD8+ nef-specific cytotoxic T cells in vaccinated macaques

In order to develop a successful subunit vaccine against infection with the human immunodeficiency virus (HIV), protective immune effector functions must be identified. Until now, there has been only indirect evidence that HIV-specific cytotoxic T lymphocytes (CTLs) fulfill this role. Using the macaque simian immunodeficiency virus (SIV) model, the protective potential of nef-specific CTLs, stimulated by vaccination, was examined in animals challenged with a high intravenous dose of the pathogenic simian immunodeficiency virus, SIVmac251(32H)(pJ5). An inverse correlation was found between the vaccine-induced nef-specific CTL precursor frequency and virus load measured after challenge. In addition, the early decline in viraemia, observed in both vaccinated and unvaccinated control animals was associated with the development of virus-specific CTL activity and not with the presence of virus-specific neutralizing antibodies. The results imply that vaccines that stimulate strong CTL responses could protect against HIV infection.

A Live Attenuated Dengue-L Vaccine Candidate (45AZ5) Passaged In Primary Dog Kidney Cell Culture Is Attenuated And Immunogenic For Humans

A dengue-1 candidate vaccine (45AZ5), previously found to be underattenuated in 2 volunteers, was further attenuated by passage in primary dog kidney (PDK) cell cultures. New candidate vaccines prepared from three levels of PDK-passaged virus, PDK-10, PDK-20, and PDK-27, were each injected into 9 or 10 volunteers. There was a significant, progressive decline in viremia, clinical illness, and hematologic changes from low to high PDK cell passage level. PDK-20 infected all 10 vaccinees and induced viremia in 5, transient fever in 3, symptoms that resulted in curtailed activities for < or = 1 day in 4, and neutralizing antibody in all 10, which persisted for > or = 1 year in 5 of 8 vaccinees tested. Progressive passage in PDK cell culture progressively attenuates vaccine candidate strain 45AZ5 for humans. Because passage level PDK-20 may be suitable for healthy adults at high risk of dengue fever, additional clinical trials of this strain are warranted.

Hepatitis C viraemia rebound after "successful" interferon therapy in patients with chronic non-A, non-B hepatitis.

A quantitative polymerase chain reaction (PCR) assay for hepatitis C viral RNA (HCV-RNA) was used to monitor viraemia levels in six patients at multiple time points before, during, and after interferon therapy for chronic non-A, non-B hepatitis (NANBH). Prior to therapy, serum HCV-RNA was detected in all patients at approximately 10(4)-10(5) HCV genomes/ml. HCV viraemia became undetectable within 1 month of commencing interferon in three of the five patients whose alanine aminotransferase (ALT) levels decreased to normal on therapy. In the remaining two responder patients, viraemia levels declined more slowly, becoming undetectable after a period of several months. Recurrence of viraemia during therapy was observed in two cases. The one patient whose serum ALT levels remained elevated throughout therapy showed no decline in viraemia. On stopping interferon after a 6 months course, HCV genome titres climbed rapidly in all patients, reaching higher levels than had been observed prior to therapy. Biochemical relapse occurred within 7 months of ending interferon treatment in all but one of the patients who demonstrated this viraemia "rebound" phenomenon.