In vivo expression and localization of Candida albicans secreted aspartyl proteinases during oral candidiasis in HIV-infected patients.
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Isoforms of aspartyl proteinase (Sap), which are encoded by at least nine related SAP genes, have been implicated to be a major virulence factor of the opportunistic yeast Candida albicans in experimental infections. Although it is generally assumed that proteinases are important for infections, detailed information on the pathogenetic role of Saps is still lacking. The same applies to the question whether the genes and corresponding isoforms of the enzyme are expressed during oral infection. For in vivo investigations, parts of the lesional oral epithelium were collected from three HIV-infected patients with oropharyngeal candidiasis. Immunoelectron microscopy was performed (pre- and post-embedding gold labeling with silver enhancement) using an anti-Sap murine monoclonal antibody directed against the gene products Sap1-3. It was possible to demonstrate expression of Sap antigens in each of the three samples of human oral candidiasis. This suggests that at least one of the genes SAP1-3 was expressed at the time of sample collection. Furthermore, a possible role of the enzymes during the interaction of yeast cells and mucosal cells is suggested: the majority of Sap antigens is secreted by those C. albicans cells that adhere directly to the epithelial surface. Sap immunoreactivity can be detected in particular at the site of close contact between C. albicans and epithelial cells, suggesting a pathogenetic role of the Saps in host-fungal interaction. Thus, inhibition of the enzyme might prove to be an important alternative in the prevention and treatment of candidiasis. (+info)
Safer sex strategies for women: the hierarchical model in methadone treatment clinics.
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Women clients of a methadone maintenance treatment clinic were targeted for an intervention aimed to reduce unsafe sex. The hierarchical model was the basis of the single intervention session, tested among 63 volunteers. This model requires the educator to discuss and demonstrate a full range of barriers that women might use for protection, ranking these in the order of their known efficacy. The model stresses that no one should go without protection. Two objections, both untested, have been voiced against the model. One is that, because of its complexity, women will have difficulty comprehending the message. The second is that, by demonstrating alternative strategies to the male condom, the educator is offering women a way out from persisting with the male condom, so that instead they will use an easier, but less effective, method of protection. The present research aimed at testing both objections in a high-risk and disadvantaged group of women. By comparing before and after performance on a knowledge test, it was established that, at least among these women, the complex message was well understood. By comparing baseline and follow-up reports of barriers used by sexually active women before and after intervention, a reduction in reports of unsafe sexual encounters was demonstrated. The reduction could be attributed directly to adoption of the female condom. Although some women who had used male condoms previously adopted the female condom, most of those who did so had not used the male condom previously. Since neither theoretical objection to the hierarchical model is sustained in this population, fresh weight is given to emphasizing choice of barriers, especially to women who are at high risk and relatively disempowered. As experience with the female condom grows and its unfamiliarity decreases, it would seem appropriate to encourage women who do not succeed with the male condom to try to use the female condom, over which they have more control. (+info)
Clonal dominance patterns of CD8 T cells in relation to disease progression in HIV-infected children.
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CD8 T cells are important mediators of cellular immune responses as evidenced by clonal expansions in the CD8 TCR V beta repertoire during primary HIV infection in adults. This study investigated the CD8 TCR V beta repertoire by complementarity-determining region 3 length analysis using multiplex PCR in purified peripheral blood CD8 T cells of 22 HIV-infected children (age range was 0.75-15 yr, mean was 8.2 +/- 4.1 yr). Evidence of clonal dominance in one or more V beta families was obtained in 15 of 22 children. The patterns of clonal dominance were designated as major, minor, single, and none to indicate the involvement of three or more, two, one, or no V beta families, respectively. A pattern of major or minor clonal dominance was observed in 12 children (group 1), whereas 10 children had single or no clonal dominance (group 2). In comparison with group 2, the children in group 1 had a higher percentage of CD4 cells (28.3 +/- 11.6 vs 8.6 +/- 4.8, p < 0.001); a higher stimulation index in lymphoproliferative responses to Candida (92.0 +/- 59.5 vs 12.3 +/- 14.4, p = 0.002), tetanus (76.3 +/- 51.2 vs 11.2 +/- 12.7, p = 0.002), and alloantigens (178.3 +/- 298.9 vs 32.9 +/- 35.2, p < 0.001); and a lower percentage of CD8+HLA-DR+CD38+ cells (37.4 +/- 13.1 vs 54.6 +/- 14.2, p < 0.01). The number of dominant CD8 T cell clones was significantly correlated with the percentage of CD4 T cells (r = 0.669, p < 0.001) but not with plasma HIV RNA. Compared with group 1, patients in group 2 had a 4.8 times greater probability of having < 15% CD4 cells. These findings indicate that CD8 clonal dominance in HIV-infected children reflects robustness of immune responses, regardless of time since infection and virus load. (+info)
Differential effects of CD40 ligand/trimer stimulation on the ability of dendritic cells to replicate and transmit HIV infection: evidence for CC-chemokine-dependent and -independent mechanisms.
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The role of exogenous stimulation of CD40 by CD40 ligand (CD40L) in dendritic cell (DC) maturation, CC-chemokine production, and CCR5 receptor expression was examined using a soluble trimeric CD40L agonist protein (CD40LT). Stimulation of monocyte-derived DCs with CD40LT enhanced the production of the CC-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES and diminished surface expression of CCR5. Based on these findings, the functional role of CD40LT stimulation on the ability of DCs to replicate and transmit HIV viral infection was studied. The addition of CD40LT to cocultures of naive CD4+ T cells and autologous DCs (T/DC) infected with the macrophage-tropic isolate, HIVBaL, caused a striking reduction in reverse transcriptase (RT) activity after 10 and 14 days of culture. The addition of a mixture of Abs against CC-chemokines abrogated the decrease in RT activity, demonstrating that the inhibitory effect mediated by CD40LT was CC-chemokine-dependent. In contrast, the presence of CD40LT in T/DC cocultures infected with the T cell-tropic isolate, HIV IIIB, caused an increase in RT activity that was CC-chemokine-independent. Of note, CD40LT stimulation also inhibited RT activity in cultures containing macrophage-tropic virus (HIVBaL)-infected DC only. However, in contrast to the results seen in the T/DC cocultures, CD40LT stimulation inhibited RT activity in cultures of DCs alone in a CC-chemokine-independent manner. Together, these results show that CD40LT stimulation of DCs suppresses HIV replication and transmission to CD4+ T cells by two potentially different mechanisms. (+info)
Kinetics of the changes of lymphocyte subsets defined by cytokine production at single cell level during highly active antiretroviral therapy for HIV-1 infection.
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The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets. (+info)
Studies of human immunodeficiency virus type 1 mucosal viral shedding and transmission in Kenya.
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If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures. (+info)
Transmission of human immunodeficiency virus type 1 through breast-feeding: how can it be prevented?
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One-third to two-thirds of maternal transmission of human immunodeficiency virus type 1 (HIV-1) infection to breast-fed infants can be attributed to ingestion of breast milk. The presence of HIV-1 as cell-free and as cell-associated virus in milk has been documented. Several substances in breast milk may be protective against transmission, including maternal anti-HIV antibodies, vitamin A, lactoferrin, and secretory leukocyte protease inhibitor. The portal of virus entry in the infant's gastrointestinal tract is unknown but may involve breaches in mucosal surfaces, transport across M cells, or direct infection of other epithelial cells, such as enterocytes. Timing of transmission of HIV-1 during lactation should be further clarified. An early rebound of plasma viremia after withdrawal of antiretrovirals was recently detected. This rebound may reduce the benefit of antiretroviral prophylaxis when women breast-feed their infants. Interventions should be viewed from the public health perspective of risks of infant morbidity and mortality associated with breast-feeding versus risks from formula-feeding. (+info)
T cell-tropic simian immunodeficiency virus (SIV) and simian-human immunodeficiency viruses are readily transmitted by vaginal inoculation of rhesus macaques, and Langerhans' cells of the female genital tract are infected with SIV.
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Intravaginal inoculation with T cell-tropic molecular clones of simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) or some dual-tropic strains of SIV or SHIV produced systemic infection in rhesus macaques. Vaginal inoculation with other dual-tropic molecular clones of SIV or SHIV did not infect rhesus macaques even after multiple inoculations. While in vitro measures of macrophage tropism do not predict which primate lentiviruses will produce systemic infection after intravaginal inoculation, the level to which a virus replicates in vivo after intravenous inoculation does predict the outcome of intravaginal inoculation. Another series of studies, using combined in situ hybridization and immunolabeling to simultaneously detect SIV RNA and identify the immunophenotype of infected cells, demonstrated that a large proportion (approximately 40% in some animals) of the SIV-infected cells in the vagina and cervix were Langerhans' cells. This is the first in vivo demonstration that Langerhans' cells in the genital tract are infected with SIV and that dendritic cells are significant reservoirs for lentiviruses. (+info)