Synthesis and Evaluation of 3-Halobenzo[]thiophenes as Potential Antibacterial and Antifungal Agents.

The global health concern of antimicrobial resistance has harnessed research interest to find new classes of antibiotics to combat disease-causing pathogens. In our studies, 3-halobenzo[]thiophene derivatives were synthesized and tested for their antimicrobial activities using the broth microdilution susceptibility method. The 3-halo substituted benzo[]thiophenes were synthesized starting from 2-alkynyl thioanisoles using a convenient electrophilic cyclization methodology that utilizes sodium halides as the source of electrophilic halogens when reacted along with copper(II) sulfate.

A one-pot successive cyclization-alkylation strategy for the synthesis of 2,3-disubstituted benzo[]thiophenes.

In this study, a new environmentally benign iodine-mediated one-pot iodocyclization/alkylation strategy for the synthesis of benzo[b]thiophene derivatives starting from 2-alkynylthioanisoles was developed. The synthesis of a diverse population of 2,3-disubstituted benzo[b]thiophenes was achieved in high yields by employing moderate reaction conditions using 1,3-dicarbonyl substrates as the nucleophile and various substituted propargyl alcohols as both the cyclization precursor and the alkylating agent. This method resulted in the formation of a series of complex structures obtained in a single step.

Nursing students' perceptions of substance abusers: The effect of social status on stigma.

The stigma associated with drug addiction in the U.S. has been found to be a deterrent for individuals seeking treatment (SAMHSA, 2013).

Activation of NK cell granulysin by mycobacteria and IL-15 is differentially affected by HIV.

NK cells play an important role in innate immunity to mycobacteria and are a significant source of the bactericidal effector molecule granulysin. Defects in NK cells have been described in HIV-infected patients, though mechanistic studies have focused on effector molecules relevant to anti-viral, and not anti-bacterial, function. Here we used primary NK cells from healthy human donors and an in vitro system to identify the phenotype of granulysin expressing NK cells, characterize activation stimuli that regulate granulysin, and to study the immediate effects of HIV on innate activation of NK cell granulysin expression.

Recovery of replication-competent residual HIV-1 from plasma of a patient receiving prolonged, suppressive highly active antiretroviral therapy.

The clinical significance of persistent residual viremia in patients on prolonged highly active antiretroviral therapy (HAART) is not clear. Moreover, it remains to be demonstrated whether residual viremia consists of viruses capable of spreading infection in vivo upon termination of therapy. Using residual viral RNAs (vRNAs) isolated from a HAART-treated patient's plasma, we cloned full-length viral genomes and found that most of them could produce infectious, replication-competent HIVs when transfected into TZM-bl cells, suggesting that residual viruses produced in the absence of therapy can initiate fresh cycles of infection and spread in host cells.

Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1.

Immunosuppression following infection with HIV-1 predisposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb. Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood.

HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression.

The establishment and persistence of many chronic infections have been demonstrated to depend on restraint of the vigor of the anti-microbial immune responses by CD4+CD25+ regulatory T (Treg) cells. In HIV-infected individuals, Treg cells suppress both HIV-specific and general CD4+ and CD8+ T cell responses. Increases of CD4+CD25+ Treg cell function during viral infections might be mediated by host-derived pro-inflammatory molecules or directly by viral infection or binding.

Low-level plasma HIVs in patients on prolonged suppressive highly active antiretroviral therapy are produced mostly by cells other than CD4 T-cells.

The cellular source(s) and the clinical significance of persistent low-level viremia, below 50 HIV RNA copies per ml of plasma, achieved in many patients with high adherence to highly active antiretroviral therapy (HAART) remain unclear. Also, it is not clear if residual plasma HIVs during HAART can become predominant populations in the rebounding plasma viral loads after therapy interruption. Since, different HIV quasispecies tend to compartmentalize in various cell types and tissue locations in patients during chronic infection, the phylogenetic relationships between HIV sequences amplified from residual plasma viruses and CD4 T cells of five patients on long-term suppressive therapy were examined.

Apoptosis induced in HIV-1-exposed, resting CD4+ T cells subsequent to signaling through homing receptors is Fas/Fas ligand-mediated.

The hallmark of HIV-1 disease is the gradual disappearance of CD4+ T cells from the blood. The mechanism of this depletion, however, is still unclear. Evidence suggests that lymphocytes die in lymph nodes, not in blood, and that uninfected bystander cells are the predominant cells dying.

A novel in vitro system to generate and study latently HIV-infected long-lived normal CD4+ T-lymphocytes.

Studies of mechanisms of HIV-latency and its reactivation in long-lived resting CD4+ T-lymphocytes in patients have been limited due to the very low frequency of these cells ( approximately 1-10 cells per 10(6) CD4+ T-cells). To circumvent this obstacle, an in vitro culture system for post-activation long-term survival of normal CD4+ T-cells in a quiescent (non-cycling) state was developed and used to generate latently infected, long-lived quiescent CD4+ T-cells from HIV-infected, activated normal CD4+ T-lymphocytes. This yielded a frequency of approximately 5x10(4) latently infected cells per 10(6) cells in culture, which is approximately 10(3)- to 10(4)-fold higher than that available from patients.

Detection of very early antibody to native HIV antigens by HIV neutralization and live-cell immunofluorescence assays.

Very early detection of HIV infection could help decrease the spread of HIV, improve safety of the blood supply, and permit earlier treatment. Early detection was reported when native gp41 antigen was used to detect antibodies that occurred 2-6 weeks earlier than detection of antibodies to denatured antigens by the current EIA or WB tests or detection by the HIV RNA test. We hypothesized that early antibodies to native gp41/160 could be detected, not only by the reported live-cell immunofluorescence (IFA) but also by a neutralization test, since virions as well as HIV-infected cells contain native gp41/160.

Transient or occult HIV infections may occur more frequently than progressive infections: changing the paradigm about HIV persistence.

Evidence of transient HIV infections was found in 8 subjects at high-risk for HIV infection among 47 longitudinally studied over 2-5 (average approximately 3.5) years, whereas only two subjects developed progressive infection. All of these subjects developed serum antibodies (Ab) to conformational epitopes of HIV gp41 (termed "early HIV Ab"), but the 8 transiently infected subjects lost this Ab within 4-18 months, and did not seroconvert to positivity in denatured antigen EIA or Western Blot (WB).

HIV-1 induces IL-10 production in human monocytes via a CD4-independent pathway.

In HIV-infected patients, increased levels of IL-10, mainly produced by virally infected monocytes, were reported to be associated with impaired cell-mediated immune responses. In this study, we investigated how HIV-1 induces IL-10 production in human monocytes. We found that CD14(+) monocytes infected by either HIV-1(213) (X4) or HIV-1(BaL) (R5) produced IL-10, IL-6, tumor necrosis factor-alpha (TNF-alpha), and to a lesser extent, IFN-gamma.

Preventing sexual transmission of HIV: anti-HIV bioregulatory and homeostatic components of commercial sexual lubricants.

Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes.

CD4 lymphocytes in the blood of HIV(+) individuals migrate rapidly to lymph nodes and bone marrow: support for homing theory of CD4 cell depletion.

The mechanism(s) by which human immunodeficiency virus (HIV) causes depletion of CD4 lymphocytes remains unknown. Evidence has been reported for a mechanism involving HIV binding to (and signaling) resting CD4 lymphocytes in lymphoid tissues, resulting in up-regulation of lymph node homing receptors and enhanced homing after these cells enter the blood, and induction of apoptosis in many of these cells during the homing process, caused by secondary signaling through homing receptors. Supportive evidence for this as a major pathogenic mechanism requires demonstration that CD4 lymphocytes in HIV(+) individuals do migrate to lymph nodes at enhanced rates.

Detection of antibodies to human immunodeficiency virus (HIV) that recognize conformational epitopes of glycoproteins 160 and 41 often allows for early diagnosis of HIV infection.

On the basis of human immunodeficiency virus (HIV) needlestick studies, the time to seroconversion for anti-HIV antibodies is 1-9 months (mean, approximately 2-3 months). However, an earlier marker of an immune response to HIV often occurs-serum anti-HIV antibodies reactive with live HIV-infected cells, termed "early HIV antibodies." The specificities of these antibodies are characterized by the recognition of type-specific conformational epitopes of the HIV envelope glycoprotein (gp) 160 and gp41.

Dynamics of naive and memory CD4+ T lymphocytes in HIV-1 disease progression.

Understanding the dynamics of naive and memory CD4+ T cells in the immune response to HIV-1 infection can help elucidate typical disease progression patterns observed in HIV-1 patients. Although infection markers such as CD4+ T-cell count and viral load are monitored in patient blood, the lymphatic tissues (LT) have been shown to be an important viral reservoir. Here, we introduce the first comprehensive theoretical model of disease progression based on T-cell subsets and virus circulating between the two compartments of LT and blood.

Is human immunodeficiency virus RNA load composed of neutralized immune complexes?

During acute human immunodeficiency virus (HIV) infection, both virus load (HIV RNA) and infectivity are high (10(3)-10(7) RNA copies/mL or TCID(50)/mL) until antibody is produced, which may reduce the HIV infectivity. In HIV carriers, the HIV RNA load is elevated (10(3)-10(5) copies/mL), but infectivity is low (10(0)-10(2) TCID(50)/mL). The low infectivity in carriers could be due to neutralization by antibody in serum, resulting in immune complexes (ICs).

How does HIV cause depletion of CD4 lymphocytes? A mechanism involving virus signaling through its cellular receptors.

HIV infection causes an acquired immunodeficiency, principally because of depletion of CD4 lymphocytes. The mechanism by which the virus depletes these cells, however, is not clearly understood. Since the virus predominantly infects CD4 lymphocytes in vivo, some have assumed that HIV replication directly kills the infected cells or that the anti-HIV immune response destroys them.

Practical prevention of vaginal and rectal transmission of HIV by adapting the oral defense: use of commercial lubricants.

HIV is transmitted to 6.4 million human beings per year and the majority of these transmissions are sexual. Condoms are highly effective and are recommended as the primary preventive.

Model of HIV-1 disease progression based on virus-induced lymph node homing and homing-induced apoptosis of CD4+ lymphocytes.

Several proposed theories have described the progression of HIV infection. Even so, no concrete evidence supports any as comprehensive, including, for example, why the CD4+ T-cell counts fall from 1000/mm3 of blood to roughly 100/mm3 over an average 10-year period, whereas concomitant viral loads are relatively constant, increasing by several orders of magnitude in late-stage disease. Here, we develop and validate a theoretical model that altered lymphocyte circulation patterns between the lymph system and blood due to HIV-induced enhanced lymph-node homing and subsequent apoptosis of resting CD4+ T cells can explain many aspects of HIV-1 disease progression.

How does HIV cause AIDS? The homing theory.

The mechanism by which HIV causes depletion of CD4+ T cells in infected individuals remains unknown. Numerous theories have been proposed, but none can fully explain all of the events observed to occur in patients. Recent studies have shown that HIV binding to resting CD4+ T cells upregulates L-selectin, causing the cells to home from the blood into lymph nodes at an enhanced rate.