The highly sensitive quantitation of virus-specific CD8(+) T cells using major histocompatibility complex-peptide tetramer assays has revealed higher levels of cytotoxic T lymphocytes (CTLs) in acute ...and chronic virus infections than were recognized previously. However, studies in lymphocytic choriomeningitis virus infection have shown that tetramer assays may include measurement of a substantial number of tetramer-binding cells that are functionally inert. Such phenotypically silent CTLs, which lack cytolytic function and do not produce interferon (IFN)-gamma, have been hypothesized to explain the persistence of virus in the face of a quantitatively large immune response, particularly when CD4 help is impaired. In this study, we examined the role of functionally inert CTLs in chronic HIV infection. Subjects studied included children and adults (n = 42) whose viral loads ranged from <50 to >100,000 RNA copies/ml plasma. Tetramer assays were compared with three functional assays: enzyme-linked immunospot (Elispot), intracellular cytokine staining, and precursor frequency (limiting dilution assay LDA) cytotoxicity assays. Strong positive associations were observed between cell numbers derived by the Elispot and the tetramer assay (r = 0.90). An even stronger association between tetramer-derived numbers and intracellular cytokine staining for IFN-gamma was present (r = 0.97). The majority (median 76%) of tetramer-binding cells were consistently detectable via intracellular IFN-gamma cytokine staining. Furthermore, modifications to the LDA, using a low input cell number into each well, enabled LDAs to reach equivalence with the other methods of CTL enumeration. These data together show that functionally inert CTLs do not play a significant role in chronic pediatric or adult HIV infection.
Objective: Our purpose was to determine whether pregnant women infected with human immunodeficiency virus-1 have an increased risk of herpes simplex virus-2 seropositivity and herpes simplex virus ...reactivation at delivery.
Study design: Sixty women infected with human immunodeficiency virus and 8408 other patients who were delivered at the University of Washington between 1989 and 1995 had herpes simplex virus serologic determinations at delivery. Genital herpes simplex virus cultures were obtained for 48 (80%) of the human immunodeficiency virus–infected women and 5567 (66%) of the controls. Logistic regression was used to adjust for possible confounding factors.
Results: Forty-five (75%) of human immunodeficiency virus–infected women and 2709 (32%) controls were seropositive for herpes simplex virus-2 (
p < 0.0001). Eight percent of human immunodeficiency virus–infected women and 2% of controls had herpes simplex virus reactivation in labor (
p < 0.05).
Conclusions: Infection with herpes simplex virus-2 is common among pregnant women infected with human immunodeficiency virus. Herpes simplex virus reactivation complicates labor in this group more often than in other obstetric patients. The role of herpes simplex virus in perinatal human immunodeficiency virus transmission warrants further study. (Am J Obstet Gynecol 1997;177:450-4.)
The pharmacokinetics, safety, tolerance, and antiviral effects of ganciclovir (Gcv) administered orally were evaluated in 36 children infected with cytomegalovirus (CMV) who were severely ...immunocompromised by infection with human immunodeficiency virus type 1. In this dose-escalation study, 30 mg/kg of Gcv administered every 8 h produced serum levels similar to the dose (1 g/8 h) effective for maintenance treatment of CMV retinitis in adults. In older children, serum Gcv concentrations were similar after the administration of capsules and suspension. All doses (10–50 mg/kg/8 h) studied were safe and, except for the volume of suspension or number of pills, were well tolerated. Oral Gcv was associated with a decrease in the detection of CMV by culture or polymerase chain reaction. CMV disease occurred in 3 children during the study: one developed Gcv resistance, another had harbored resistant virus at study entry, and a third had wild-type CMV
During a 5 degree C and a 5/-1 degree C cold acclimation (CA) regime there was a significant decline in the water potential of winter barley, and a concurrent decline in tissue water content of the ...5/-1 degree C CA plants. Results of carbohydrate analysis illustrated a significant (P < 0.001) accumulation of sucrose, fructose and glucose in the 5/-1 degree C CA plants, which was inversely correlated to water potential. Using an infrared imaging radiometer during a convection frost test the water release time (WRT) of 5/-1 degree C CA was demonstrated to be significantly (P < 0.001) longer than that observed in non-cold acclimated plants. This observation is consistent with visual analysis of exotherm curves where the rate of cellular water release to extracellular ice is reduced in the 5/-1 degree C CA plants, compared to the non-cold acclimated plants. These biochemical and physiological changes were correlated to increased plant health following a non-lethal freezing test to -5 degree C, where non-cold acclimated plants produced 2.3 +/- 0.3 tillers and 5 degree C and 5/-1 degree C CA plants produced 2.4 +/- 0.3 and 4.7 +/- 0.7 tillers, respectively. Results from this study imply that cold acclimation leads to changes in the physical state of water that result in a less osmotically responsive cellular environment and subsequently significantly less damage to meristematic tissue.
We assessed CD4 cell recovery in 175 children with advanced human immunodeficiency virus disease who had received a 4-drug antiretroviral regimen and were categorized as viral load (VL) responders ...(VLRs), partial VLRs, or non-VLRs. Median CD4 cell counts increased from baseline to week 48, and, among children with maximal follow-up, increases in CD4 cell counts were sustained to week 96 among VLRs and partial VLRs but not among non-VLRs. For VL rebounders still in the study, CD4 cell counts remained increased for 32 weeks after VL rebound. Sustained immunologic benefits can be achieved even with partial VL response in children with advanced disease
Zidovudine pharmacokinetics was determined in three human immunodeficiency virus type I-seropositive women receiving zidovudine (200 mg orally every 4 h) from 19 to 39 weeks ofpregnancy and ...postpartum. Zidovudine concentrations were measured using high-pressure liquid chromatography, and pharmacokinetic analyses were done using model-independent methods. For the pregnant versus postpartum periods, peak zidovudine levels (mean ± 1 SD) were 3.9 ± 1.7 µmol/l versus 4.3 ± 0.04 µmol/l (P = .56); elimination half-lives were 1.3 ± 0.6 versus 1.0 ± 0.3 h (P = .41); areas under the concentration curve were 4.5 ± 1.0 µmol/l × hand 6.8 ± 0.5 µmol/l × h (P = .02); apparent total body clearances were 2.5 ± 0.6/1h/kg and 1.7 ± 0.4 l/h/kg (P = .05); and apparent steady state volumes of distribution were 3.9 ± 1.0 1/kg and 2.6 ± 0.81/kg (P = .07), respectively. Umbilical cord serum levels ranged from 113%–127% of maternal levels. No persistent adverse effects of zidovudine therapy were seen in the three women or their babies.
An expression for the coarsening rate of the Pb-rich phase particles was determined through isothermal aging experiments and comparative literature data as: lambda identical with lambda ...sub(o)+{4.10x10 super(-5) e super(-11023 /T)+15.6x10 super(-8) e super(-3123/T) (d gamma /dt)t} super(0.256) where gamma sub(o) and gamma are the initial and final mean Pb-rich particle diameters, respectively (mm); T is temperature ( degree K); t is time (s); and d gamma /dt is the strain rate (s super(-1)). The phase coarsening behavior showed good agreement with previous literature data from isothermal aging experiments. The power-law exponent, p, for the Pb-rich phase size coarsening kinetics: gamma super(p)- gamma super(p) sub(o) approximately t increased from a value of 3.3 at the low aging temperature regime (70-100 degree C) to a value of 5.1 at the high temperature regime (135-170 degree C), suggesting that the number of short-circuit diffusion paths had increased with further aging. This expression provides an important basis for the microstructurally-based, constitutive equation used in the visco-plastic model for TMF in Sn-Pb solder. The revised visco-plastic model was exercised using a through-hole solder joint configuration. Initial data indicate a satisfactory compatibility between the coarsening expression and the constitutive equations.
Interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in response to herpes simplex virus (HSV) antigen were assessed in 13 neonates and 3 parturient women with ...primary HSV infection. In comparison with 9 nonparturient adults, the neonates and parturient women showed significantly (P < .01) diminished HSV antigen-stimulated lymphocyte proliferation and IFN-γ production in the first 3–6 weeks after onset of infection. TNFα production did not differ significantly among HSV-infected groups. The impairment in neonatal cellular immunity was due, at least in part, to a specific deficit in response to HSV antigen. Lymphocyte proliferation and TNFα production in response to the mitogen concanavalin A (ConA) were comparable in adults and infants, but ConA-stimulated IFN-γ production in infants was diminished throughout the study period. In contrast, HSV antigen-stimulated IFN-γ production was comparable in infants and adults after 6 weeks. Not all patients with diminished cellular immune responses to HSV antigen manifested severe clinical disease. Nevertheless, patients with significant clinical morbidity had diminished cellular immune responses to HSV antigen. These results suggest that delayed acquisition of antigen-specific cellular immunity in primary HSV infection predisposes to more severe clinical disease.
Reduced lopinavir concentrations have been demonstrated with use of the capsule formulation during the third trimester of pregnancy. This study determined lopinavir exposure with an increased dose of ...the new tablet formulation during the third trimester.
International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is a prospective nonblinded pharmacokinetic study in HIV-infected pregnant women, including a cohort receiving 2 lopinavir/ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, 3 tablets (600 mg/150 mg) twice daily during the third trimester, and 2 tablets (400 mg/100 mg) twice daily post delivery through 2 weeks postpartum.
Steady-state 12-hour pharmacokinetic profiles were performed during pregnancy and at 2 weeks postpartum. Lopinavir and ritonavir were measured by reverse-phase high-performance liquid chromatography (detection limit, 0.09 mcg/mL).
Thirty-three women were studied. Median lopinavir AUC for the second trimester (n = 11), third trimester (n = 33), and postpartum (n = 27) were 72, 96, and 133 mcg x hr/mL, respectively. Median minimum lopinavir concentrations were 3.4, 4.9, and 6.9 mcg/mL.
The higher lopinavir/ritonavir tablet dose (600 mg/150 mg) provided exposure during the third trimester similar to the average AUC (98 mcg x hr x mL(-1) in nonpregnant adults taking 400 mg/100 mg twice daily. The higher dose should be used during the second and third trimesters of pregnancy. Postpartum dosing can be reduced to standard dosing before 2 weeks postpartum.
Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine ...(NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited.
In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases.
NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01).
The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.
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