The orientation of HIV-1 gp120 binding to the CD4 receptor differentially modulates CD4+ T cell activation.

Progressive quantitative and qualitative decline of CD4(+) T cell responses is one hallmark of HIV-1 infection and likely depends on several factors, including a possible contribution by the HIV-1 envelope glycoprotein gp120, which binds with high affinity to the CD4 receptor. Besides virion-associated and cell-expressed gp120, considerable amounts of soluble gp120 are found in plasma or lymphoid tissue, predominantly in the form of gp120-anti-gp120 immune complexes (ICs). Because the functional consequences of gp120 binding to CD4(+) T cells are controversially discussed, we investigated how gp120 affects TCR-mediated activation of human CD4(+) T cells by agonistic anti-CD3 mAb or by HLA class II-presented peptide Ags. We show that the spatial orientation of gp120-CD4 receptor binding relative to the site of TCR engagement differentially affects TCR signaling efficiency and hence CD4(+) T cell activation. Whereas spatially and temporally linked CD4 and TCR triggering at a defined site promotes CD4(+) T cell activation by exceeding local thresholds for signaling propagation, CD4 receptor engagement by gp120-containing ICs all around the CD4(+) T cell undermine its capacity in supporting proximal TCR signaling. In vitro, gp120 ICs are efficiently captured by CD4(+) T cells and thereby render them hyporesponsive to TCR stimulation. Consistent with these in vitro results we show that CD4(+) T cells isolated from HIV(+) individuals are covered with ICs, which at least partially contain gp120, and suggest that IC binding to CD4 receptors might contribute to the progressive decline of CD4(+) T cell function during HIV-1 infection.

Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies.

To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.

Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy.

Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8(+) T-cell function; in contrast, CD8(+) T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8(+) T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8(+) T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8(+) T-cell dysfunction. Under viremic conditions, HIV-specific CD8(+) T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8(+) T cells was gradually restored, IL-7Ralpha and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8(+) T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8(+) T cells.

Prevalence of non-communicable diseases and access to care among non-camp Syrian refugees in northern Jordan.

BACKGROUND: Tackling the high non-communicable disease (NCD) burden among Syrian refugees poses a challenge to humanitarian actors and host countries. Current response priorities are the identification and integration of key interventions for NCD care into humanitarian programs as well as sustainable financing. To provide evidence for effective NCD intervention planning, we conducted a cross-sectional survey among non-camp Syrian refugees in northern Jordan to investigate the burden and determinants for high NCDs prevalence and NCD multi-morbidities and assess the access to NCD care. METHODS: We used a two-stage cluster design with 329 randomly selected clusters and eight households identified through snowball sampling. Consenting households were interviewed about self-reported NCDs, NCD service utilization, and barriers to care.We estimated the adult prevalence of hypertension, diabetes type I/II, cardiovascular- and chronic respiratory conditions, thyroid disease and cancer and analysed the pattern of NCD multi-morbidities. We used the Cox proportional hazard model to calculate the prevalence ratios (PR) to analyse determinants for NCD prevalence and logistic regression to determine risk factors for NCD multi-morbidities by calculating odds ratios (ORs). RESULTS: Among 8041 adults, 21.8%, (95% CI: 20.9-22.8) suffered from at least one NCD; hypertension (14.0, 95% CI: 13.2-14.8) and diabetes (9.2, 95% CI: 8.5-9.9) were the most prevalent NCDs. NCD multi-morbidities were reported by 44.7% (95% CI: 42.4-47.0) of patients. Higher age was associated with higher NCD prevalence and the risk for NCD-multi-morbidities; education was inversely associated.Of those patients who needed NCD care, 23.0% (95% CI: 20.5-25.6) did not seek it; 61.5% (95% CI: 54.7-67.9) cited provider cost as the main barrier. An NCD medication interruption was reported by 23.1% (95% CI: 20-4-26.1) of patients with regular medication needs; predominant reason was unaffordability (63.4, 95% CI: 56.7-69.6). CONCLUSION: The burden of NCDs and multi-morbidities is high among Syrian refugees in northern Jordan. Elderly and those with a lower education are key target groups for NCD prevention and care, which informs NCD service planning and developing patient-centred approaches.Important unmet needs for NCD care exist; removing the main barriers to care could include cost-reduction for medications through humanitarian pricing models. Nevertheless, it is still essential that international donors agencies and countries fulfill their commitment to support the Syrian-crisis response.

GeneXpert for TB diagnosis: planned and purposeful implementation.

Xpert MTB/RIF is a major advance for TB diagnostics, especially for multidrug-resistant (MDR) TB and HIV-associated TB. But implementation concerns including cost, technical support requirements, and challenging demands of providing second-line TB drugs for diagnosed MDR-TB cases call for gradual, careful introduction based on country circumstances.

HIV-1 replication activates CD4+ T cells with specificities for persistent herpes viruses.

Hyperactivation of CD4+ T cells is a hallmark of untreated HIV-1 infection. The antigenic specificities of activated CD4+ T cells and the underlying mechanisms leading to their activation remain thus far elusive. We report here that during HIV rebound the dynamics of HIV-specific CD4+ T cells is highly correlated with the dynamics of CD4+ T cells specific for persistent antigens derived from various members of the herpes virus family, whereas CD4 responses towards non-persistent antigens were unaffected by HIV replication. Notably, the dynamics of HIV and herpes viral antigen-specific CD4+ T cells responses correlated with the expression level of activation markers on dendritic cells (DCs) and activated DCs were more potent in restimulating memory T cells. These data strongly suggest that HIV replication costimulates activation of CD4+ T cells specific for persistent herpes viral antigens via activation of DCs. We propose that a large proportion of activated T cells during untreated HIV infection may be specific for herpes viral antigens and identify a novel mechanism contributing to chronic immune activation in untreated HIV-1 infection.

Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection.

In persistent viral infections, the host's immune system is challenged by the constant exposure to antigen, potentially causing continuous activation of CD8(+) T cells with subsequent immunopathology. Here we demonstrate, for experimental chronic lymphocytic choriomeningitis virus and human HIV infection, that upon prolonged in vivo exposure to antigen, TCR-triggered Ca(2+) flux, degranulation, and cytotoxicity are maintained on a cellular level, whereas cytokine production is severely impaired because of a selective defect in activation-induced NFAT nuclear translocation. During chronic infection, this differential regulation of pathways leading to diverse effector functions may allow CD8(+) T cells to sustain some degree of local viral control by direct cytotoxicity while limiting systemic immune pathology by silencing cytokine production.

Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection.

Isolated primary human cells from different donors vary in their permissiveness-the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4(+) CD45RO(+) CD57(-) T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.