Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry.

Several members of the seven-transmembrane chemokine receptor family have been shown to serve, with CD4, as coreceptors for entry by human immunodeficiency virus type 1 (HIV-1). While coreceptor usage by HIV-1 primary isolates has been studied by several groups, there is only limited information available concerning coreceptor usage by primary HIV-2 isolates. In this study, we have analyzed coreceptor usage of 15 primary HIV-2 isolates, using lymphocytes from a donor with nonfunctional CCR5 (CCR5 -/-; homozygous 32-bp deletion). Based on the infections of PBMCs, seven of these primary isolates had an absolute requirement for CCR5 expression, whereas the remaining eight exhibited a broader coreceptor usage. All CCR5-requiring isolates were non-syncytium inducing, whereas isolates utilizing multiple coreceptors were syncytium inducing. Blocking experiments using known ligands for chemokine receptors provided indirect evidence for additional coreceptor utilization by primary HIV-2 isolates. Analysis of GHOST4 cell lines expressing various chemokine receptors (CCR1, CCR2b, CCR3, CCR4, CCR5, CXCR4, BONZO, and BOB) further defined specific coreceptor usage of primary HIV-2 isolates. The receptors used included CXCR4, CCR1-5, and the recently described receptors BONZO and BOB. However, the efficiency at which the coreceptors were utilized varied greatly among the various isolates. Analysis of V3 envelope sequences revealed no specific motif that correlated with coreceptor usage. Our data demonstrate that primary HIV-2 isolates are capable of using a broad range of coreceptors for productive infection in vitro. Additionally, our data suggest that expanded coreceptor usage by HIV-2 may correlate with disease progression.

Atopy, asthma, and emphysema in patients with severe alpha-1-antitrypysin deficiency.

Bronchial asthma is characterized by episodic airway obstruction and associated with wheezing, a bronchodilator response, an elevation in total serum IgE, and atopy. To determine whether asthma is more common in subjects with severe alpha 1-antitrypsin deficiency (alpha 1-ATD) and airway obstruction, we compared 38 patients who had this condition (Group 1) with 22 control patients with chronic obstructive pulmonary disease (COPD) (Group 2) and with five subjects with alpha 1-ATD and normal spirometry (Group 3). Subjects were evaluated with a symptom questionnaire, pulmonary function testing, intradermal allergen testing, and serum IgE measurement. Self-reported wheezing was a common symptom in all patient groups, but attacks of wheezing with dyspnea were significantly more common in Group 1. Of those patients with airway obstruction, more than 50% showed a bronchodilator response whether suffering from alpha 1-ATD or not. Atopy was more common in Group 1 than in Group 2 (48% versus 27%). Mean serum IgE for all groups was similar but significantly greater in patients with atopy. We estimated the prevalence of asthma in the study groups on the basis of the criteria of attacks of wheezing, reversible airway obstruction, atopy, and that increased IgE. The proportion of patients with asthma in Group 1 was significantly greater than that in Group 2 (22% versus 5%, p < 0.05). Our study shows that with control for the degree of airway obstruction, asthma, as defined, is more common in patients with alpha 1-ATD than in those without it. We suggest that a lack of alpha 1-AT in airways increases the propensity to develop asthma.

Effect of immunotherapy on sCD23 levels in patients allergic to Hymenoptera venom.

BACKGROUND: sCD23 is the designation given to the low affinity IgE receptor. The soluble fragment of this receptor (sCD23) participates in the regulation of IgE synthesis. OBJECTIVE: The purpose of this study is to examine the effect of a venom immunotherapy regimen on sCD23 levels. METHODS: We measured sCD23 levels by ELISA in Hymenoptera venom-allergic patients (positive skin tests and a history of systemic reactions to Hymenoptera sting) in serial sera collected over a course of venom immunotherapy with a mean duration of 54 months. Mean pre-sCD23 and post-sCD23 levels were compared using a Student's two-tailed t test. RESULTS: sCD23 levels were found to be unchanged over the course of venom immunotherapy. CONCLUSIONS: This is the first longitudinal study that has been done. It suggests that while both immunotherapy and sCD23 are known to be involved in the regulations of IgE synthesis in the atopic patient, the immunomodulation seen in venom immunotherapy is not mediated through sCD23 in any simple regulatory manner.

In vitro release of soluble CD23 by human lymphocytes in ragweed-sensitive versus nonatopic patients following stimulation with ragweed antigen E.

BACKGROUND: Soluble CD23 is the proteolytic cleavage product of the low affinity receptor (FcERII). Functions of CD23 and its soluble products may include upregulation of IgE production and stimulation of B lymphocyte growth. METHODS: Soluble CD23 was quantitated in supernatants of lymphocytes from nine ragweed-sensitive and eight nonatopic subjects stimulated in vitro by antigen E (amb Al), crude ragweed extract, and pokeweed mitogen (PWM). RESULTS: Although PWM stimulation produced no significant difference between groups, sCD23 release was significantly elevated in the cells of nonatopic patients stimulated with antigen E and crude ragweed extract (P less than .05). CONCLUSIONS: This finding supports the concept of separate pathways of activation by antigen and mitogen for sCD23 release and suggests ragweed-sensitive and nonatopic patients have fundamental differences in the response of sCD23 release to ragweed antigen stimulation.

Serum IgE in patients with human immunodeficiency virus infection.

BACKGROUND: Dysregulation of IgE synthesis has been noted in the past in several immunodeficiency states. More recently, analysis of IgE synthesis and atopy in patients who are infected with the human immunodeficiency virus (HIV) has been conflicting. OBJECTIVE: To determine whether IgE dysregulation occurs in HIV-infected patients and if so, whether this dysregulation is antigen-specific and accompanied by any significant changes in T and B cell markers. METHODS: Thirty-six HIV-infected patients were enrolled in the study. Twenty-nine patients completed the study. All patients completed an allergy questionnaire and physical examination. Interval visits occurred every 3 months. Blood was obtained at baseline and every 3 months for total IgE, antigen-specific IgE to eight environmental allergens and lymphocyte markers. Study was not blinded. RESULTS: Analysis of results at baseline and 1 year revealed a subset of patients who had marked elevations in serum IgE protein. This increase was not accompanied by any detectable antigen-specific IgE to the measured allergens nor was any significant change noted in lymphocyte markers. Student's paired t tests were used for data analysis. CONCLUSION: In a subset of patients with HIV infection, acquired dysregulation of IgE synthesis occurs that results in increased circulatory levels of IgE protein not attributable to atopic allergens or associated with detectable changes in lymphocyte markers.

Evaluation of infection control measures in preventing the nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in a New York City hospital.

OBJECTIVE: To evaluate the efficacy of Centers for Disease Control and Prevention (CDC)-recommended infection control measures implemented in response to an outbreak of multidrug-resistant (MDR) tuberculosis (TB). DESIGN: Retrospective cohort studies of acquired immunodeficiency syndrome (AIDS) patients and healthcare workers. The study period (January 1989 through September 1992) was divided into period I, before changes in infection control; period II, after aggressive use of administrative controls (eg, rapid placement of TB patients or suspected TB patients in single-patient rooms); and period III, while engineering changes were made (eg, improving ventilation in TB isolation rooms). SETTING: A New York City hospital that was the site of one of the first reported outbreaks of MDR-TB among AIDS patients in the United States. PARTICIPANTS: All AIDS patients admitted during periods I and II. Healthcare workers on nine inpatient units with TB patients and six without TB patients. RESULTS: The epidemic (38 patients) waned during period II and only one MDR-TB patient presented during period III. The MDR-TB attack rate among AIDS patients hospitalized on the same ward on the same days as an infectious MDR-TB patient was 8.8% (19 of 216) during period I, decreasing to 2.6% (5 of 193; P = 0.01) during period II. In a small group of healthcare workers with tuberculin skin test data, conversions during periods II through III were higher on wards with than without TB patients (5 of 29 versus 0 of 15; P = 0.15), although the difference was not statistically significant. CONCLUSIONS: Transmission of MDR-TB among AIDS patients decreased markedly after enforcement of readily implementable administrative measures, ending the outbreak. However, tuberculin skin-test conversions among healthcare workers may not have been prevented by these measures. CDC guidelines for prevention of nosocomial transmission of TB should be implemented fully at all US hospitals.

Alternating and intermittent regimens of zidovudine and dideoxycytidine in patients with AIDS or AIDS-related complex.

OBJECTIVE: To determine whether alternating regimens consisting of zidovudine and 2',3'-dideoxycytidine (ddC) reduce the toxicity and maintain or increase the antiretroviral effect associated with each drug alone. DESIGN: An unblinded, randomized (phase II) clinical trial in which seven treatment regimens were compared. SETTING: Outpatient clinics of 12 AIDS Clinical Trials Units. PATIENTS: One hundred thirty-one patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and serum p24 antigenemia (> or = 70 pg/mL). INTERVENTION: Treatments included weekly or monthly alternating zidovudine (200 mg every 4 hours) and ddC (0.01 or 0.03 mg/kg body weight every 4 hours); weekly intermittent zidovudine, 200 mg every 4 hours, or ddC, 0.03 mg/kg every 4 hours; and continuous zidovudine. MEASUREMENTS: Toxicity, CD4 cell counts, serum p24 antigen levels, and clinical end points. Data were analyzed for the first 48 weeks of therapy (median follow-up, 40 weeks). RESULTS: Hematologic toxicity was significantly less frequent in patients who received zidovudine therapy every other week (11% to 15%) or every other month (11% to 14%) than in those who received continuous zidovudine therapy (33%) (P < 0.02). Weekly alternating therapy with zidovudine and ddC, 0.03 mg/kg, or intermittent therapy with ddC, 0.03 mg/kg, produced high rates of peripheral neuropathy (41% and 50%, respectively). Neuropathy occurred in 10% to 21% of patients in the other three alternating-therapy limbs and in 17% of patients receiving zidovudine alone (intermittently or continuously). Initial increases in CD4 cell counts were sustained in three alternating-therapy limbs, but counts returned to baseline by week 28 in the remaining limbs. The median weight gain at week 48 was significantly greater in patients treated with alternating regimens (0.9 to 3.8 kg) compared with those treated with continuous zidovudine therapy (-0.7 kg) (P = 0.008). Patients treated with alternating regimens and those treated with continuous zidovudine had similarly sustained decreases in p24 antigen levels. CONCLUSIONS: These findings suggest that alternating therapy with zidovudine and ddC reduces the toxicity associated with each drug alone while maintaining strong antiretroviral activity.

Elevated levels of soluble CD54 (ICAM-1) in human immunodeficiency virus infection.

Soluble CD54 levels in sera were quantitated in asymptomatic intravenous drug users, homosexuals, and patients with lymphadenopathy, AIDS-related complex, or acquired immunodeficiency syndrome. Soluble CD54 levels were elevated in human immunodeficiency virus (HIV)-seronegative asymptomatic intravenous drug users, reflecting infections like cytomegalovirus, Epstein-Barr virus, and hepatitis B virus. The sera of human immunodeficiency virus-seropositive groups of patients also had elevated levels of soluble CD54, reflecting infections like cytomegalovirus and human immunodeficiency virus infection.

The voyage of Columbus led to the spread of syphilis to Europe.

The discovery of the New World by the Old World had a massive impact on subsequent events. It appears likely, but not certain, that the syphilitic epidemic in Europe may have been an imported affliction. It is impressive to appreciate how little was known in 1492 about infectious diseases and how much has been learned since the later decades of the nineteenth century. Syphilis represents the first major infectious disease for which discovery of etiology, development of a diagnostic test, and effective therapy was achieved, a major accomplishment of modern medicine.

Effect of foscarnet therapy on human immunodeficiency virus p24 antigen levels in AIDS patients with cytomegalovirus retinitis.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured in 22 AIDS patients who had detectable serum antigen at baseline after induction and maintenance therapy of foscarnet for cytomegalovirus retinitis in phase I/II multicenter trials. The HIV p24 antigen levels decreased from a baseline value of 199 +/- 236 (mean +/- SD) and 140 pg/mL (median) to 106 +/- 218 and 28 pg/mL after 14 days of foscarnet induction therapy (60 mg/kg every 8 h). During chronic foscarnet maintenance, there was a sustained decrease in mean HIV p24 antigen levels below pre-foscarnet therapy baseline concentrations for a median of 16 weeks after foscarnet induction. These results provide evidence for a sustained clinical antiretroviral effect of chronic foscarnet maintenance therapy, consistent with a recent report that foscarnet-treated AIDS patients live longer than ganciclovir-treated patients.

Circulating elevated levels of soluble CD23, interleukin-4, and CD20+CD23+ lymphocytes in atopic subjects with elevated serum IgE concentrations.

Circulating IgE protein levels, leukocyte counts, lymphocyte subsets, IL-4, and soluble CD23 levels were quantitated in 43 atopic and 19 nonatopic subjects. Mean values of IgE protein levels, total eosinophil counts, CD20+CD23+ cells (B cells with low-affinity IgE receptor), IL-4 and sCD23 levels were elevated in atopic patients compared with nonatopic controls. The results suggest that sCD23, IL-4, and CD20+CD23+ lymphocytes may play a role in the increased production of IgE in atopic subjects in a manner similar to that observed by other investigators in prior in vitro studies.

An outbreak of multidrug-resistant tuberculosis among hospitalized patients with the acquired immunodeficiency syndrome.

BACKGROUND: Since 1990 several clusters of multidrug-resistant tuberculosis have been identified among hospitalized patients with the acquired immunodeficiency syndrome (AIDS). We investigated one such cluster in a voluntary hospital in New York. METHODS: We compared exposures among 18 patients with AIDS in whom tuberculosis resistant to isoniazid and streptomycin was diagnosed from January 1989 through April 1990 (the case patients) with exposures among 30 control patients who had AIDS and tuberculosis susceptible to isoniazid, streptomycin, or both. We also compared exposures among the 14 case patients hospitalized during the six months before the diagnosis of tuberculosis (the exposure period) with those among 44 control patients with AIDS matched for duration of hospitalization. Mycobacterium tuberculosis isolates were typed with analysis of restriction-fragment-length polymorphism (RFLP). RESULTS: Case patients with drug-resistant tuberculosis were significantly more likely than controls with drug-susceptible tuberculosis to have been hospitalized during their exposure periods (14 of 18 vs. 10 of 30) (odds ratio, 7.0; 95 percent confidence interval, 1.6 to 36; P = 0.006). Case patients hospitalized during their exposure periods were significantly more likely to have been hospitalized on the same ward as a patient with infectious drug-resistant tuberculosis than were either controls with drug-susceptible tuberculosis hospitalized during their exposure periods or controls matched for duration of hospitalization (13 of 14 vs. 2 of 10 and 23 of 44) (odds ratio, 52; 95 percent confidence interval, 3.1 to 2474; P less than 0.001; and odds ratio, infinity; 95 percent confidence interval, 2.4 to infinity; P = 0.005, respectively). Among those hospitalized on the same ward, the rooms of case patients were closer to that of the nearest patient with infectious tuberculosis than were the rooms of controls matched for duration of hospitalization. M. tuberculosis isolates from 15 of 16 case patients had identical patterns on RFLP analysis. Of 16 patients' rooms tested with air-flow studies, only 1 had the recommended negative-pressure ventilation. CONCLUSIONS: Multidrug-resistant tuberculosis is readily transmitted among hospitalized patients with AIDS. Physicians must be alert to this danger and must enforce adherence to the measures recommended to prevent nosocomial transmission of tuberculosis.

Modulation of alpha interferon levels by AZT treatment in HIV-seropositive patients.

The effect of AZT on serum HIV p24 antigen and endogenous serum alpha interferon levels was studied in AIDS and ARC patients. Following administration of AZT there was a rapid decline in the serum levels of both HIV p24 antigen and alpha interferon. When AZT treatment was interrupted, the levels of both HIV p24 antigen and of interferon rapidly increased. These findings suggest that HIV or some other AZT sensitive microorganism is the inducer of interferon which is characteristically found in the serum of AIDS and symptomatic HIV infected patients. They also suggest that the rapid decline in interferon levels may underlie some of the symptomatic benefit that follows administration of AZT.

An improved method for monitoring efficacy of anti-retroviral therapy in HIV-infected individuals: a highly sensitive HIV p24 antigen assay.

Circulating human immunodeficiency virus (HIV) p24 antigen levels were measured by a highly sensitive HIV p24 antigen-capture enzyme-linked immunosorbent assay (ELISA) in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) otherwise negative for HIV p24 antigen measured by a commercial antigen-capture ELISA. The assays were performed at baseline and at several intervals during treatment with either zidovudine (ZDV) or dideoxyinosine (ddl). To further enhance the rate of antigen detection, serum was pretreated with hydrochloric acid to denature antibody in immune complexes. Utilizing this assay system, we monitored these patients for drug efficacy. HIV p24 antigen levels obtained by using this sensitive assay decreased in 3 of 8 patients receiving ZDV during 8 weeks of ZDV treatment. Similarly, ddl administration was associated with a decrease of HIV p24 antigen levels in 3 of 5 patients. Thus, the use of the highly sensitive HIV p24 antigen assay permitted the monitoring of surrogate HIV p24 antigen as a measure of efficacy of anti-retroviral therapy in all of these patients who were otherwise HIV p24 antigen-negative at the onset of anti-retroviral therapy.

Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

BACKGROUND: Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS: In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS: Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS: Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.

Nocardial infection as a complication of AIDS: report of six cases and review.

Nocardiosis has been increasingly recognized as a serious infection among persons who otherwise appear healthy and among those with underlying chronic disease, neoplasms, and immunosuppression. Nocardial infection as a complication of AIDS has been reported infrequently. Six patients with AIDS and nocardiosis were identified at one New York City hospital from January 1980 through March 1989. Sites of nocardial infection in these patients included the lungs, brain, esophagus, and suprarenal and paraspinal masses. Mycobacteria, fungi, viruses, and bacteria other than Nocardia species caused concomitant infections in three patients. Three patients died of nocardiosis. Because of such factors as the growth properties of Nocardia species, the presence of other organisms, the common use of sulfonamides for treatment of patients with AIDS, and a low index of suspicion among physicians, the incidence of nocardiosis as a complication of AIDS may possibly be underreported. Early recognition of nocardial infection may lead to an improved prognosis.

HIV-1 infection complicated by food allergy and allergic gastroenteritis: a case report.

A 34-year-old female with HIV-1 infection detected by positive serology in 1983 subsequently developed acute granulomatous interstitial pneumonitis, eosinophilic gastroenteritis, and angioedema associated with the ingestion of vanilla ice cream and tangerines. The enteritis and angioedema symptoms appeared to respond to large doses of oral sodium cromoglycate. Sera collected over several years before clinical symptoms revealed a sharp rise of IgE antibody in 1985 and a subsequent decline to baseline values followed by markedly increased levels of IgE antibodies to a number of inhalant and food allergens. The findings suggest disordered IgE antibody regulation as a consequence of HIV-1 infection and as a cause of allergic manifestations including eosinophilic gastroenteritis and food-induced angioedema.