Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis [published erratum appears in Blood 1989 Jun;73(8):2232]

B-chronic lymphocytic leukemia (CLL) patients frequently suffer from moderate to severe hypogammaglobulinemia. This complication is a serious cause of morbidity and mortality in this disorder. There is recent evidence that natural killer (NK) cells modulate B-cell immunoglobin (Ig) synthesis/secretion. The authors therefore evaluated the circulating NK cells from B-CLL patients on their ability to regulate mitogen-induced B-cell Ig synthesis. Blood, NK cells (CD16+, CD3-) from three B-CLL patients with hypogammaglobulinemia were able to clearly down-regulate the pokeweed mitogen (PWM)-induced-B-cell Ig secretion. In contrast, CD16+, CD3- cells from age-sex-matched controls or B-CLL patients with normal Ig were either nonregulatory or enhanced mitogen-induced B-cell Ig secretion. An alternative explanation for hypogammaglobulinemia in B-CLL patients is the immunomodulation of B- cell Ig production/secretion by CD16+, CD3- blood cells.     

HIV-1 prophylactic vaccine comprised of topical DermaVir prime and protein boost elicits cellular immune responses and controls pathogenic R5 SHIV162P3

Topical DNA vaccination (DermaVir) facilitates antigen presentation to naive T cells. DermaVir immunization in mice, using HIV-1 Env and Gag, elicited cellular immune responses. Boosting with HIV-1 gp120 Env and p41 Gag augmented Th1 cytokine levels. Intramuscular DNA administration was less efficient in priming antigen-specific cytokine production and memory T cells. In rhesus macaques, DermaVir immunization induced Gag- and Env-specific Th1 and Th2 cytokines and generation of memory T cells. Boosting of DermaVir-primed serum antibody levels was noted following gp140(SHIV89.6P)/p27(SIV) immunization. Rectal challenge with pathogenic R5-tropic SHIV162P3 resulted in control of plasma viremia (4/5 animals) that was reflected in jejunum, colon and mesenteric lymph nodes. An inverse correlation was found between Gag- and Env-specific central memory T cell responses on the day of challenge and plasma viremia at set point. Overall, the topical DermaVir/protein vaccination yields central memory T cell responses and facilitates control of pathogenic SHIV infection.     

Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine

Recent evidence supports the contribution of a multidrug efflux mechanism to fluoroquinolone resistance in Streptococcus pneumoniae. In this paper I show that reserpine, an inhibitor of multidrug transporters in gram-positive bacteria, dramatically suppresses the in vitro emergence of ciprofloxacin-resistant variants of S. pneumoniae, suggesting that the combination of a fluoroquinolone with an inhibitor of multidrug transport may help preserve the efficacy of this class of antibiotics.     

Patterns of HIV-1 evolution in individuals with differing rates of CD4 T cell decline

Evolution of HIV-1 env sequences was studied in 15 seroconverting injection drug users selected for differences in the extent of CD4 T cell decline. The rates of increase of either sequence diversity at a given visit or divergence from the first seropositive visit were both higher in progressors than in nonprogressors. Viral evolution in individuals with rapid or moderate disease progression showed selection favoring nonsynonymous mutations, while nonprogressors with low viral loads selected against the nonsynonymous mutations that might have resulted in viruses with higher levels of replication. For 10 of the 15 subjects no single variant predominated over time. Evolution away from a dominant variant was followed frequently at a later time point by return to dominance of strains closely related to that variant. The observed evolutionary pattern is consistent with either selection against only the predominant virus or independent evolution occurring in different environments within the host. Differences in the level to which CD4 T cells fall in a given time period reflect not only quantitative differences in accumulation of mutations, but differences in the types of mutations that provide the best adaptation to the host environment.     

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

Background

Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel^®) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model.

Methods

Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs.

Results

Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected).

Conclusion

These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV.

     

Conditional reduction of human immunodeficiency virus type 1 replication by a gain-of-herpes simplex virus 1 thymidine kinase function.

The development of an effective vaccine for human immunodeficiency virus type 1 (HIV-1) would be a major advance toward controlling the AIDS pandemic. Several disparate strategies for a safe and effective HIV vaccine have been proposed. Recent data suggest that loss-of-function live-attenuated virus could be a safe lentivirus vaccine. Here, we propose a gain-of-function approach that can complement loss-of-function in enhancing the safety profile of a live-attenuated virus. We describe an example in which ganciclovir (GCV) was used to treat effectively nef(-)HIV-1 engineered to express herpes simplex virus (HSV-1) thymidine kinase (TK). This treatment was found to be highly efficient in controlling HIV-1 spread in tissue culture and in a small animal (hu-PBL-SCID) model. We demonstrate that one distinct advantage of GCV-HSV-TK treatment is the elimination of integrated proviruses, a goal not easily achieved with other antiretrovirals.     

Host induced alteration of avian sarcoma virus B-77 genome.

The genome of an avian oncornavirus was altered after infection of a heterologous host. This was studied with avian sarcoma virus B-77 in duck embryonic fibroblasts (DEF) and chicken embryonic fibroblasts (CEF). To detect alteration of the viral genome, we hybridized 35S B-77 RNA with normal duck DNA by either one of two techniques:when viral RNA was in excess and when DNA was in excess. The RNA of B-77 passaged only in gs minus chf minus CEF does not have homology with duck DNA. However, after several passages of B-77 through DEF the viral genome acquired duck specific RNA sequences. After 4 and 10 passages, B-77 RNA acquired 2.2 and 6.6%, respectively, complementarity to normal duck DNA. The duck specific RNA sequences were found to be covalently linked to the B-77 RNA genome. Also, the host specific sequences acquired by the virus appear to be from a region of the duck DNA which is repeated four to six times per cell. After 5 back passages in CEF some of the duck specific RNA sequences in the viral genome were lost.     

Innervation Patterns May Limit Response to Endovascular Renal Denervation

Background

Renal denervation is a new interventional approach to treat hypertension with variable results.

Objectives

The purpose of this study was to correlate response to endovascular radiofrequency ablation of renal arteries with nerve and ganglia distributions. We examined how renal neural network anatomy affected treatment efficacy.

Methods

A multielectrode radiofrequency catheter (15 W/60 s) treated 8 renal arteries (group 1). Arteries and kidneys were harvested 7 days post-treatment. Renal norepinephrine (NEPI) levels were correlated with ablation zone geometries and neural injury. Nerve and ganglion distributions and sizes were quantified at discrete distances from the aorta and were compared with 16 control arteries (group 2).

Results

Nerve and ganglia distributions varied with distance from the aorta (p < 0.001). A total of 75% of nerves fell within a circumferential area of 9.3, 6.3, and 3.4 mm of the lumen and 0.3, 3.0, and 6.0 mm from the aorta. Efficacy (NEPI 37 ng/g) was observed in only 1 of 8 treated arteries where ablation involved all 4 quadrants, reached a depth of 9.1 mm, and affected 50% of nerves. In 7 treated arteries, NEPI levels remained at baseline values (620 to 991 ng/g), ≤20% of the nerves were affected, and the ablation areas were smaller (16.2 ± 10.9 mm²) and present in only 1 to 2 quadrants at maximal depths of 3.8 ± 2.7 mm.

Conclusions

Renal denervation procedures that do not account for asymmetries in renal periarterial nerve and ganglia distribution may miss targets and fall below the critical threshold for effect. This phenomenon is most acute in the ostium but holds throughout the renal artery, which requires further definition.     

Effects of the It’s Your Game . . . Keep It Real Program on Dating Violence in Ethnic-Minority Middle School Youths: A Group Randomized Trial

Objectives. We examined whether It’s Your Game . . . Keep It Real (IYG) reduced dating violence among ethnic-minority middle school youths, a population at high risk for dating violence.Methods. We analyzed data from 766 predominantly ethnic-minority students from 10 middle schools in southeast Texas in 2004 for a group randomized trial of IYG. We estimated logistic regression models, and the primary outcome was emotional and physical dating violence perpetration and victimization by ninth grade.Results. Control students had significantly higher odds of physical dating violence victimization (adjusted odds ratio [AOR] = 1.52; 95% confidence interval [CI] = 1.20, 1.92), emotional dating violence victimization (AOR = 1.74; 95% CI = 1.36, 2.24), and emotional dating violence perpetration (AOR = 1.58; 95% CI = 1.11, 2.26) than did intervention students. The odds of physical dating violence perpetration were not significantly different between the 2 groups. Program effects varied by gender and race/ethnicity.Conclusions. IYG significantly reduced 3 of 4 dating violence outcomes among ethnic-minority middle school youths. Although further study is warranted to determine if IYG should be widely disseminated to prevent dating violence, it is one of only a handful of school-based programs that are effective in reducing adolescent dating violence behavior.Adolescent dating violence is a serious public health concern in the United States. National estimates indicate that almost 10% of high school youths (9th–12th graders) are victims of physical dating violence,1 and more than 20% are victims of emotional dating violence.2 In addition to being associated with many negative health outcomes (i.e., substance abuse, suicide, depression, and sexual activity),3–8 adolescent dating violence may be predictive of intimate partner violence in adulthood,8–10 which has exceedingly high economic costs (particularly those related to health care).11 Thus, preventing adolescent dating violence may not only protect youths from severe health consequences, but also reduce the short- and long-term health costs associated with this type of violence.Although most research on adolescent dating violence focuses on high school youths, recent studies indicate that adolescent dating violence begins in middle school.12–14 For example, in a survey of seventh graders from diverse geographic locations, 37% reported being victims of psychological dating violence, and 15% reported being victims of physical dating violence in the last 6 months.14 Furthermore, there is mounting evidence that dating violence disproportionately affects ethnic-minority middle school youths. For instance, in a sample of multiethnic sixth graders from 4 US states, approximately one third of Hispanics and African Americans with a history of dating each reported physical dating violence perpetration, compared with only 14% of Whites.15 A similar racial/ethnic pattern emerged for physical dating violence victimization. Thus, it is becoming increasingly evident that dating violence is prevalent among middle school youths, especially among those who belong to ethnic-minority groups.Adolescent dating violence prevention programs are available, but only a few have been rigorously evaluated. Of these, only 2 school-based programs—Safe Dates and Fourth R: Skills for Youth Relationships (Fourth R)—have been shown to produce significant behavioral effects: both reduced dating violence perpetration or victimization.16–18 However, these programs may not be as effective in ethnic-minority middle school youths because they were developed for and evaluated in older, predominantly White youths. Of the relatively fewer dating violence programs developed for and evaluated in ethnic-minority youths, most have been shown to produce either no19 or inconsistent20 behavioral effects, or have been limited by a weak study design (i.e., lack of control group).21,22 Thus, there is a need for rigorously evaluated, effective dating violence prevention programs16 that specifically target younger, ethnic-minority youths.It’s Your Game…Keep It Real (IYG) is a health education program designed to delay sexual behavior and promote healthy dating relationships in ethnic-minority middle school youths. It is based on the premise that healthy relationships are foundational to healthy adolescent sexual health. In 2 previous randomized controlled trials, IYG was shown to be effective in delaying sexual initiation and reducing other sexual risk behaviors.23,24 An additional research question was whether IYG had an impact on emotional and physical dating violence perpetration and victimization. Thus, our goal was to determine if IYG reduces dating violence behavior among ethnic-minority middle school youths. We hypothesized that, by ninth grade, students who did not receive IYG would report more physical and emotional dating violence perpetration and victimization than students who did receive IYG.