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Biomedical subjects

C W Hendrix

Publications and source records attributed to C W Hendrix.

At least 19 recordsLinked to original sources
PubMed2001

Increased resource use associated with catheter-related bloodstream infection in the surgical intensive care unit.

HYPOTHESIS: Catheter-related bloodstream infection (CRBSI) in critically ill surgical patients with prolonged intensive care unit (ICU) stays is associated with a significant increase in health care resource use. DESIGN: Prospective cohort study. SETTING: Surgical ICU at a large tertiary care center. PATIENTS: Critically ill surgical patients (N = 260) with projected surgical ICU length of stay greater than 3 days. INTERVENTIONS: Central venous catheters were cultured for clinical suspicion of infection. MAIN OUTCOME MEASURES: Increases in total hospital cost, ICU cost, hospital days, and ICU days attributable to CRBSI were estimated using multiple linear regression after adjusting for demographic factors and severity of illness (APACHE III [Apache Physiology and Chronic Health Evaluation III] score). RESULTS: The incidence of CRBSI per 1000 catheter-days was 3.6 episodes (95% confidence interval [CI], 2.1-5.8 episodes). Microbiologic isolates were Gram-positive bacteria in 75%, Gram-negative bacteria in 20%, and yeast in 5%. After adjusting for demographic factors and severity of disease, CRBSI was associated with an increase of $56 167 (95% CI, $11 523-$165 735; P =.001) (in 1998 dollars) in total hospital cost, an increase of $71 443 (95% CI, $11 960-$195 628; P<.001) in ICU cost, a 22-day increase in hospital length of stay, and a 20-day increase in ICU length of stay. CONCLUSIONS: For critically ill surgical patients, CRBSI is associated with a profound increase in resource use. Prevention, early diagnosis, and intervention for CRBSI might result in cost savings in this high-risk population.

APACHE↗
PubMed2001

Surveillance strategies and impact of vancomycin-resistant enterococcal colonization and infection in critically ill patients.

OBJECTIVE: To determine the optimal site and frequency for vancomycin-resistant enterococci (VRE) surveillance to minimize the number of days of VRE colonization before identification and subsequent isolation. SUMMARY BACKGROUND DATA: The increasing prevalence of VRE and the limited therapeutic options for its treatment demand early identification of colonization to prevent transmission. METHODS: The authors conducted a 3-month prospective observational study in medical and surgical intensive care unit (ICU) patients with a stay of 3 days or more. Oropharyngeal and rectal swabs, tracheal and gastric aspirates, and urine specimens were cultured for VRE on admission to the ICU and twice weekly until discharge. RESULTS: Of 117 evaluable patients, 23 (20%) were colonized by VRE. Twelve patients (10%) had VRE infection. Of nine patients who developed infections after ICU admission, eight were colonized before infection. The rectum was the first site of colonization in 92% of patients, and positive rectal cultures preceded 89% of infections acquired in the ICU. This was supported by strain delineations using pulsed-field gel electrophoresis. Twice-weekly rectal surveillance alone identified 93% of the maximal estimated VRE-related patient-days; weekly or admission-only surveillance was less effective. As a test for future VRE infection, rectal surveillance culture twice weekly had a negative predictive value of 99%, a positive predictive value of 44%, and a relative risk for infection of 34. CONCLUSIONS: Twice-weekly rectal VRE surveillance of critically ill patients is an effective strategy for early identification of colonized patients at increased risk for VRE transmission, infection, and death.

Critical Illness↗
PubMed2001

Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients.

OBJECTIVE: To evaluate the prophylactic use of enteral fluconazole to prevent invasive candidal infections in critically ill surgical patients. SUMMARY BACKGROUND DATA: Invasive fungal infections are increasingly common in the critically ill, especially in surgical patients. Although fungal prophylaxis has been proven effective in certain high-risk patients such as bone marrow transplant patients, few studies have focused on surgical patients and prevention of fungal infection. METHODS: The authors conducted a prospective, randomized, placebo-controlled trial in a single-center, tertiary care surgical intensive care unit (ICU). A total of 260 critically ill surgical patients with a length of ICU stay of at least 3 days were randomly assigned to receive either enteral fluconazole 400 mg or placebo per day during their stay in the surgical ICU at Johns Hopkins Hospital. RESULTS: The primary end point was the time to occurrence of fungal infection during the surgical ICU stay, with planned secondary analysis of patients "on-therapy" and alternate definitions of fungal infections. In a time-to-event analysis, the risk of candidal infection in patients receiving fluconazole was significantly less than the risk in patients receiving placebo. After adjusting for potentially confounding effects of the Acute Physiology and Chronic Health Evaluation (APACHE) III score, days to first dose, and fungal colonization at enrollment, the risk of fungal infection was reduced by 55% in the fluconazole group. No difference in death rate was observed between patients receiving fluconazole and those receiving placebo. CONCLUSIONS: Enteral fluconazole safely and effectively decreased the incidence of fungal infections in high-risk, critically ill surgical patients.

APACHE↗
PubMed2000

The diagnostic value of fungal surveillance cultures in critically ill patients.

BACKGROUND: Heavy fungal colonization is a known risk factor for fungal infection, yet the value of fungal surveillance cultures is uncertain. METHODS: To evaluate the utility of fungal surveillance cultures in predicting fungal infections, we evaluated surveillance fungal cultures over a three month period in a prospective, cohort study conducted at a university medical center with a large tertiary referral population. We enrolled 172 patients in the Oncology Center and the medical and surgical intensive care units at Johns Hopkins Hospital. RESULTS: Surveillance cultures from five sites were obtained twice weekly and evaluated for prediction of subsequent fungal infection. Infections were prospectively defined and evaluated by a panel of clinicians. Test characteristics were assessed. Of 159 eligible patients, 14 (9%) developed invasive fungal infections. Having two or more surveillance sites positive in a single day had an odds ratio of 8.2 (1.1-358.0) (p = 0.03), a negative predictive value of 0.98, sensitivity of 0.92, and a likelihood ratio of 1.6 for a fungal infection. In a multiple logistic regression model and Kaplan-Meier analysis, fungal burden was strongly and independently associated with infection (p < 0.05). CONCLUSIONS: Surveillance cultures are helpful in determining fungal colonization but do not have a high positive predictive value for fungal infection in a broad population of intensive care unit patients. However, fungal infection is more likely in heavily colonized patients, and surveillance cultures show that fungal infection is extremely unlikely in patients without fungal colonization.

Adolescent↗
PubMed2000

Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers.

AMD-3100, a bicyclam, is a novel agent that uniquely inhibits the entry of human immunodeficiency virus type 1 (HIV-1) into CD4(+) T cells via selective blockade of the chemokine CXCR-4 receptor. Twelve healthy volunteers were given AMD-3100 as a single 15-min intravenous infusion at 10, 20, 40, or 80 microg/kg. Five subjects also received a single subcutaneous injection of AMD-3100 (40 or 80 microg/kg). Three subjects received two escalating oral doses each (80 and 160 microg/kg). All subjects tolerated their dose(s) well without any grade 2 toxicity or dose adjustment. Six subjects experienced mild, transient symptoms, primarily gastrointestinal in nature and not dose related. All subjects experienced a dose-related elevation of the white blood cell count, from 1.5 to 3.1 times the baseline, which returned to the baseline 24 h after dosing. AMD-3100 demonstrated dose proportionality for the maximum drug concentration in serum (C(max)) and the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) over the entire dose range. At the highest intravenous dose (80 microg/kg), the median C(max) was 515 (range, 470 to 521) ng/ml and the AUC(0-infinity) was 1,044 (range, 980 to 1,403) ng-h/ml. The median systemic absorption after subcutaneous dosing was 87% (range, 67 to 106%). No drug was detectable in the blood following oral dosing. Using a two-compartment model, the median pharmacokinetic parameter estimates (ranges) were as follows: volume of distribution, 0.34 (0. 27 to 0.36) liter/kg; clearance, 1.30 (0.97 to 1.34) liters/h; elimination half-life, 3.6 (3.5 to 4.9) h. After a single, well-tolerated intravenous dose of AMD-3100, concentrations were sustained for 12 h above the in vitro antiretroviral 90% inhibitory concentrations and for 8 h above antiviral concentrations identified in the SCID-hu Thy/Liv mouse model of HIV infection.

Animals↗
PubMed2000

International military human immunodeficiency virus/acquired immunodeficiency syndrome policies and programs: strengths and limitations in current practice.

A survey was conducted to evaluate military human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) policies and programs in 119 countries. Ninety-eight percent of the 62 respondents provide prevention education, 95% in group settings but only 53% individually. Predeployment briefings are more common than postdeployment briefings. Condoms are promoted more often than provided. Seventy-eight respondents report some form of mandatory HIV testing, and 58% perform mandatory recruit testing, with recruitment denied to HIV-positive individuals in 17%. Counseling accompanies mandatory testing less than voluntary testing. In-service care for AIDS patients is universal. Many military prevention programs can be improved through postdeployment briefings and proactive interventions involving education, condom distribution, and counseling combined with testing. Mandatory testing is often inconsistent with stated goals, and AIDS care policies may strain military budgets. Testing based on cost-benefit assessments may increase efficiency in military HIV control. Military budgets may benefit from greater civil-military cost sharing in AIDS care.

AIDS Serodiagnosis↗
PubMed1999

Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173.

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia (>20%) was seen in 3 of 6 study subjects who received 150 mg/day for > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.

AIDS-Related Opportunistic Infections↗
PubMed1999

The effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive.

BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.

Adult↗
PubMed1998

Size and duration of zidovudine benefit in 1003 HIV-infected patients: U.S. Army, Navy, and Air Force natural history data. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVES: The study's objectives were to determine the size and duration of benefits of early versus delayed versus late treatment with zidovudine (ZDV) on disease progression and mortality in HIV-infected patients, and whether patients rapidly progressing before ZDV treatment had a different outcome from those not rapidly progressing before ZDV. DESIGN: The design was an inception cohort of 1003 HIV-infected patients. One hundred and seventy-four of the 1003 patients were treated before CD4 counts fell to <400 x 10(9)/L, ("early treatment"); 183 of 1003 patients were treated after CD4 counts fell to <400 x 10(9)/L but before clinical disease developed ("delayed treatment"); and 646 of the 1003 patients had either been treated after clinical disease developed or had not been treated at all by the end of follow-up ("late treatment"). Outcomes were progression to clinical HIV disease and mortality. RESULTS: The relative risk (RR) of progression for early versus delayed treatment was 0.58 (p < .03), and durability of ZDV benefits on progression was estimated at no more than 2.0 years; however, this estimate had wide confidence intervals. The RR of progression for delayed versus late treatment was 0.54 p < .0001, and durability of ZDV benefits was estimated at 1.74 years; this estimate had narrow confidence intervals. Survival was better for the early versus delayed treatment (RR = 0.55), but this difference was not statistically significant. In the subgroup of patients with more rapid CD4 decline prior to ZDV therapy, significant benefits on progression were observed for early versus delayed ZDV therapy (RR = 0.42, p = .02) and delayed versus late ZDV therapy (RR = 0.51; p = .0004). Duration of benefit was estimated to be 4.5 years (early versus delayed) and 1.7 years (delayed versus late). For patients with less rapid pre-ZDV decline in CD4 levels, a significant progression benefit was observed for delayed versus late therapy (RR = 0.50; p = .02). Duration of benefit in this subgroup was estimated to be 1.8 years. No significant benefit was found for early versus delayed treatment (RR = 1.12) in the less rapid pre-ZDV CD4 cell decline subgroup. CONCLUSIONS: Early treatment compared with delayed treatment was associated with a sizable reduction in HIV progression, but the duration of benefits was estimated to last only about 2 years. Delayed treatment compared with late treatment with ZDV was associated with substantial reduction of progression, but this reduction was also clearly limited in duration. Benefits on progression and mortality for the early treatment group were heavily dependent on the pre-ZDV CD4 slope. In the subgroup of patients with the most rapid pre-ZDV CD4 cell declines, the duration of benefit was much longer, possibly as long as 4 years.

Adult↗
PubMed1997

Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients.

A randomized, double-blind, placebo-controlled, dose-escalation study of adefovir dipivoxil, an oral prodrug of adefovir, was conducted in 36 human immunodeficiency virus (HIV)-infected subjects to evaluate its anti-HIV activity, safety, and pharmacokinetics. Subjects received placebo or one of three dosages of adefovir dipivoxil daily for 14 days. Median decreases in serum p24 antigen of 31% (P = .02), 25% (P = .31), and 30% (P = .01) occurred in each drug-treated group, respectively, compared with an increase of 17% in the placebo group. Median decreases in serum HIV RNA of 0.4-0.6 log10 copies/mL occurred in the drug-treated groups (P = .03), compared with no change in the placebo group. Gastrointestinal complaints and reversible liver transaminase elevations were the most frequently noted adverse events. Decreases in serum free carnitine occurred in each drug-treated group during treatment. After 14 days of dosing, adefovir dipivoxil demonstrated anti-HIV activity and was best tolerated at the lowest dosage studied, 125 mg daily.

Adenine↗
PubMed1997

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.

Adult↗
PubMed1996

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Antibodies↗
PubMed1995

Modulation of alpha-interferon's antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers.

The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day). Peripheral blood mononuclear cells were assayed for resistance to vesicular stomatitis virus infection and induction of 2'-5'-oligoadenylate synthetase activity as evidence of interferon's antiviral effect. Co-administration of acetaminophen increased both antiviral parameters by more than 70% (P < 0.05) and reduced symptoms after interferon dosing, compared to controls. Aspirin and prednisone did not demonstrate any significant differences from controls in antiviral effect. As a group, acetaminophen, aspirin, and prednisone reduced the clinical symptoms by 47% compared to controls (P = 0.03) after interferon dosing, although individual drug comparisons failed to reach statistical significance. Independent of treatment group, the changes in antiviral markers after interferon dosing correlated closely with each other (r = 0.72, P < 0.001), but neither correlated with symptoms or fever (r < 0.30, P > 0.05). Acetaminophen enhances the antiviral effects of a single intramuscular dose of alpha-interferon, considering the parameters measured in these healthy volunteers.

2',5'-Oligoadenylate Synthetase↗
PubMed1995

In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis.

In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.

Apoptosis↗
PubMed1994

Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.

In vitro activation of PBLs from HIV+ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells from HIV+ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV+ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV+ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV+ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.

Apoptosis↗