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Biomedical subjects

L Corey

Publications and source records attributed to L Corey.

At least 163 records · Page 9Linked to original sources
PubMed1996

Asymptomatic maternal shedding of herpes simplex virus at the onset of labor: relationship to preterm labor.

OBJECTIVE: To determine if fetal growth restriction and prematurity are observed with subclinical shedding of herpes simplex virus (HSV) at the onset of labor. METHODS: Within 48 hours of delivery, cultures were taken from the cervix and external genitalia of 15,923 asymptomatic pregnant women without symptoms or signs of genital HSV infection; results were positive for HSV in 57. Each of these 57 women were compared with a control group composed of the three culture-negative women delivering immediately before and the three delivering immediately after each woman shedding HSV. RESULTS: The median birth weight for infants born to the 57 women with asymptomatic shedding was 3050 g, compared with 3360 g among the 342 women without asymptomatic shedding, a statistically significant difference (P < .002). These differences were due to very low birth weight (LBW) among the five infants of women with subclinical viral shedding secondary to recently acquired primary genital herpes; these five infants had a median gestational age of 33 weeks, compared with 37 weeks for the 14 infants of mothers with nonprimary, first-episode disease and 39 weeks for the 33 infants of women with reactivation disease, also a significant difference (P = .018). CONCLUSIONS: Asymptomatic genital shedding of HSV at the onset of labor because of subclinical primary genital HSV infection is associated with preterm delivery. Women who acquire genital HSV-2 before pregnancy and are shedding subclinically at the onset of labor experience no increase in adverse outcome. Thus, prevention of the prematurity and LBW associated with genital herpes means that acquisition of the infection in late pregnancy must be prevented.

Birth Weight↗
PubMed1996

Combination therapy with zidovudine, didanosine and saquinavir.

The goal of AIDS Clinical Trials Group (ACTG) Protocol 229 was to evaluate the shorter term (24 week) and longer term (48 week) safety and activity of the HIV-1 proteinase inhibitor saquinavir in combination with zalcitabine (ddC) and zidovudine (ZDV) versus saquinavir in combination with ZDV versus ddC in combination with ZDV. This study confirms and extends the conclusions from the first 24 weeks of this study and showed that in subjects with extensive prior antiretroviral experience, the triple combination of saquinavir, ddC and ZDV was well-tolerated, safe and remained superior to the other double drug regimens as measured by CD4+ cell counts, quantitative HIV-1 microculture and plasma HIV-1 RNA levels.

Antiviral Agents↗
PubMed1996

T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients.

The introduction and expression of genes in somatic cells is an innovative therapy for correcting genetic deficiency diseases and augmenting immune function. A potential obstacle to gene therapy is the elimination of such gene-modified cells by an immune response to novel protein products of the introduced genes. We are conducting an immunotherapy trial in which individuals seropositive for human immunodeficiency virus (HIV) receive CD8+ HIV-specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection. However, five of six subjects developed cytotoxic T-lymphocyte responses specific for the novel protein and eliminated the transduced cytotoxic T cells. The rejection of genetically modified cells by these immunocompromised hosts suggests that strategies to render gene-modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.

Antigen Presentation↗
PubMed1996

Relationship between antibodies to herpes simplex virus (HSV) and symptoms of HSV infection.

To determine the relationship between antibodies to herpes simplex virus (HSV) types 1 and 2 and diagnosis of orolabial and genital herpes, a cross-sectional survey was done among 869 sexually transmitted disease clinic attendees and 1594 blood donors in London. Among clinic attenders, the prevalence of HSV-1 infection was 59.5% and that of HSV-2 infection was 22.7%, and among blood donors the prevalence was 44.6% and 7.6%, respectively. The sensitivity and specificity of a diagnosis of oral herpes for the presence of HSV-1 antibody was almost identical in the 2 groups (clinic attendees: sensitivity, 33.1%, and specificity, 91.4%; blood donors: sensitivity, 32.3%, and specificity, 94.3%). A diagnosis of genital herpes was less sensitive for antibody for HSV-2 among donors than among clinic attenders (P < .001); however, the specificity was similar in the 2 populations (clinic attendees: sensitivity, 32.1%, and specificity, 96.6%; blood donors: sensitivity, 17.5%, and specificity, 99.5%). False-positive clinical histories were also relatively common (clinic attenders, 12%; donors, 6%). The sensitivity of the diagnosis of genital herpes would be improved if accurate serologic assays for detection of HSV type-specific antibodies were more widely available.

Antibodies, Viral↗
PubMed1996

Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Cerebrospinal fluid (CSF) specimens from 77 neonates with herpes simplex virus (HSV) disease were evaluated retrospectively by polymerase chain reaction (PCR). Samples were collected from 202 infants enrolled in a National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial that compared vidarabine with acyclovir for the treatment of neonatal HSV infection. HSV DNA was detected in the CSF of 26 (76%) of 34 infants with CNS disease, in 13 (93%) of 14 infants with disseminated infection, and in 7 (24%) of 29 with skin, eye, or mouth (SEM) involvement. One of the 7 PCR-positive SEM patients subsequently developed severe neurologic impairment. Eighteen (95%) of 19 infants with positive CSF PCR results after the completion of 10 days of antiviral therapy experienced significant morbidity or mortality. Application of PCR to neonatal HSV disease may provide additional information on which clinical decisions may be based, although its diagnostic utility outside the research setting is unproven.

Brain↗
PubMed1996

Coinfection with human herpesvirus 6 variants A and B in lung tissue.

Human herpesvirus 6 (HHV-6) variant B is frequently identified in peripheral blood, but identification of HHV-6 variant A is relatively rare. We devised a PCR-based method for sensitive, simultaneous detection of both HHV-6 variants. The method was applied to 34 lung tissue specimens that were previously shown to contain HHV-6 DNA. A total of 22 lung tissue samples showed coinfections with HHV-6 variants A and B, 2 had only HHV-6 variant A DNA, and 10 had only HHV-6 variant B DNA. The prevalences of coinfections in lung tissues from healthy controls (54% coinfected) and in those from bone marrow transplant patients with pneumonia (67% coinfected) were similar. These data indicate that coinfections of HHV-6 variants A and B commonly occur in lung tissues of healthy and diseased individuals.

Base Sequence↗
PubMed1996

Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients.

To evaluate the possibility that distinct viral quasispecies play a role in the pathogenesis of progressive hepatitis C virus (HCV) infection, we performed a detailed evaluation of HCV quasispecies before and after liver transplantation in five patients infected with HCV genotype 1, three of whom developed severe recurrent hepatitis C and two of whom developed asymptomatic posttransplant infections with high-titered viremia. HCV quasispecies were characterized by using a combination of nucleotide sequencing plus heteroduplex tracking assay of the second envelope gene hypervariable region (HVR). An average of 30 HVR clones were analyzed per specimen; an average of five specimens were analyzed per patient over a 6- to 24-month study period. The complexity of HCV quasispecies in pretransplant serum varied, ranging from one to nine genetically distinct variants for the five patients. However, in all five cases, relatively homogenous quasispecies variants emerged after liver transplantation. In the three patients who developed recurrent hepatitis, quasispecies major variants present in pretransplant serum were efficiently propagated immediately after liver transplantation and were propagated throughout the course of acute and chronic hepatitis. In contrast, in the two asymptomatic cases, we observed rapid depletion of pretransplant quasispecies major variants from posttransplant serum, followed by emergence of new quasispecies variants by posttransplant day 30. Genetic analysis suggested that in these cases, the new quasispecies variants were derived from minor variants present at relatively low clonal frequency (less than 5% of HVR clones) within the pretransplant quasispecies populations. These data demonstrate that quasispecies tracking patterns are associated with the rapidity and severity of HCV-associated liver disease after liver transplantation. Further characterization of HCV quasispecies in animal model systems is warranted.

Amino Acid Sequence↗
PubMed1996

High frequency of CD8+ cytotoxic T-lymphocyte precursors specific for herpes simplex viruses in persons with genital herpes.

Herpes simplex virus (HSV)-specific CD8+ cytotoxic T lymphocytes (CTL) have rarely been detected in humans, presumably because of virus-induced mechanisms that downregulate major histocompatibility complex class I expression. We have developed a method that has allowed us to consistently demonstrate HSV-specific CD8+ precursor CTL (pCTL) from HSV type 1- and 2-seropositive persons. Major histocompatibility complex-restricted HSV-specific CD8+ pCTL were found in 10 consecutively tested HSV type 1- and 2-seropositive subjects at frequencies ranging from 1 in 21,000 to 1 in 300 (median, 1 in 6,000) versus a pCTL frequency of 1 in 100,000 in HSV-seronegative donors. These results suggest that CD8+ CTL are important effector cells in resolving HSV lesions.

Herpes Genitalis↗
PubMed1996

Intrapatient sequence variation of the gag gene of human immunodeficiency virus type 1 plasma virions.

Because certain regions of the gag gene, such as p24, are highly conserved among human immunodeficiency virus (HIV) isolates, many therapeutic strategies have been directed at gag gene targets. Although intrapatient variation of segments of gag have been determined, little is known about the variability of the full-length gag gene for HIV isolated from a single individual. To evaluate intrapatient full-length gag variability, we derived the nucleotide sequences of at least 10 cDNA gag clones of virion RNA isolated from plasma for each of four asymptomatic HIV type 1-infected patients with relatively high CD4+ T-cell counts (300 to 450 cells per mm3). Mean values of intrapatient gag nucleotide variation obtained by pairwise comparisons ranged from 0.55 to 2.86%. For three subjects, this value was equivalent to that reported for intrapatient full-length env variation. The greatest range of intrapatient mean nucleotide variation for individual protein-coding regions was observed for p7. We did not detect any G-to-A hypermutation, as A-to-G and G-to-A transitions occurred at similar frequencies, accounting for 29 and 25%, respectively, of the changes. Mean variation values and phylogenetic analysis suggested that the extent of nucleotide variation correlated with the length of viral infection. Furthermore, no distinct subpopulations of quasispecies were detectable within an individual. The predicted amino acid sequences indicated that there were no regions within a gag protein that were comprised of clustered changes.

Amino Acid Sequence↗
PubMed1996

Detection of simian immunodeficiency virus (SIV)-specific CD8+ T cells in macaques protected from SIV challenge by prior SIV subunit vaccination.

Vaccines for lentiviruses would ideally induce in the host complete resistance to infection of host cells. However, such sterilizing immunity may be neither readily achievable nor absolutely necessary to provide protection from exposure to the immunodeficiency viruses. To examine the nature of protective immunity to simian immunodeficiency virus (SIV), we studied three macaques that had been immunized with a recombinant vaccinia virus-based SIV subunit vaccine regimen and exhibited protection from a challenge with cell-free SIV (MNE) as determined by viral cultures, serology, and PCR for viral genomes. Peripheral blood mononuclear cells were obtained from the protected macaques and analyzed for CD8+ cytotoxic T-lymphocyte (CTL) responses to SIV proteins. CTL reactive to SIV proteins not included in the subunit vaccine, and thus to which these animals had not been exposed prior to challenge, were detected postchallenge in the vaccine-protected animals and persisted for up to 1 year. These CTL, as reflected by studies of cytolytic lines and derived T-cell clones, were CD8+, did not recognize allogeneic targets, and recognized the SIV proteins in the context of class I major histocompatibility complex molecules. The frequency of precursor CD8+ CTL reactive to SIV proteins was determined by limiting-dilution analysis and demonstrated that the responses elicited following challenge of protected animals to SIV proteins not present in the vaccine were quantitatively similar to those of animals persistently infected with SIV. The presence of these CD8+ CTL responses to SIV proteins present only in the challenge virus suggests that infection of some host cells occurred postchallenge. These results suggest that the development of a low level of SIV infection following exposure of vaccinated hosts to SIV does not preclude protection from lethal SIV disease by vaccine-induced immunity.

Animals↗
PubMed1995

Virologic characteristics of subclinical and symptomatic genital herpes infections.

BACKGROUND: The frequency, pattern, and anatomical sites of subclinical shedding of herpes simplex virus (HSV) in the genital tract, along with factors that predict such shedding, have not been well characterized. METHODS: We studied prospectively the clinical and virologic course of genital herpes in 110 women. The women kept symptom diaries and provided daily samples from the vulva, cervix, and rectum for viral culture. RESULTS: During a median follow-up of 105 days, subclinical shedding of virus was identified in 36 of 65 women (55 percent) with HSV type 2 (HSV-2), in 16 of 31 women (52 percent) with HSV type 1 (HSV-1) and HSV-2, and in 4 of 14 women (29 percent) with only HSV-1. Among women with genital HSV-2 infection, subclinical shedding occurred on a mean of 2 percent of the days. The mean duration of viral shedding during subclinical episodes was 1.5 days, as compared with 1.8 days during symptomatic episodes. HSV was isolated from several sites in the genital tract and rectum in 17 percent of subclinical episodes and 22 percent of symptomatic episodes. Half the episodes of subclinical shedding of HSV occurred within seven days of a symptomatic recurrence. The risk of subclinical shedding increased with the frequency of symptomatic recurrences. Subclinical shedding was more frequent among women with more than 12 recurrences per year than among those with no symptomatic recurrences (odds ratio, 3.3; 95 percent confidence interval, 1.4 to 7.9); it was also more frequent among women who had recently acquired genital herpes (odds ratio for women with HSV acquired in the past year as compared with those who had had the infection for a year or more, 1.85; 95 percent confidence interval, 1.1 to 3.1). CONCLUSIONS: Among women with a history of genital herpes infection, subclinical shedding of HSV is common and accounts for nearly one third of the total days of reactivation of HSV infection in the genital tract. Women with frequent symptomatic recurrences also have frequent subclinical shedding and may be at high risk for transmitting HSV.

Adolescent↗
PubMed1995

Assessment of hepatitis C viremia using molecular amplification technologies: correlations and clinical implications.

OBJECTIVE: To compare two recently developed molecular techniques for quantitating the levels of hepatitis C virus (HCV) RNA in the serum of patients with a wide spectrum of chronic hepatitis C. DESIGN: Serum samples from 299 patients with HCV viremia, 101 control patients without HCV infection, and 19 consecutive patients receiving systemic interferon therapy were evaluated by a commercially available branched-chain DNA (bDNA) assay and a quantitative competitive polymerase chain reaction (PCR). SETTING: University-based hepatology clinics and reference virology laboratory. PATIENTS: Patients with HCV viremia as defined by results of qualitative RNA PCR, including 53 HCV-infected blood donors, 34 patients receiving renal dialysis, and 212 patients attending a hepatology clinic. RESULTS: Results of in vitro and in vivo experiments indicated that the sensitivity and dynamic range of the PCR assays were greater than those of the bDNA assay. Detection of HCV viremia by the bDNA assay was highly dependent on viral RNA titers, with a sensitivity of 5% at HCV RNA titers of 5.0 logs per mL or less and 94% at titers of 5.5 logs per mL or greater. The best correlation between assays was observed in specimens with HCV RNA titers between 6.0 and 7.5 logs per mL (r = 0.73). In patients with high-titer HCV viremia, including liver transplant recipients and patients with cirrhosis, quantitative PCR results were an average of 12-fold higher than bDNA assay results. Results of repetitive testing of discordant specimens showed that these discrepancies were caused by a high kit-to-kit coefficient of variation (112%) in the bDNA assay. Of 19 patients receiving interferon therapy, 9 (47%) became bDNA negative, but only 5 became quantitative PCR negative. The bDNA-negative, quantitative PCR-positive patients all had relapse when therapy was discontinued. CONCLUSIONS: The bDNA assay has a narrower linear range for quantitation of HCV viremia than quantitative PCR. Because persons with low HCV titers may respond well to therapy, seropositive persons with negative bDNA results should be retested with PCR-based assays. Similarly, the bDNA assay may underestimate the true degree of HCV viremia in persons with end-stage infection (> 10(7) RNA equivalents/mL of sera). Despite these limitations, the combination of bDNA- and PCR-based assays appears to be optimal for selecting and following patients during interferon therapy.

Case-Control Studies↗
PubMed1995

A recombinant glycoprotein vaccine for herpes simplex virus type 2: safety and immunogenicity [corrected].

OBJECTIVE: To evaluate the safety and immunogenicity of a recombinant glycoprotein vaccine for herpes simplex virus type 2 (HSV-2), which contains glycoproteins gD2 and gB2 combined with the novel MF59 adjuvant emulsion, in HSV-2-seronegative persons. DESIGN: Integrated summary of two phase I and two phase II studies. SETTING: University and private outpatient clinics. PATIENTS: 137 persons seronegative for HSV-2 antibodies as determined by HSV Western blot assay. INTERVENTION: Open-label vaccine administration with a dose-escalating design (phase I) was followed by randomized vaccine administration (phase II). Vaccine was administered intramuscularly into the deltoid at 0, 1, and 6 months. MEASUREMENTS: Neutralizing, HSV-2-binding antibodies and HSV-2-stimulated proliferative responses were measured before and after immunization. RESULTS: Among HSV-seronegative patients, the gD2 and gB2 enzyme-linked immunosorbent assay (ELISA) and HSV-2-neutralizing antibody titers increased to levels equal to or higher than those seen in naturally acquired HSV-2 infection after the full three-dose immunization schedule. Among HSV-1-seropositive patients, one immunization produced increases in gD2 and gB2 ELISA antibody titers and HSV-2-neutralizing antibody titers that were 3 to 5 times greater than those in persons with naturally acquired HSV-2 infection. Among HSV-seronegative patients, frequency analysis assays showed a marked increase in the precursor frequency of gD2- and gB2-specific T cells after vaccination: T-cell responses after two immunizations were equal to the responses of HSV-2-seropositive patients and were sustained at day 180. The vaccine was well tolerated. CONCLUSIONS: This subunit vaccine induces both humoral and cellular responses to HSV-2 that are equal to or greater than those of persons with naturally acquired HSV-2 infection. Studies to evaluate this vaccine for the prevention of genital herpes appear warranted.

Adjuvants, Immunologic↗
PubMed1995

Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection.

In vitro, recombinant soluble CD4 (rsCD4) attaches to and inactivates human immunodeficiency virus (HIV). To determine if prolonged therapy with high-dose intravenous rsCD4 provides an in vivo benefit, we gave three HIV-1-infected patients with AIDS, whose isolates were susceptible in vitro to rsCD4, 10 mg/kg of rsCD4 for 4 weeks, 5 mg/kg for 4 weeks, and 1 mg/kg for 2 weeks. Single-dose pharmacokinetic studies performed prior to this showed transient in vivo decreases of HIV-1 plasma viremia in all three subjects. Surrogate markers of HIV activity, clinical status, HIV-1 p24 antigen, plasma HIV-1 titers, and peripheral blood mononuclear cell (PBMC) intracellular titers of virus were measured at entry, and every other week after onset of therapy. All subjects demonstrated rsCD4 concentration-dependent reduction in plasma viremia, with two subjects having complete neutralization of cell-free virus. The third subject's isolate was relatively resistant to the in vivo effects of rsCD4 and only partial reduction in plasma virus titers was obtained, even at the highest dose of 10 mg/kg. There was no change in the PBMC intracellular viral titer or surrogate markers of HIV-1 activity (including CD4 cell count and beta 2-microglobulin). There was subjective improvement in clinical symptoms, and all subjects gained weight with the highest doses of rsCD4. rsCD4 exhibited linear pharmacokinetics over the dose range studied. We conclude that high-dose intravenous rsCD4 can be safely given for up to 10 weeks and that it has a stable pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1995

Seroprevalence of herpes simplex virus infections in a family medicine clinic.

OBJECTIVES: To determine the prevalence of herpes simplex virus (HSV) antibody in a general medical practice setting and to assess the frequency of subclinical infection. DESIGN: Prevalence study. SETTING: A family practice clinic at the University of Washington Medical Center, Seattle. PARTICIPANTS: Five hundred randomly selected patients between the ages of 18 and 45 years. MAIN OUTCOME MEASURES: Serum samples were tested by Western blot assay to detect the presence of antibody to HSV type 1 (HSV-1) and HSV-2. Demographic information and clinical history of oral and genital herpes were obtained. RESULTS: One hundred fourteen patients (23%) were seropositive for HSV-2 antibody, 277 patients (56%) were seropositive for HSV-1 antibody, 59 patients (12%) were seropositive for both HSV-2 and HSV-1 antibodies, and 163 patients (33%) were seronegative for both. Women were almost twice as likely as men to be seropositive for HSV-2 antibody (28% vs 15%, P < .001). Blacks had the highest rates of HSV-2 antibody seropositivity (60%) compared with whites (20%) and Asians (6%) (P < .001). Other demographic correlates of seropositivity included being older, having fewer years of education, and having public insurance. The specificity of a clinical history of genital herpes or sores for HSV-2 infection was high (99%), but the sensitivity was low (27%). CONCLUSIONS: Herpes simplex virus infection is common among patients seeking primary care. Women, blacks, and patients of lower socioeconomic status are most likely to be seropositive for HSV-2 antibody. The high frequency of unrecognized HSV infection has implications for primary care physicians in counseling patients regarding HSV infection and transmission.

Adult↗
PubMed1995

A comparison between detailed and simple histories in the diagnosis of genital herpes complicating pregnancy.

OBJECTIVE: All women seropositive for herpes simplex virus-2 are at risk for asymptomatic viral shedding at the onset of labor and neonatal transmission of the virus. Unfortunately, only 20% to 35% of seropositive adults give a history consistent with genital herpes. We evaluated whether more detailed questioning during pregnancy might elucidate symptoms predictive of seropositivity and therefore better identify women at risk for herpes simplex virus shedding at delivery. STUDY DESIGN: During pregnancy 201 randomly selected women were asked in-depth questions about recurrent genital symptoms and whether they "currently have or have ever had genital herpes." An assessment was made whether the patient had a history compatible with genital herpes. This assessment and the "yes/no" history of genital herpes obtained by physicians at the initial prenatal visit were both compared with herpes simplex virus serologic studies by Western blot. RESULTS: Of 201 patients interviewed, 177 gave no history of genital herpes. Of these, 30.4% were seropositive for herpes simplex virus-2. Detailed histories on these 177 patients indicated that among the 159 subjects without suggestive symptoms or with somewhat suggestive symptoms the corresponding rates of seropositivity were 28% and 30%. Among the 18 (10.2%) subjects with highly suggestive symptoms, only 50% were seropositive. The positive predictive values for recurrent genital symptoms to predict herpes simplex virus-2 seropositivity ranged from 30% to 57%. CONCLUSION: A detailed history of genital symptoms is no better at identifying an herpes simplex virus-2 seropositive patient than is simply asking if she has ever had genital herpes. Serologic screening is a more accurate method of identifying women with past genital herpes or those who are at risk for acquiring genital herpes during pregnancy.

Adolescent↗