Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study.

We conducted this study to determine whether infection with human herpesvirus (HHV) 6A, HHV-6B, or HHV-7 differed between patients with chronic fatigue syndrome and control subjects. We recruited 26 patients and 52 nonfatigued matched control subjects from Atlanta. Serum samples were tested by enzyme immunoassay for seroreactivity to HHV-6, and all were seropositive. Lymphocyte specimens were cocultivated with cord blood lymphocytes and assayed for HHV-6 and HHV-7; neither virus was isolated. Finally, lymphocytes were tested by use of 3 polymerase chain reaction methods for HHV-6A, HHV-6B, and HHV-7 DNA. HHV-6A or HHV-6B DNA was detected in 17 (22.4%) of 76 samples, and there were no significant differences (by matched analyses) between patients (3 [11.5%] of 26) and control subjects (14 [28%] of 50). HHV-7 DNA was detected in 14 subjects, and although control subjects (12 [24%]) were more likely than patients (2 [7.7%]) to be positive, the difference was not statistically significant. We found no evidence that active or latent infection with HHV-6A, HHV-6B, HHV-7, or any combination these 3 HHVs is associated with chronic fatigue syndrome.

Chronic multisymptom illness affecting Air Force veterans of the Gulf War.

CONTEXT: Gulf War (GW) veterans report nonspecific symptoms significantly more often than their nondeployed peers. However, no specific disorder has been identified, and the etiologic basis and clinical significance of their symptoms remain unclear. OBJECTIVES: To organize symptoms reported by US Air Force GW veterans into a case definition, to characterize clinical features, and to evaluate risk factors. DESIGN: Cross-sectional population survey of individual characteristics and symptoms and clinical evaluation (including a structured interview, the Medical Outcomes Study Short Form 36, psychiatric screening, physical examination, clinical laboratory tests, and serologic assays for antibodies against viruses, rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING: The cross-sectional questionnaire survey included 3723 currently active volunteers, irrespective of health status or GW participation, from 4 air force populations. The cross-sectional clinical evaluation included 158 GW veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES: Symptom-based case definition; case prevalence rate for GW veterans and nondeployed personnel; clinical and laboratory findings among veterans who met the case definition. RESULTS: We defined a case as having 1 or more chronic symptoms from at least 2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155 GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness was not associated with time or place of deployment or with duties during the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases, 86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical examination, laboratory, or serologic findings identified cases, veterans who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS: Among currently active members of 4 Air Force populations, a chronic multisymptom condition was significantly associated with deployment to the GW. The condition was not associated with specific GW exposures and also affected nondeployed personnel.

Factor analysis of unexplained severe fatigue and interrelated symptoms: overlap with criteria for chronic fatigue syndrome.

The objective of this study was to identify factors explaining the correlations among unexplained severe fatigue of different durations (1-5 months or > or =6 months) and symptoms reported as being significant health problems during a preceding 4-week period. Between June and December of 1994, a cross-sectional, random digit dialing telephone survey was conducted among residents of San Francisco, California. All subjects who reported having severe fatigue lasting for > or =1 month and a random sample of nonfatigued subjects were asked to participate in a detailed telephone interview. Data from 1,510 individuals aged 18-60 years who did not have medical or psychiatric conditions that could explain their severe fatigue were analyzed. Common factor analyses identified three correlated factors (defined as "fatigue-mood-cognition" symptoms, "flu-type" symptoms, and "visual impairment") that explained the correlations among fatigue lasting for > or =6 months and 14 interrelated symptoms. No factor explained the correlations among fatigue lasting for 1-5 months and other symptoms. The combination of fatigue of > or =6 months' duration and selected symptoms overlaps with published criteria used to define cases of chronic fatigue syndrome (CFS). Although symptoms described in this study were reported as appearing within the preceding month, and CFS symptoms must have been present for the previous 6 months, these results provide empirical support for the interrelations among unexplained fatigue of > or =6 months' duration and symptoms included in the CFS case definition.

Surveillance for chronic fatigue syndrome--four U.S. cities, September 1989 through August 1993.

PROBLEM/CONDITION: Although chronic fatigue syndrome (CFS) has been recognized as a cause of morbidity in the United States, the etiology of CFS is unknown. In addition, information is incomplete concerning the clinical spectrum and prevalence of CFS in the United States. REPORTING PERIOD COVERED: This report summarizes CFS surveillance data collected in four U.S. cities from September 1989 through August 1993. DESCRIPTION OF SYSTEM: A physician-based surveillance system for CFS was established in four U.S. metropolitan areas: Atlanta, Georgia; Wichita, Kansas; Grand Rapids, Michigan; and Reno, Nevada. The objectives of this surveillance system were to collect descriptive epidemiologic information from patients who had unexplained chronic fatigue, estimate the prevalence and incidence of CFS in defined populations, and describe the clinical course of CFS. Patients aged > or = 18 years who had had unexplained, debilitating fatigue or chronic unwellness for at least 6 months were referred by their physicians to a designated health professional(s) in their area. Those patients who participated in the surveillance system a) were interviewed by the health professional(s); b) completed a self-administered questionnaire that included their demographic information, medical history, and responses to the Beck Depression Inventory, the Diagnostic Interview Schedule, and the Sickness Impact Profile; c) submitted blood and urine samples for laboratory testing; and d) agreed to a review of their medical records. On the basis of this information, patients were assigned to one of four groups: those whose illnesses met the criteria of the 1988 CFS case definition (Group I); those whose fatigue or symptoms did not meet the criteria for CFS (Group II); those who had had an identifiable psychological disorder before onset of fatigue (Group III); and those who had evidence of other medical conditions that could have caused fatigue (Group IV). Patients assigned to Group III were further evaluated to determine the group to which they would have been assigned had psychological illness not been present, the epidemiologic characteristics of the illness and the frequency of symptoms among patients were evaluated, and the prevalence and incidence of CFS were estimated for each of the areas. RESULTS: Of the 648 patients referred to the CFS surveillance system, 565 (87%) agreed to participate. Of these, 130 (23%) were assigned to Group I; 99 (18%), Group II; 235 (42%), Group III; and 101 (18%), Group IV. Of the 130 CFS patients, 125 (96%) were white and 111 (85%) were women. The mean age of CFS patients at the onset of illness was 30 years, and the mean duration of illness at the time of the interview was 6.7 years. Most (96%) CFS patients had completed high school, and 38% had graduated from college. The median annual household income/for CFS patients was $40,000. In the four cities, the age-, sex-, and race-adjusted prevalences of CFS for the 4-year surveillance period ranged from 4.0 to 8.7 per 100,000 population. The age-adjusted 4-year prevalences of CFS among white women ranged from 8.8 to 19.5 per 100,000 population. INTERPRETATION: The results of this surveillance system were similar to those in previously published reports of CFS. Additional studies should be directed toward determining whether the data collected in this surveillance system were subject to selection bias (e.g., education and income levels might have influenced usage of the health-care system, and the populations of these four surveillance sites might not be representative of the U.S. population). ACTIONS TAKEN: In February 1997, CDC began a large-scale, cross-sectional study at one surveillance site (Wichita) to describe more completely the magnitude and epidemiology of unexplained chronic fatigue and CFS.

Chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) has emerged as a public health concern over the past decade. A working case definition was created in 1988 and revised in 1994, and this has been used to establish prevalence estimates using physician-based surveillance and an a random digit dial telephone survey. Although CFS has some characteristics of an infectious disease, so far no infectious agent has been associated with the illness. Studies of immune function in CFS patients failed to detect differences between cases and healthy controls. However, when cases were subgrouped according to whether they had a sudden or gradual onset, differences in immunologic markers were detected between cases and their matched controls.

Immune responses associated with chronic fatigue syndrome: a case-control study.

An exploratory case-control study was conducted to assess whether the many reported differences in the immune function of chronic fatigue syndrome (CFS) patients are detectable in rigorously defined cases of CFS. Although many studies have reported differences between cases and controls in various measures of immune function, none of these differences were found in all studies. In this study, no differences were found in white blood cell numbers; immune complex, complement, or serum immunoglobulin levels; delayed type hypersensitivity and allergic responses; NK cell function; and proliferative responses to mitogens and antigens. Marginal differences were detected in cytokine responses and in cell surface markers in the total CFS population. However, when the patients were subgrouped by type of disease onset (gradual or sudden) or by how well they were feeling on the day of testing, more pronounced differences were seen.

Seroepidemiology of chronic fatigue syndrome: a case-control study.

We performed serological testing for a large number of infectious agents in 26 patients from Atlanta who had chronic fatigue syndrome (CFS) and in 50 controls matched by age, race, and sex. We did not find any agent associated with CFS. In addition, we did not find elevated levels of antibody to any of a wide range of agents examined. In particular, we did not find elevated titers of antibody to any herpesvirus, nor did we find evidence of enteroviral exposure in this group of patients.

Idiopathic CD4+ T-lymphocytopenia--an analysis of five patients with unexplained opportunistic infections.

BACKGROUND: Although patients with idiopathic CD4+ T-lymphocytopenia and serious opportunistic infections have been described previously, the clinical and immunologic features of this condition have not been well defined. METHODS: We studied in detail five patients with idiopathic CD4+ T-lymphocytopenia. The studies included serologic testing, culture, and polymerase chain reaction for the human immunodeficiency virus (HIV) types 1 and 2, serologic testing for the human T-cell lymphotropic virus (HTLV) types I and II, lymphocyte phenotyping, immunoglobulin quantitation, and lymphocyte-transformation assays, as well as attempts to isolate a retroviral agent. The results were compared with those in HIV-infected persons matched for CD4+ T-cell counts and with those in normal controls. We also studied the spouses of patients and the blood donors for one patient. RESULTS: In these five patients, there was no evidence of either HIV or HTLV infection. All the patients had both low percentages and low counts of CD4+ T cells, with relative increases in percentages, but not counts, of CD8+ cells. Numbers of B cells and natural killer cells were generally normal. As compared with HIV-infected persons, our patients had lower percentages and counts of CD8+ cells and more lymphopenia. CD4+ counts were relatively stable over time. Instead of the high immunoglobulin levels seen in HIV infection, these patients had normal or slightly low levels of immunoglobulins. The lymphocyte-transformation response to mitogens and antigens was depressed. Results in spouses and blood donors were normal. CONCLUSIONS: Idiopathic CD4+ T-lymphocytopenia differs from HIV infection in its immunologic characteristics and in its apparent lack of progression over time. Nothing about the immunologic or viral-culture studies performed in these patients or about their family members or blood donors suggests that a transmissible agent causes this condition.

Inhibition of HSV-1-specific cytotoxic T lymphocytes by recombinant-derived gp120 of HIV-1.

The ability of human immunodeficiency virus type-1 (HIV-1) and recombinant HIV-1 gp120 to prevent target cell lysis by herpes simplex virus type 1 (HSV-1)-specific cytotoxic T lymphocytes (CTL) was assessed by limiting dilution analysis. Live and inactivated HIV-1 as well as recombinant-derived gp120 all substantially inhibited HSV-1-specific CTL. Soluble CD4 antigen reversed the inhibition by gp120 when simultaneously added with gp120 to the assay. In addition, the monoclonal anti-CD4 antibody a-Leu3a mimicked the effects of gp120 in these experiments. These data suggest that the observed decrease in measurable CTL activity is caused by direct or steric hindrance of the CD4-class II major histocompatibility complex interaction between the effector and target cells.

T cell responses to herpes simplex viruses in humans.

Much of the evidence that implicates cytotoxic T lymphocytes (CTLs) in the control of infections due to herpes simplex virus (HSV) is circumstantial. However, the ease of induction of HSV-specific CTLs in vitro, the evidence from clinical observations in humans, and the protection afforded by adoptively transferred CTLs all tend to support an important role for CTLs in the resolution of HSV disease. One salient feature of the response of human CTLs to HSV that has emerged quite clearly is the presence of CD4+ T cells as a predominant killer cell phenotype. Given the importance of CD4+ T cells in mediating delayed type hypersensitivity responses and in clearing local infections on adoptive transfer, this T cell subset probably plays a critical role in the resolution of HSV recrudescent disease. Moreover, it is tempting to speculate that viral agents that impair the function of CD4+ T cells, such as human immunodeficiency virus type 1, may predispose patients to severe local infections.

Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics.

From a prospective cohort study, 24 asymptomatic men were identified who had been antibody positive for human immunodeficiency virus (HIV) for at least 5 years (median = 9.1) with CD4+ lymphocyte counts greater than or equal to 400 cells/mm3. Of these "nonprogressors", 23 (96%) had evidence of HIV infection by either HIV culture or the polymerase chain reaction (PCR) for HIV DNA, although only 1 (4%) had a positive assay for HIV RNA (by PCR) and no one was positive for p24 antigen. Compared with 24 antibody-negative men and 14 men with AIDS, nonprogressors had higher CD8+ counts and lower natural killer cell activity. Nonprogressors had higher beta 2-microglobulin levels than did seronegative controls, suggesting some degree of immune system activation. Compared with men with AIDS, nonprogressors seemed to have a stronger antibody response to six different HIV-related proteins but did not differ significantly in neutralizing antibody or antibody-dependent cellular cytotoxic activity.

Prolonged CD4+ lymphocytopenia and thrombocytopenia in a chimpanzee persistently infected with human immunodeficiency virus type 1.

The immunologic and virologic status of a chimpanzee inoculated with multiple isolates of the human immunodeficiency virus type 1 (HIV-1) were assessed over 57 months to determine whether prolonged thrombocytopenia and CD4+ lymphocytopenia observed in the animal might be associated with long-term HIV infection. Although the chimpanzee showed no signs of disease, it lost both CD4+ (as low as 134 cells/microliter) and CD8+ lymphocytes approximately 30 months after initial infection, followed by thrombocytopenia that has persisted for greater than 2 years. Lymphopenia and thrombocytopenia were preceded by or coincided with the appearance of antibodies cross-reactive with histone H2B and decreased levels of complement component C4; an eightfold decrease in HIV-specific antibody titers; the inability of CD8+ lymphocytes to suppress virus replication; impaired proliferative responses to T cell mitogens; and the isolation of cell-free HIV from plasma. These data suggest that, given sufficient time, HIV-infected chimpanzees may develop disease.

Inhibition of the in vitro generation of class II-restricted, HSV-1-specific, CD4+ CTL by HIV-1.

Previously, we demonstrated that cultures of human peripheral blood lymphocytes (PBL) stimulated with herpes simplex virus type 1 (HSV-1) generate antigen-specific, major histocompatibility complex (MHC) restricted cytotoxic T lymphocytes (CTL) that tend to be CD4+ and restricted to HLA-DR antigens. In this study, we present evidence that when HSV-1 stimulated human peripheral blood lymphocytes (PBL) are cocultured with human immunodeficiency virus type 1 (HIV-1), the generation of CD4+, DR-restricted CTL during the 5-day culture period is inhibited. In contrast, HIV-1 had no effect on either natural killer (NK) activity, or on the unrestricted NK-like killers which are often detected in HSV-1-stimulated cultures after the depletion of CD16+ cells. HIV-1 also failed to inhibit the generation of CTL against Epstein-Barr virus (EBV), a response that principally involves CD8+, CD4-, class I-restricted killers.

CD2 and other surface molecules in the regulation of non-MHC-restricted cytolytic function.

The effect of anti-CD2 and Fc receptor binding molecules on the cytolytic function of a highly enriched population of CD3- large granular lymphocytes (LGL) was studied. These cells could mediate natural killer (NK) activity, antibody-dependent cellular cytotoxicity (ADCC) and lectin-dependent cellular cytotoxicity (LDCC). Both ADCC and LDCC were enhanced by anti-CD2. The enhanced LDCC could also be observed with IL-2-activated LGL. However, NK cell activity was usually slightly diminished or unaffected by anti-CD2 binding. Immune complex and aggregated human IgG had no effect on ADCC but an anti-CD16 showed a dose-dependent inhibition of ADCC, reversible by anti-HLA-ABC and anti-CD2. Cross-linking of LGL surface-bound anti-CD2 caused an almost complete inhibition of LDCC and ADCC but had much less effect on NK activity. These experiments show that ADCC and LDCC mediated by CD3- LGL can be influenced by perturbing the CD2 molecule. NK activity was, however, affected differently, suggesting some basic differences in the pathway of ADCC and NK function.

Evaluation of target cells for HIV-1-specific antibody-dependent cellular cytotoxicity assays.

The T cell line, CEM-E5, acutely and chronically infected with HIV-1, was used as a target cell in a standard 51Cr release HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) assay. CEM-E5, acutely infected with HIV-1, showed peak sensitivity to lysis in an HIV-1 specific ADCC assay on day 9 after infection. CEM-E5 clones, chronically infected with HIV-1, that productively express the virus were better ADCC targets than infected clones that do not express HIV-1. One clone, C5D7, was identified which was particularly sensitive to lysis in the ADCC assay. This cell line grows continually and is stable in culture and appears to be the best target for HIV-1-specific ADCC in our system.

Binding of the human retrovirus HTLV-III/LAV/ARV/HIV to the CD4 (T4) molecule: conformation dependence, epitope mapping, antibody inhibition, and potential for idiotypic mimicry.

Human immunodeficiency virus (HIV), the retrovirus that causes the acquired immunodeficiency syndrome, is cytopathic for CD4+ T cells and binds to these cells via a complex of the 110,000 m.w. viral-envelope glycoprotein, gp110, and the CD4 molecule. We treated virus with several physical, chemical, and enzymic agents to determine their effect on the capacity of HIV to bind to the CD4+ T cell line, CEM. Reduction and alkylation (but not alkylation alone) and trypsin digestion (but not glycolytic enzyme digestions) of HIV destroyed its capacity to bind. If the tertiary protein structure conferred by disulfide bonding is not disrupted, the tertiary and secondary conformations dependent on noncovalent forces appear to be thermodynamically favored, because treatment with denaturants such as sodium dodecyl sulfate, 8 M urea, alcohol, or heat (56 degrees C or 65 degrees C for 30 min) followed by removal of the denaturants did not affect binding. Irreversible denaturation and loss of binding occurred after heating at 100 degrees C for 10 min. HIV binding to CD4+ T cells was inhibited either by murine monoclonal antibodies to the CD4 molecule or by human polyclonal or murine monoclonal antibodies to the gp110 molecule. On the basis of results of binding inhibition obtained with a panel of alpha-CD4 monoclonal antibodies, the receptor site for virus on the CD4 molecule was mapped to the amino-terminal portion of the molecule. Four candidate alpha-CD4 monoclonal antibodies that were potent inhibitors of virus binding (OKT4A, OKT4D, OKT4F, and Leu-3a) were examined for the possibility that their binding sites (idiotopes) might share structural and conformational similarity with the CD4-binding site on gp110. Polyclonal human or rabbit anti-HIV sera (that reacted with gp110 and inhibited virus binding) did not react with or inhibit the binding of these four alpha-CD4 monoclonal antibodies. Conversely, rabbit anti-idiotypic sera raised against each of the four candidate CD4 monoclonal antibodies did not react with virus or inhibit virus binding to CD4+ T cells. Further search or different approaches may yet yield an idiotype that is a structural and conformational "internal image" of the CD4-binding site of virus.