Biomedical subjects

Lawrence Corey

Publications and source records attributed to Lawrence Corey.

At least 73 records · Page 4Linked to original sources

PubMed2004

Pretransplantation respiratory syncytial virus infection: impact of a strategy to delay transplantation.

BACKGROUND: Delay of hematopoietic stem cell transplantation (HSCT) has been suggested if upper respiratory tract infection (URTI) due to respiratory syncytial virus (RSV) occurs in transplantation candidates, but the efficacy of this strategy in preventing posttransplantation RSV infection is unknown. METHODS: In a retrospective study, we reviewed charts of patients who underwent transplantation at Fred Hutchinson Cancer Research Center (Seattle, WA) during the period of June 1987 through December 2000 and evaluated the strategy of delaying HSCT in candidates with laboratory-confirmed RSV URTI. RESULTS: Thirty-one of 37 patients had RSV URTI before conditioning, 2 (6.5%) of whom developed RSV infection after HSCT. In 6 of 37 patients, symptoms of URTI were present during the start of conditioning, but RSV virologic confirmation occurred a median of 4.5 days (range, 2-5 days) into the conditioning regimen. Conditioning was aborted for 3 of 6 patients; none had progression to RSV pneumonia. Of the 3 patients in whom HSCT proceeded as scheduled, 2 developed RSV pneumonia. Overall, RSV pneumonia occurred in 1 of 34 patients for whom HSCT was delayed, compared with 2 of 3 patients for whom there was no delay (P=.01). CONCLUSIONS: In patients with pretransplantation RSV URTI, delay of HSCT was associated with a lower risk of pneumonia than was no delay. Because URTIs can progress to severe complications in patients receiving HSCTs, these results support Centers for Disease Control and Prevention/American Society of Blood and Marrow Transplantation recommendations that HSCT be delayed on the basis of symptoms of URTI rather than waiting for virologic confirmation.

Adolescent↗

PubMed2004

Analysis of genetic polymorphisms in CCR5, CCR2, stromal cell-derived factor-1, RANTES, and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1.

To determine the influence of host genetics on human immunodeficiency virus (HIV) type 1 infection, we examined 94 repeatedly exposed seronegative (ES) individuals for polymorphisms in multiple genes and compared the results with those for 316 HIV-1-seropositive and 425 HIV-1-seronegative individuals. The frequency of homozygous C-C chemokine receptor (CCR) 5- Delta 32 was higher in ES (3.2%) than in HIV-1-seropositive individuals (0.0%; P=.012). However, the CCR5-59029A, CCR2-64I, stromal cell-derived factor (SDF)-1-3'A, RANTES (regulated on activation, normally T cell-expressed and -secreted)-403A, and RANTES-28G polymorphisms were not associated with resistance to HIV-1 infection. Furthermore, we identified novel variants in the DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) repeat region and observed that heterozygous DC-SIGN reduced the risk of HIV-1 infection (3.2% in ES individuals vs. 0.0% in HIV-1-seropositive individuals; P=.011).

Alleles↗

PubMed2004

Surveillance of clinical isolates of respiratory syncytial virus for palivizumab (Synagis)-resistant mutants.

Premature infants and those with chronic lung disease or congenital heart disease are at high risk of severe respiratory syncytial virus (RSV) disease. Palivizumab (Synagis), a humanized anti-RSV monoclonal antibody, has been used extensively since 1998 to prevent severe RSV disease in high-risk infants. To monitor for possible palivizumab-resistant mutants, an immunofluorescence binding assay that predicts palivizumab neutralization of RSV was developed. RSV isolates were collected at 8 US sites from 458 infants hospitalized for RSV disease (1998-2002). Palivizumab bound to all 371 RSV isolates able to be evaluated, including 25 from active-palivizumab recipients. The palivizumab epitope appears to be highly conserved, even in infants receiving prophylaxis with palivizumab.

Antibodies, Monoclonal↗

PubMed2004

Frequent reactivation of herpes simplex virus among HIV-1-infected patients treated with highly active antiretroviral therapy.

The effect of highly active antiretroviral therapy (HAART) on control of herpes simplex virus (HSV) in human immunodeficiency virus (HIV) type 1-infected subjects is not known. Among 28 HAART-treated and 49 untreated subjects with HIV-1 and HSV-2 infections, mucosal HSV shedding (median, 18% and 29% of days positive for HSV DNA, respectively; P=.08) and HSV DNA level (median, 56,250 and 50,000 copies/mL, respectively; P=.20) were similar. Treated subjects reported significantly fewer days with HSV lesions, compared with untreated subjects (2.8% vs. 11.3% of days, respectively; P=.001). Thus, mucosal HSV shedding and HSV-2 reactivation were still frequent among treated subjects, even though HAART was associated with fewer days with HSV lesions.

Adult↗

PubMed2004

Persistence of low levels of simian immunodeficiency virus in macaques that were transiently viremic by conventional testing.

Transient SIV viremia after experimental SIV challenge has been documented. Whether SIV persists in these transiently viremic macaques remains unclear. In the present study, we applied a sensitive PCR and found persistent low levels of SIVmne infection (LLSI) (range: 0.1-5.3 SIV DNA copies/10(6) PBMC) in seven macaques that were transiently positive by conventional assays, which was 10(2)- to 10(6)-fold less than those of SIVmne infected monkeys with typical disease progression. SIV envelope V1 sequences remained homogeneous in these macaques for the 6-year study period, with a mean evolution rate of 0.005% per site per year, which was not different from zero (P = 0.612) and significantly lower than that (0.56-1.18%) in macaques with progressive infection of SIVmne. LLSI macaques have remained free from SIV-associated illness, and are still alive 10 years after virus inoculation. Understanding the mechanisms underlying this outcome may provide valuable insight into therapy and vaccine development.

Amino Acid Sequence↗

PubMed2004

Reduced levels of neutralizing antibodies to Kaposi sarcoma-associated herpesvirus in persons with a history of Kaposi sarcoma.

Kaposi sarcoma-associated herpesvirus (KSHV) has been identified as the etiologic agent of Kaposi sarcoma (KS). Although KSHV is required for the development of KS, immune dysfunction is a common and important cofactor in the development of KS, as illustrated by the presence of KS in association with HIV infection or immunosuppressive-drug treatment after transplantation. Because neutralizing antibodies (NAb) constitute an important component of an antiviral immune response, we examined the functionality of the humoral immune response associated with KS, by measuring KSHV NAb titers in 3 groups of subjects. Group 1 included subjects who were KSHV positive, KS positive, and human immunodeficiency virus (HIV) positive; group 2 included subjects who were KSHV positive, KS negative, and HIV positive; and group 3 included subjects who were KSHV positive, KS negative, and HIV negative. NAb titers were significantly lower among subjects with KS, compared with subjects who were infected with KSHV but who did not have clinical evidence of KS, in a multivariate model adjusted for HIV infection and CD4 T cell count. The data from the present study suggest that NAb may play a role in the control of KSHV infection and the prevention of progression of KSHV infection to KS.

Adult↗

PubMed2004

The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics.

Increasing evidence demonstrates a substantial link between the epidemics of sexually transmitted HIV-1 and herpes simplex virus (HSV)-2 infection. More than 30 epidemiologic studies have demonstrated that prevalent HSV-2 is associated with a 2- to 4-fold increased risk of HIV-1 acquisition. Per-sexual contact transmission rates among couples from Rakai, Uganda indicate that at all levels of plasma HIV-1 RNA in the source partner, HSV-2-seropositive HIV-1-susceptible persons have a 5-fold greater risk of acquiring HIV-1 compared with HSV-2-negative persons. In vitro and in vivo studies suggest that mucosal HIV-1 shedding is more frequent and in greater amounts during mucocutaneous HSV-2 replication, including subclinical mucosal reactivations. Most HIV-1-infected persons are coinfected with HSV-2, and most experience frequent subclinical and clinical reactivations of HSV-2. Subclinical HSV reactivation elevates serum HIV-1 RNA levels, and daily therapy with acyclovir appears to reduce plasma HIV-1 RNA. These data show that greater attention to the diagnosis and treatment of HSV-2 among HIV-1-infected persons is warranted, especially those who continue to be sexually active, those not on antiretroviral therapy, or those whose disease is not well suppressed by antiretrovirals.

Acyclovir↗

PubMed2004

Vitamin A supplementation and genital shedding of herpes simplex virus among HIV-1-infected women: a randomized clinical trial.

Cross-sectional analyses have associated vitamin A deficiency with genital shedding of herpes simplex virus (HSV) among human immunodeficiency virus type 1 (HIV-1)-infected women. A randomized clinical trial of vitamin A supplementation given daily for 6 weeks was conducted among 376 women in Mombasa, Kenya, who were coinfected with HSV-2 and HIV-1. At follow-up, there was no significant difference in the detection of genital HSV DNA between women receiving vitamin A supplementation and women receiving placebo (40% vs. 44%, respectively; P = .5) Among women shedding HSV, there was no significant difference in the mean HSV DNA quantity between the group that received vitamin A supplementation and the group that received placebo (4.51 vs. 4.67 log10 copies/swab; P = .6). HSV shedding was associated with significantly higher vaginal and cervical HIV-1 shedding, even after controlling for the plasma HIV-1 load and the CD4 count. Vitamin A supplementation is unlikely to decrease HSV shedding and infectivity.

Adult↗

PubMed2004

HIV infection and human herpesvirus-8 oral shedding among men who have sex with men.

Human herpesvirus-8 (HHV-8) is frequently detected in oropharyngeal secretions from HIV-infected men who have sex with men (MSM), and contact with saliva may be an important mode of HHV-8 transmission. A total of 196 MSM were followed over 2 years to determine the correlates of HHV-8 oropharyngeal shedding. A total of 134 (68%) of 196 participants were HHV-8 seropositive upon enrollment, and 9 (15%) of 62 participants seroconverted to HHV-8 during follow-up. HHV-8 DNA was detected in 43 (22%) of 196 participants: 39 (27%) of 134 HHV-8 seropositive, 4 (8%) of 53 HHV-8 seronegative, and 5 (56%) of 9 seroconverters to HHV-8. HHV-8 was detected in 101 (15%) of 696 total oral specimens: 84 (17%) of 481 samples from HHV-8-seropositive men, 6 (3%) of 180 samples from HHV-8-seronegative men, and 11 (31%) of 35 samples from seroconverters. Using adjusted marginal structural models, HHV-8 shedding was higher in men not receiving highly active antiretroviral therapy (odds ratio 2.4, 95% CI 1.0-6.0, P = 0.06), with CD4 counts > 200 cells/mm (odds ratio 4.8, 95% CI 1.0-22.8, P = 0.05), or with detectable oral leukocyte esterase (odds ratio 5.0, 95% CI 2.0-12.5, P < 0.01). CD4 count, antiretroviral therapy, and oral inflammation may influence HHV-8 oropharyngeal shedding.

Adult↗

PubMed2004

Dual HIV-1 infection associated with rapid disease progression.

Infection with two strains of HIV-1 has implications for understanding HIV transmission and vaccine development; however, frequency and pathogenic consequences of dual infection are unknown. We assessed 64 patients for dual infection with heteroduplex mobility assay, viral sequencing, and phylogenetic methods. HIV disease outcomes were available in 34 patients. Five of these with AIDS endpoints had dual infection with HIV-1: four were cases of coinfection and one was superinfection. In all five, time from seroconversion to clinical AIDS or to CD4+ T-cell count less than 200 cells per microL was very rapid (<3.4 and <3.1 years, respectively). Our findings should prompt larger studies to assess the effect of dual infection at the population level.

Acquired Immunodeficiency Syndrome↗

PubMed2004

Safety profile of recombinant canarypox HIV vaccines.

Attenuated poxviruses have been developed for use as candidate vaccine vectors. ALVAC, a strain of the Avipoxvirus canarypox, has been extensively evaluated as a vector for vaccines against the human immunodeficiency virus type 1 (HIV-1). This report presents the safety and reactogenicity data derived from 11 multicenter, randomized controlled trials of ALVAC-HIV vaccines conducted by the HIV Vaccine Trials Network (HVTN) and its predecessor, the AIDS Vaccine Evaluation Group (AVEG). Five different ALVAC vaccine constructs were tested among 1497 volunteers. Reactogenicity was similar for different ALVAC constructs. Local reactions of any grade to ALVAC vaccines were common. However, fewer than 2% of vaccinees had severe local responses, and less than 1% experienced severe local pain or tenderness. Systemic responses were mild and transient. As combination vaccine regimens are in common use, we also evaluated side effects of ALVAC vectors given in combination with a recombinant subunit protein. No significant differences were noted in the reactogenicity of ALVAC given with or without a recombinant envelope subunit vaccine. Black, non-Hispanic and male recipients of ALVAC-HIV reported less pain following vaccination than White, non-Hispanics and females, respectively. ALVAC-HIV vaccines are well tolerated at tested doses. The reactogenicity profiles are comparable to those reported for existing vaccines licensed for use among adults. Reactogenicity does not appear to be related to the number or type of inserted genes, and did not vary between different ALVAC constructs.

AIDS Vaccines↗

PubMed2004

The danger within.

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Adjuvants, Immunologic↗

PubMed2004

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Acyclovir↗

PubMed2004

Prolonged outbreak of human parainfluenza virus 3 infection in a stem cell transplant outpatient department: insights from molecular epidemiologic analysis.

Human parainfluenza virus type 3 (hPIV3) infections cause considerable morbidity and mortality after stem cell transplantation, and inpatient nosocomial outbreaks are common. From September 1998 to July 1999, 93 stem cell transplantation recipients at our institution contracted hPIV3, of which 66 (71%) were being followed up in our outpatient department (OPD). The peak incidence was in September and October, when 39 cases were identified; thereafter, hPIV3 incidence decreased to approximately 5 cases per month. Nucleotide sequences (778 nucleotides from variable regions of the hemagglutinin-neuraminidase gene) from 46 patient and 8 community hPIV3 isolates were compared to determine epidemiologic relatedness. Sequence analysis of OPD isolates revealed that 18 of 19 isolates from September and October and 11 of 15 isolates from November 1998 to July 1999 were genetically similar. In contrast, 2 of 3 community isolates from September and October and 0 of 5 from November to July were linked to this cluster. Symptomatic surveillance and isolation were ineffective in terminating the outbreak, suggesting asymptomatic shedding among patients, staff, or visitors or viral persistence on environmental surfaces as possible explanations. The concept of nosocomial transmission should be expanded to include the OPD for immunosuppressed patients.

Cross Infection↗

PubMed2004

Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center.

Hematopoietic stem cell transplantation (HCT) in patients with prior or active invasive aspergillosis (IA) is a frequent consideration. We reviewed outcomes of 2319 patients who underwent transplantation between 1992 and 2001 in our institution, among whom 45 patients (1.9%) had a known history of IA before HCT. Posttransplantation IA occurred in 13 of these 45 patients with a pretransplantation history (29%). Nine infections were considered recurrent by anatomic site and timing. Compared with all other patients who received allogeneic HCT during the same period, patients with histories of IA had lower overall survival (56% versus 77%; P =.0001) and higher transplant-related mortality (TRM; 38% versus 21%; P =.0001) 100 days after HCT, associated mainly with IA and other pulmonary complications. Among patients with prior IA, posttransplantation IA occurred more frequently in patients who received <1 month of antifungal therapy before HCT (4/6 versus 6/39; P =.001). The probability of posttransplantation IA and overall survival among patients who received >1 month of antifungal therapy and had resolution of radiographic abnormalities were not different from those of patients without prior IA. Patients with prior IA who received conditioning with total body irradiation (TBI) had higher TRM compared with those who received nonmyeloablative and non-total body irradiation-based regimens (16/31 versus 2/14; P =.024). Thus, the duration of antifungal therapy before transplantation, the resolution of radiographic abnormalities, and conditioning regimens are important variables to consider for minimizing the risk for IA recurrence and TRM after allogeneic HCT.

Academic Medical Centers↗

PubMed2004

Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR.

Previous studies have shown that detection of cytomegalovirus (CMV) DNA in plasma is less sensitive than the antigenemia assay for CMV surveillance in blood. In 1,983 blood samples, plasma PCR assays with three different primer sets (UL125 alone, UL126 alone, and UL55/UL123-exon 4) were compared to the pp65 antigenemia assay and blood cultures. Plasma PCR detected CMV more frequently in blood specimens than either the antigenemia assay or cultures, but of the three PCR assays, the double-primer assay (UL55/UL123-exon 4) performed best with regard to sensitivity, specificity, and predictive values compared to antigenemia: 122 of 151 antigenemia-positive samples were detected (sensitivity, 80.1%), and there were 122 samples that were PCR positive-antigenemia negative (specificity, 93%). Samples with discrepant results had a low viral load (median, 0.5 cells per slide; 1,150 copies per ml) and were often obtained from patients receiving antiviral therapy. CMV could be detected by other methods in 15 of 29 antigenemia positive-PCR negative samples compared to 121 of 122 PCR positive-antigenemia negative samples (P < 0.001). On a per-subject basis, 21 of 25 patients (antigenemia positive-PCR negative) and all 57 (PCR positive-antigenemia negative) could be confirmed at different time points during follow-up. The higher sensitivity of the double-primer assay resulted in earlier detection compared to antigenemia in a time-to-event analysis of 42 CMV-seropositive stem cell transplant recipients, and two of three patients with CMV disease who were antigenemia negative were detected by plasma PCR prior to the onset of disease. Interassay variability was low, and the dynamic range was >5 log(10). Automated DNA extraction resulted in high reproducibility, accurate CMV quantitation (R = 0.87, P < 0.001), improved sensitivity, and increased speed of sample processing. Thus, primer optimization and improved DNA extraction techniques resulted in a plasma-based PCR assay that is significantly more sensitive than pp65 antigenemia and blood cultures for detection of CMV in blood specimens.

Antigens, Viral↗

PubMed2004

Use of the MagNA pure LC automated nucleic acid extraction system followed by real-time reverse transcription-PCR for ultrasensitive quantitation of hepatitis C virus RNA.

Hepatitis C virus (HCV) infection is an increasing health problem worldwide. Quantitative assays for HCV viral load are valuable in predicting response to therapy and for following treatment efficacy. Unfortunately, most quantitative tests for HCV RNA are limited by poor sensitivity. We have developed a convenient, highly sensitive real-time reverse transcription-PCR assay for HCV RNA. The assay amplifies a portion of the 5' untranslated region of HCV, which is then quantitated using the TaqMan 7700 detection system. Extraction of viral RNA for our assay is fully automated with the MagNA Pure LC extraction system (Roche). Our assay has a 100% detection rate for samples containing 50 IU of HCV RNA/ml and is linear up to viral loads of at least 10(9) IU/ml. The assay detects genotypes 1a, 2a, and 3a with equal efficiency. Quantitative results by our assay correlate well with HCV viral load as determined by the Bayer VERSANT HCV RNA 3.0 bDNA assay. In clinical use, our assay is highly reproducible, with high and low control specimens showing a coefficient of variation for the logarithmic result of 2.8 and 7.0%, respectively. The combination of reproducibility, extreme sensitivity, and ease of performance makes this assay an attractive option for routine HCV viral load testing.

Automation↗

PubMed2004

Compartmentalization of human immunodeficiency virus type 1 between blood monocytes and CD4+ T cells during infection.

Distinct sequences of human immunodeficiency virus type 1 (HIV-1) have been found between different tissue compartments or subcompartments within a given tissue. Whether such compartmentalization of HIV-1 occurs between different cell populations is still unknown. Here we address this issue by comparing HIV-1 sequences in the second constant region through the fifth hypervariable region (C2 to V5) of the surface envelope glycoprotein (Env) between viruses in purified blood CD14(+) monocytes and CD4(+) T cells obtained longitudinally from five infected patients over a time period ranging from 117 to 3,409 days postseroconversion. Viral populations in both cell types at early infection time points appeared relatively homogeneous. However, later in infections, all five patients showed heterogeneous populations in both CD14(+) monocytes and CD4(+) T cells. Three of the five patients had CD14(+) monocyte populations with significantly more genetic diversity than the CD4(+) T-cell population, while the other two patients had more genetic diversity in CD4(+) T cells. The cellular compartmentalization of HIV-1 between CD14(+) monocytes and CD4(+) T cells was not seen early during infections but was evident at the later time points for all five patients, indicating an association of viral compartmentalization with the time course of HIV-1 infection. The majority of HIV-1 V3 sequences indicated a macrophage-tropic phenotype, while a V3 sequence-predicted T-cell tropic virus was found in the CD4(+) T cells and CD14(+) monocytes of two patients. These findings suggest that HIV-1 in CD14(+) monocytes could disseminate and evolve independently from that in CD4(+) T cells over the course of HIV-1 infection, which may have implications on the development of new therapeutic strategies.

Acquired Immunodeficiency Syndrome↗