Viral sensing at the blood-brain barrier: new roles for innate immunity at the CNS vasculature.

Neurotropic viral infections are a major source of disease worldwide and represent a growing burden to public health. While the central nervous system (CNS) is normally protected from viral infection by the blood-brain barrier (BBB), many viruses are able to cross the BBB and establish CNS infection through processes that largely remain poorly understood. A growing body of recent research has begun to shed light on the viral and host factors that modulate BBB function, contributing to both protective and pathological disease processes. Central to these studies have been the actions of host cytokines and chemokines, which have increasingly been shown to be key regulators of BBB physiology. This review summarizes recent advances in understanding how BBB function governs both viral pathogenesis and host immune responses during neurotropic viral infections.

Incident hypertension in older women and men with or at risk for HIV infection.

OBJECTIVES: Antiretroviral (ARV) therapy has prolonged the life expectancy of HIV-infected persons, increasing their risk of age-associated diseases, including atherosclerosis (AS). Decreased risk of AS has been associated with the prevention and control of hypertension (HTN). We conducted a cohort study of perimenopausal women and older men with or at risk of HIV infection to identify risk factors for incident HTN. METHODS: Standardized interviews, physical examinations, and laboratory examinations were scheduled at 6-month intervals. Interview data included demographics, medical, family, sexual behaviour and drug use histories, and physical activity. RESULTS: There were 330 women and 329 men eligible for inclusion in the study; 27% and 35% of participants developed HTN during a median follow-up period of 1080 and 1071 days, respectively. In gender-stratified analysis, adjusting for traditional HTN risk factors (age, race, body mass index, smoking, diabetes, family history of HTN, alcohol dependence, physical activity and high cholesterol), HIV infection was not associated with incident HTN in women [hazard ratio (HR) 1.31; 95% confidence interval (CI) 0.56, 3.06] or men (HR 1.67; 95% CI 0.75, 3.74). Among HIV-infected women, although exposure to ARVs was not significantly associated with incident HTN (HR 0.72; 95% CI 0.26, 1.99), CD4 T-cell count was positively associated with incident HTN (HR 1.15 per 100 cells/µL; 95% CI 1.03, 1.28). Among physically active HIV-infected men, exposure to ARVs was negatively associated with incident HTN (HR 0.15; 95% CI 0.03, 0.78). CONCLUSIONS: HIV infection was not associated with incident HTN in older men or women. This study provides additional evidence supporting a causal relationship between immune function and incident HTN, which warrants further study.

Abnormal thyroid function in older men with or at risk for HIV infection.

OBJECTIVES: The aim of the study was to evaluate the prevalence of and factors associated with abnormal thyroid function in older men with or at risk for HIV infection. METHODS: A cross-sectional analysis of 636 men > or =49 years old was carried out using data obtained from interviews, from measurements of body mass index (BMI), HIV-1 serology and viral load, CD4 cell count, hepatitis C virus (HCV) assays, thyroid-stimulating hormone (TSH) and free thyroid hormone levels. RESULTS: Participants were 54% black, 57% overweight/obese, 57% HIV seropositive, and 72% HCV seropositive; 38% reported recent cocaine or heroin use. Decreased TSH was found in 56 men (8.8%) and raised TSH in 23 men (3.6%). Only three men had abnormal free thyroxine levels. CONCLUSIONS: Abnormal TSH levels were noted in 12.4% of older men with or at risk for HIV infection, but nearly all reflected subclinical hyperthyroidism or subclinical hypothyroidism.

Body image in older men with or at-risk for HIV infection.

We performed a cross-sectional analysis of factors associated with negative body image among 550 older men with or at-risk for HIV infection, including demographics, depression, illicit drug use, and antiretroviral therapy adherence. Overall, 31 per cent of participants reported negative body image, which was independently associated with increased BMI, self-rated fair/poor health, depression, and erectile dysfunction, but not HIV status. Screening for and treating depression, sexual dysfunction, and obesity in older men should be considered.

Abnormal glucose metabolism among older men with or at risk of HIV infection.

OBJECTIVES: To determine factors associated with diabetes, insulin resistance, and abnormal glucose tolerance in older men with or at risk of HIV infection. METHODS: Diabetes was assessed by self-report in 643 men >or=49 years old with or at risk of HIV infection. In a subset of 216 men without previously diagnosed diabetes [including 90 HIV-uninfected men, 28 HIV-infected, antiretroviral-naive men, 28 HIV-infected men taking non-protease inhibitor (PI)-containing highly active antiretroviral therapy (HAART), and 70 HIV-infected men taking PI-containing HAART], an oral glucose tolerance test with insulin levels was performed. HIV serology, CD4 cell count, weight, height and waist circumference were measured. Antiretroviral use, drug use, family history of diabetes, physical activity and sociodemographic data were obtained using standardized interviews. RESULTS: Of 643 participants, 116 (18%) had previously diagnosed diabetes. With the oral glucose tolerance test, 15 of 216 men (7%) were found to have undiagnosed diabetes and 40 (18%) impaired glucose tolerance. Factors independently associated with previously diagnosed diabetes included use of non-PI-containing HAART, methadone treatment, positive CAGE test for alcoholism, obesity and family history of diabetes. Factors independently associated with greater insulin resistance included waist circumference and heroin use. Factors independently associated with abnormal glucose tolerance (impaired glucose tolerance or diabetes) included age >or=55 years and Hispanic ethnicity. CONCLUSIONS: HIV-infected men with diabetes risk factors should undergo screening for diabetes regardless of HAART use. Interventions targeting modifiable risk factors, including overweight and physical inactivity, are warranted. The potential impact of opiate and alcohol abuse on glucose metabolism should be recognized in clinical care, and addressed in future research studies of HIV-infected persons.

Serum prostate-specific antigen levels in older men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to determine the rate of, and factors associated with, elevated prostate-specific antigen (PSA) levels in older men with or at risk of HIV infection. METHODS: Using a cross-sectional analysis, we interviewed 534 men > or =49 years old at risk for HIV infection on demographics, behaviours and medical history. Laboratory testing included serum PSA level and HIV serology, and T-cell subsets for those who were HIV seropositive. Elevated PSA level was defined as >4.0 ng/mL, and men with elevated PSA levels were referred for urological evaluation. RESULTS: Fifteen per cent of men were white, 55% black, and 23% Hispanic; median age was 53 years (range 49-80 years); 74% were sexually active; 65% currently smoked cigarettes; and 16% had taken androgens. Among 310 HIV-positive men, CD4 counts were >500 cells/microL in 31%, 200-500 cells/microL in 51%, and <200 cells/microL in 19%. Twenty men (4%) had elevated PSA. On univariate analysis, only older age was significantly associated with elevated PSA, and there was no significant difference in the number of men with elevated PSA between HIV-positive and HIV-negative men (nine of 310 vs 11 of 224; P = 0.28). On multivariate analysis, older age remained the only variable associated with elevated PSA level [reference group < or =50 years; adjusted odds ratio (OR(adj)) 1.0 for age 51-60 years; OR(adj) 5.9 (95% confidence interval 1.2-30.1) for age > or =61 years] adjusted for HIV status, family history of prostate cancer, and androgen use. CONCLUSIONS: Among older men, PSA levels increased with age but did not differ by HIV status. The clinical use of PSA levels in older men currently do not need to be modified for those with HIV infection.

Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS.

Human immunodeficiency virus (HIV) infection is characterized by viral entry into the central nervous system (CNS), which is mediated, in part, by the transmigration of HIV-infected monocytes into the brain. The elaboration of chemokines and other factors by these infected cells contributes to CNS inflammation and cognitive impairment in a significant number of HIV-infected individuals. Recently, we demonstrated that HIV-infected monocyte transmigration into the CNS is enhanced greatly by the chemokine CC chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1. Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays an important role in leukocyte transmigration across the endothelium of the systemic vasculature by mediating homophilic interactions between endothelial cells (EC)-EC and EC-leukocytes, thus preserving vessel integrity. The role of PECAM-1 in HIV-infected leukocyte transmigration across the blood brain barrier (BBB) and NeuroAIDS has not been characterized. We demonstrate that in brain tissue from individuals with HIV encephalitis, there is an accumulation of cleaved, soluble forms of the extracellular region of PECAM-1 (sPECAM-1). In addition, HIV-infected individuals have elevated levels of sPECAM-1 in their sera. Our in vitro data demonstrate that HIV-infected leukocytes, when treated with CCL2, shed sPECAM-1, suggesting a mechanism of extracellular PECAM-1 cleavage and release dependent on HIV infection and CCL2. We hypothesize that sPECAM-1 production by HIV-infected leukocytes, resulting in the accumulation of sPECAM-1 within the CNS vasculature and the generation of truncated, intracellular forms of PECAM-1 within leukocytes, alters PECAM-1 interactions between EC-EC and EC-leukocytes, thus contributing to enhanced transmigration of HIV-infected leukocytes into the CNS and changes in BBB permeability during the pathogenesis of NeuroAIDS.

Staphylococcus aureus colonization in a community sample of HIV-infected and HIV-uninfected drug users.

HIV-infected individuals, especially those with a history of injecting drug use, are at high risk of Staphylococcus aureus infection. Moreover, the use of antimicrobial agents for opportunistic infections may increase nasal colonization by antimicrobial-resistant Staphylococcus aureus in this population and, subsequently, levels of infection with multidrug-resistant Staphylococcus aureus in the community. Between February 1999 and March 2000, 500 subjects from a community-based cohort of drug users completed an interview and underwent a physical exam. Risk factors for colonization by Staphylococcus aureus were examined, the antibiotic susceptibility profiles of all strains were determined, and DNA strain analysis was performed. One hundred twenty (24%) subjects had positive Staphylococcus aureus nasal cultures. Only HIV infection and homelessness were associated with Staphylococcus aureus colonization. Ten (8%) isolates were methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus isolates were found more frequently among HIV-infected than HIV-uninfected respondents (14% vs. 3%, P=0.04). Among those colonized and HIV infected, the mean number of resistant isolates was higher for those currently reporting antibiotic use (5.0 vs. 2.3, P<0.001) and for those with CD4+ counts

Regional variation in CCR5-Delta32 gene distribution among women from the US HIV Epidemiology Research Study (HERS).

The CCR5-Delta32 genotype is known to influence HIV-1 transmission and disease. We genotyped 1301 US women of various races/ethnicities participating in the HIV Epidemiologic Research Study. None was homozygous for CCR5-Delta32. The distribution of heterozygotes was similar in HIV-1 infected and uninfected women. Thirty-seven (11.8%) white, 28 (3.7%) blacks/African Americans (AA), seven (3.3%) Hispanics/Latinas, and one (6.6%) other race/ethnicity were heterozygous. The frequency of heterozygotes differed among sites for all races combined (P = 0.001). More heterozygotes were found in AA women in Rhode Island (8.9%) than in the other sites (3.1%) (P = 0.02), while heterozygosity in white women was most common in Maryland (28.6%) (P = 0.025). These regional differences could be accounted for by racial admixture in AAs, but not in whites. Regional variations should be considered when studying host genetic factors and HIV-1 in US populations.

Cancer incidence in women with or at risk for HIV.

The purpose of our study was to identify the types and rates of cancers seen in high-risk human immunodeficiency virus (HIV)-infected and HIV-uninfected women. From 1993 to 1995, 1,310 women enrolled at four urban U.S. research sites in the HIV Epidemiology Research Study and were interviewed biannually to identify interval diagnoses and hospitalizations until study closure in March 2000. Cancer incidence data were collected through abstraction of medical records and death certificates. Of 871 HIV-infected and 439 HIV-uninfected women, 85% had a history of smoking and 50% a history of injection drug use. For our analysis, 4,180 person-years were contributed by HIV-infected women, and 2,308 person-years by HIV-uninfected women. HIV-infected women had 8 non-Hodgkin's lymphomas, 5 invasive cervical cancers (ICC), 1 Kaposi's sarcoma and 12 non-AIDS defining cancers, including 4 lung cancers, compared with 4 cancers in HIV-uninfected women including 1 lung cancer (all cancers, 6.22/1000 person-years vs. 1.73/1000 person-years, p = 0.01). CD4+ cell counts were above 200/mm3 in all women with ICC. HIV-infected women with lung cancer were young smokers (mean age, 40 years), and all died within 6 months of diagnosis. Lung cancer occurred at twice the rate in HIV-infected vs. uninfected women in the cohort and severalfold above expected in age- and race-matched women in U.S. national data (incidence relative risk 6.39; 95% confidence interval 3.71, 11.02; p < 10(-7)). The frequent occurrence of cervical and lung cancers have important implications for the counseling (cigarette cessation), screening (PAP smears) and care of women with HIV infection, as they live longer because of current antiretroviral therapies.

Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase.

Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine and other pyrimidine 2'-deoxyribonucleosides. In addition, TP has been shown to possess angiogenic activity in a number of in vitro and in vivo assays, and its angiogenic activity has been linked to its catalytic activity. A series of 5- and 6-substituted uracil derivatives were synthesized and evaluated for their abilities to inhibit TP activity. Among the most active compounds was a 6-amino-substituted uracil analog, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), which was a competitive inhibitor with a K(i) of 165 nM. The inhibitory activity of AEAC was selective for TP, as it did not inhibit purine nucleoside phosphorylase or uridine phosphorylase at concentrations up to 1 mM. Human recombinant TP induced human umbilical vein endothelial cell (HUVEC) migration in a modified Boyden chamber assay in vitro, and this action could be abrogated by the TP inhibitors. The actions of the inhibitors were specific for TP, as they had no effect on the chemotactic actions of vascular endothelial growth factor (VEGF). HUVEC migration was also induced when TP-transfected human colon and breast carcinoma cells were co-cultured in the Boyden chamber assay in place of the purified angiogenic factors, and a TP inhibitor blocked the tumor cell-mediated migration almost completely. These studies suggest that inhibitors of TP may be useful in pathological conditions that are dependent upon TP-driven angiogenesis.

Influence of injection drug use behavior on reported antiretroviral therapy use among women in the HIV Epidemiology Research study: on-site versus referral care.

BACKGROUND: HIV-infected injection drug users consistently report poor antiretroviral therapy use and little contact with health care providers. It has been suggested that the clinical setting where patients are seen affects the use of highly active antiretroviral therapy. OBJECTIVES: The purpose of this study was to determine whether ease of access to medical care affects self-report of taking antiretroviral therapy, particularly among female injection drug users. DESIGN: The study is a cross-sectional analysis from a prospective cohort study of HIV-infected women. SETTING: Women were enrolled at four sites in the United States: Detroit, Michigan, and Providence, Rhode Island, where on-site HIV care and treatment were offered, and Baltimore, Maryland, and the Bronx, New York, where all participants were referred elsewhere for HIV care and treatment. PATIENTS: Patients were HIV-infected women with no AIDS diagnosis or women who were at risk for HIV infection either through self-reported injection drug use since 1985 or through sexual contact. MEASUREMENTS: The study measured self-reported use of antiretroviral therapy (ART) alone or combined with Pneumocystis carinii (PCP) prophylaxis in the previous 6 months. RESULTS: In multivariate analysis including type of study site (on-site compared with referral care) and injection drug use, any self-reported ART use associated with low CD4 cell count category, older age, and race. However, at on-site care centers, women were equally likely to report ART use regardless of current, former, or no injection drug use, whereas at referral sites only women identified as sexual contacts were more likely to report any ART use, independent of all other variables. CONCLUSIONS: Easy access to medical care has an important impact on HIV-infected women receiving ART, particularly those who are active injection drug users.

Highly active antiretroviral therapy associated with improved anemia among HIV-infected women.

Anemia is common during human immunodeficiency virus (HIV) infection and is associated with increased mortality. We conducted a study to examine the impact of highly active antiretroviral therapy (HAART) on anemia in a multicenter cohort of HIV-positive women, the Human Immunodeficiency Virus Epidemiology Research (HER) Study. Among women receiving HAART (n = 188), non-HAART monotherapy or combination antiretroviral therapy (ART) (n = 111), or who had no reported treatment (n = 62), the prevalence of anemia (hemoglobin, <120 g/L) at baseline was 38.3, 36.9, and 43.6%, respectively (p = 0.58) and at 1-year follow-up was 26.1%, 36.9%, 45.2%, respectively (p = 0.01); mean hemoglobin at baseline was 125 +/- 16, 122 +/- 16, and 122 +/- 18 g/L, respectively (p = 0.29) and at 1-year follow-up was 128 +/- 14, 123 +/- 16, and 119 +/- 20 g/L, respectively (p < 0.0001). Adjusted linear regression models showed that HAART was associated with an increase of hemoglobin of 0.20 g/L per month (p = 0.007). After 1 year of treatment, HAART was associated with a 32% reduction in anemia among HIV-infected women (p = 0.01), whereas there was no significant change in the prevalence of anemia among those on non-HAART ART or those who had no reported treatment. HAART is associated with a large reduction in anemia among HIV-infected women.

Longitudinal analysis of bacterial vaginosis: findings from the HIV epidemiology research study.

OBJECTIVE: To determine the natural history of bacterial vaginosis in women with or at risk for human immunodeficiency virus (HIV). METHODS: A cohort of 854 HIV-infected women and 434 HIV-uninfected women from four US sites was followed prospectively with gynecologic exams every 6 months over a 5-year period. The prevalence, incidence, persistence, and severity of bacterial vaginosis, which was defined using a Gram-staining scoring system, were calculated using generalized estimating equation methods. RESULTS: In adjusted analyses, HIV-infected women had a higher prevalence of bacterial vaginosis than HIV-uninfected women (adjusted odds ratio [OR] 1.29; 95% confidence interval [CI] 1.08, 1.55). Although HIV-infected women were not more likely to have incident infections, they were more likely to have persistence of their infections (adjusted OR 1.49; 95% CI 1.18, 1.89). Similarly, immunocompromised women (CD4+ cell count less than 200 cells/microL) were more likely than HIV-infected women with higher CD4+ cell counts (more than 500 cells/microL) to have prevalent (adjusted OR 1.29; 95% CI 1.03, 1.60) and persistent (adjusted OR 1.38; 95% CI 1.01, 1.91) bacterial vaginosis infections, but not more likely to have incident infections. Immunocompromised women had more severe bacterial vaginosis by both clinical criteria (adjusted OR 1.40; 95% CI 1.08, 1.82) and by Gram-staining criteria (adjusted OR 1.50; 95% CI 1.12, 2.00). CONCLUSIONS: Bacterial vaginosis is more prevalent and persistent among HIV-infected women, particularly among those who are immunocompromised. Immunocompromised women are more likely than HIV-infected women with higher CD4+ cell counts to have severe bacterial vaginosis.

Tampons as a self-administered collection method for the detection and quantification of genital HIV-1.

OBJECTIVE: To assess the detection and quantitation of HIV-1 from tampon eluents in comparison with cervicovaginal lavage (CVL) and plasma specimens from the same women. METHODS: Ninety-seven tampon, 105 CVL, and 104 plasma specimens from 105 HIV-1 seropositive women were analyzed using Version 3 of the Chiron bDNA assay, with sensitivity of 50 HIV-1 RNA copies/ml. Data analyses used McNemar's test, Wilcoxon signed rank test, and Mantel--Haenszel chi-squared and odds ratios with 95% confidence intervals to assess differences in proportions. RESULTS: In women for whom both plasma and genital specimens were available, HIV-1 was detected less frequently in genital specimens: [tampons (33/97, 34%) and CVL (48/104, 46%)] than plasma specimens (86/104, 83%) (P < 0.001 for both plasma versus tampon and for plasma versus CVL). However, the proportion of genital specimens with detectable virus did not differ significantly by collection method (P = 0.14). Among women with detectable virus using both collection methods (n = 23), viral load was similar for tampon eluents (median, 355 copies/ml; range, 52--120,898) and CVL specimens (median, 265 copies/ml; range, 61--35,637;P = 0.88). CONCLUSION: Tampon eluent specimens are slightly less sensitive than CVL specimens in the detection of genital HIV-1, although quantification of viral load, when detectable by both methods, was similar.

SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells.

The chemokine SDF-1 alpha (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1 alpha both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1 alpha are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1 alpha are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through G(alpha i) activation. In conclusion, SDF-1 alpha plays a role in two important processes of granule cell maturation - proliferation and migration - assisting in the achievement of appropriate cell number and position in the cerebellar cortex.

A multicenter study of bacterial vaginosis in women with or at risk for human immunodeficiency virus infection.

BACKGROUND: Bacterial vaginosis is a common gynecologic infection that has been associated with a variety of gynecologic and obstetric complications, including pelvic inflammatory disease, postabortal infection and premature delivery. Recent studies suggest that bacterial vaginosis may increase a woman's risk for human immunodeficiency virus (HIV). We undertook this study to assess whether the prevalence and characteristics of bacterial vaginosis differed according to HIV status in high-risk US women. METHODS: Prevalence of bacterial vaginosis was assessed by Gram's stain and clinical criteria for 854 HIV-infected and 434 HIV-uninfected women enrolled in the HIV Epidemiology Research (HER) Study. Multiple logistic regression techniques were used to determine whether HIV infection independently predicted bacterial vaginosis. RESULTS: Almost half (46%) the women had bacterial vaginosis by Gram's stain. The prevalence of bacterial vaginosis was 47% in the HIV-positive women compared with 44% in the HIV-negative women; this difference was not statistically significant (p = 0.36). After adjustment for other covariates, HIV-positive women were more likely than HIV-negative women to have bacterial vaginosis (odds ratio (OR) 1.31; 95% confidence interval (CI) 1.01-1.70) by Gram's stain but not by clinical criteria (OR 1.16; CI 0.87-1.55). Among HIV-positive women, use of antiretroviral drugs was associated with a lower prevalence of bacterial vaginosis (adjusted OR 0.54; Cl 0.38-0.77). CONCLUSIONS: In this cross-sectional analysis of high-risk US women, HIV infection was positively correlated with bacterial vaginosis diagnosed by Gram's stain.

Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women.

Human immunodeficiency virus (HIV) infection and related immunosuppression are associated with excess risk for cervical neoplasia and human papillomavirus (HPV) persistence. Type-specific HPV infection was assessed at 6-month intervals for HIV-positive and HIV-negative women (median follow-up, 2.5 and 2.9 years, respectively). The type-specific incidence of HPV infection was determined, and risk factors for HPV persistence were investigated by statistical methods that accounted for repeated measurements. HIV-positive women were 1.8, 2.1, and 2.7 times more likely to have high-, intermediate-, and low-risk HPV infections, respectively, compared with HIV-negative women. In multivariate analysis, high viral signal, but not viral risk category, was independently associated with persistence among HIV-positive subjects (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-2.9). Furthermore, persistence was 1.9 (95% CI, 1.5-2.3) times greater if the subject had a CD4 cell count <200 cells/microL (vs. >500 cells/microL). Thus, HIV infection and immunosuppression play an important role in modulating the natural history of HPV infection.

The incidence of tuberculosis in drug users with small tuberculin reaction sizes.

SETTING: In persons infected with the human immunodeficiency virus (HIV), a decreased tuberculin reaction cut-point of > or = 5 mm induration is recommended. OBJECTIVE: To determine tuberculosis risk in non-anergic HIV-infected persons with 5-9 mm tuberculin reactions. DESIGN: A prospective study with semi-annual tuberculin and anergy testing, HIV antibody and T cell subset assays, and active surveillance for tuberculosis. RESULTS: Participants were 572 HIV-seronegative and 241 HIV-seropositive non-anergic drug users. No tuberculosis occurred in HIV-seronegative persons. Tuberculosis incidence among HIV-seropositive drug users was 3.3, 7.7, 0, and 0.34 per 100 person-years in those with tuberculin reaction sizes of > or = 10 mm, 5-9 mm, 1-4 mm, and 0 mm, respectively, and was significantly increased in persons with 5-9 mm induration compared with those with 0-4 mm induration (rate ratio 27.7, 95%CI 2.9-268). Among persons with reaction sizes of 5-9 mm, tuberculosis occurred exclusively in those with CD4+ lymphocyte counts <500/mm3 at the time of their 5-9 mm tuberculin reactions. CONCLUSION: HIV-infected persons with tuberculin reaction sizes of 5-9 mm are at increased risk for tuberculosis compared to non-anergic persons with smaller (0-4 mm) reaction sizes. However, this increased risk may be limited to those with low CD4+ lymphocyte counts at the time of tuberculin testing.

Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction.

Transmembrane B ephrins and their Eph receptors signal bidirectionally. However, neither the cell biological effects nor signal transduction mechanisms of the reverse signal are well understood. We describe a cytoplasmic protein, PDZ-RGS3, which binds B ephrins through a PDZ domain, and has a regulator of heterotrimeric G protein signaling (RGS) domain. PDZ-RGS3 can mediate signaling from the ephrin-B cytoplasmic tail. SDF-1, a chemokine with a G protein-coupled receptor, or BDNF, act as chemoattractants for cerebellar granule cells, with SDF-1 action being selectively inhibited by soluble EphB receptor. This study reveals a pathway that links reverse signaling to cellular guidance, uncovers a novel mode of control for G proteins, and demonstrates a mechanism for selective regulation of responsiveness to neuronal guidance cues.