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Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly active antiretroviral therapy (HAART).In the Women's Interagency HIV Study, 127 HIV-infected women studied pre and post HAART were matched to HIV-uninfected controls. Six semiannual measurements of soluble CD14, tumor necrosis factor (TNF) alfa, soluble interleukin (IL) 2 receptor, IL-6, IL-10, monocyte chemoattractant protein 1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness was measured by B-mode ultrasound.Relative to HIV-uninfected controls, HAART-naive HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P < 0.0001), TNF-α (6.3 vs 3.4 pg/mL, P < 0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P < 0.0001), IL-10 (3.3 vs 1.9 pg/mL, P < 0.0001), monocyte chemoattractant protein 1 (190 vs 163 pg/mL, P < 0.0001), and D-dimer (0.43 vs 0.31 μg/mL, P < 0.01). Elevated biomarker levels declined after HAART. Although most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-α levels remained elevated compared with HIV-uninfected women (+0.8 pg/mL, P = 0.0002). Higher post-HAART levels of soluble IL-2 receptor (P = 0.02), IL-6 (P = 0.05), and D-dimer (P = 0.03) were associated with increased carotid artery intima-media thickness.Untreated HIV infection is associated with abnormal hemostasis (eg, D-dimer), proatherogenic (eg, TNF-α), and antiatherogenic (eg, IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy. [ABSTRACT FROM AUTHOR]

Comments on Grivel and Margolis' research on the cytopathicity of CCR5- and CXCR4-tropic HIV-1. Cytokine modulation of HIV-1 chemokine receptor expression; CD4 cells; Tonsil tissue.

The article presents a study on the characterization of highly active antiretroviral therapy (HAART) in HIV-1 infected children. The study investigated 23 HIV 1-infected children, and 23 uninfected children, examined the frequency of their innate immunocells in blood which was fixed by flow cytometry, and evaluated the functional activity. The result shows that the HIV-1-infected children that are treated with HAART has displayed a decrease in plasmacytoid dendritic cell frequency.

A subset of HIV-infected individuals termed elite controllers (ECs) maintain CD4+ T cell counts and control viral replication in the absence of antiretroviral therapy (ART). Systemic cytokine responses may differentiate ECs from subjects with uncontrolled viral replication or from those who require ART to suppress viral replication. We measured 87 cytokines in four groups of women: 73 ECs, 42 with pharmacologically suppressed viremia (ART), 42 with uncontrolled viral replication (noncontrollers [NCs]), and 48 HIV-uninfected (NEG) subjects. Four cytokines were elevated in ECs but not NCs or ART subjects: CCL14, CCL21, CCL27, and XCL1. In addition, median stromal cell-derived factor-1 (SDF-1) levels were 43% higher in ECs than in NCs. The combination of the five cytokines suppressed R5 and X4 virus replication in resting CD4+ T cells, and individually SDF-1β, CCL14, and CCL27 suppressed R5 virus replication, while SDF-1α, CCL21, and CCL14 suppressed X4 virus replication. Functional studies revealed that the combination of the five cytokines upregulated CD69 and CCR5 and downregulated CXCR4 and CCR7 on CD4+ T cells. The CD69 and CXCR4 effects were driven by SDF-1, while CCL21 downregulated CCR7. The combination of the EC-associated cytokines induced expression of the anti-HIV host restriction factors IFITM1 and IFITM2 and suppressed expression of RNase L and SAMHD1. These results identify a set of cytokines that are elevated in ECs and define their effects on cellular activation, HIV coreceptor expression, and innate restriction factor expression. This cytokine pattern may be a signature characteristic of HIV-1 elite control, potentially important for HIV therapeutic and curative strategies. IMPORTANCE Approximately 1% of people infected with HIV control virus replication without taking antiviral medications. These subjects, termed elite controllers (ECs), are known to have stronger immune responses targeting HIV than the typical HIV-infected subject, but the exact mechanisms of how their immune responses control infection are not known. In this study, we identified five soluble immune signaling molecules (cytokines) in the blood that were higher in ECs than in subjects with typical chronic HIV infection. We demonstrated that these cytokines can activate CD4+ T cells, the target cells for HIV infection. Furthermore, these five EC associated cytokines could change expression levels of intrinsic resistance factors, or molecules inside the target cell that fight HIV infection. This study is significant in that it identified cytokines elevated in subjects with a good immune response against HIV and defined potential mechanisms as to how these cytokines could induce resistance to the virus in target cells. [ABSTRACT FROM AUTHOR]

Problem Identification of the types of cells that produce IL-17 and IL-22 in the genital tract can clarify the roles that these cytokines play in responses to pathogens. Method of study We isolated and stimulated cells from cervical tissue to identify and characterize cytokine-producing cells. Results Upon stimulation of CD3+ CD4+ endocervical cells, 1.6, 3.4, and 1.5% were induced to produce IL-22, IL-17, and both cytokines, respectively. Stimulation of CD3+ CD4+ ectocervical cells resulted in 3.3% IL-22+, 5.5% IL-17+ and 2.6% IL-22+ IL17+ cells. CD45+ CD3- cells had relatively high endogenous levels of cytokine expression that did not increase upon stimulation. Innate lymphoid cells (ILCs) made up 5.7-8% of CD45+ cervical cells and stimulation caused increases in IL-17 and IL-22. Conclusion These studies show that the majority of the CD45+ leukocytes that can be induced to produce IL-22 and IL-17 in cervix are CD3+ CD4+, but ILCs are also present and can make both cytokines. [ABSTRACT FROM AUTHOR]

Abstract: The mechanisms involved in controlling the establishment of HIV-1 infection are not fully understood. In particular, the role of innate immunity in natural resistance exhibited by individuals who are continuously exposed to HIV-1 but remain seronegative (ESN) has not been thoroughly evaluated. We determined the frequency and function of peripheral blood innate immune cells (plasmacytoid and myeloid dendritic cells, monocytes, NK cells, CD3+/CD56+ cells and invariant NKT cells) in ESN, chronically HIV-1-infected and low-risk HIV-1 seronegative individuals. ESN demonstrated a similar frequency of innate immune cells in comparison to controls and a higher frequency of dendritic cells, NK and invariant NKT cells compared to HIV-1-infected subjects. Incubation of mononuclear cells with stimulatory CpG ODN induced CD86 and CD69 up-regulation to a similar degree on innate cells from the three study groups. CpG ODN-stimulated secretion of cytokines was also similar between ESN and controls, while secretion of IFN-α was significantly decreased in HIV-1+ individuals. Importantly, expression of IFN-γ by PMA/Ionomycin-activated CD56bright NK cells and CD3+/CD56+ cells was significantly higher in ESN when compared with controls. The anti-viral effects of IFN-γ are well established, and so our results suggest that IFN-γ production by innate immune cells might be one of the multiple factors involved in controlling the establishment of sexually transmitted HIV-1 infection. [Copyright &y& Elsevier]

Abstract: We measured levels of six cytokines and human immunodeficiency virus (HIV) RNA in saliva from HIV-seropositive individuals and compared salivary cytokine levels in HIV-seropositives and seronegatives. All of the six tested cytokines were detected in saliva although interleukin-1β, interferon-γ and interleukin-10 were detected more frequently (90%, 68% and 61% of samples, respectively) than interleukin-6, tumor necrosis factor-α and tumor necrosis factor-α receptor II (2–17%). There was no significant association between cytokine levels in saliva and plasma suggesting that cytokines were produced locally. Interferon-γ levels were significantly higher in saliva from HIV-seropositives when compared to seronegatives while interleukin-10 levels were lower in seropositive saliva. Interleukin-10 levels were higher in individuals with low CD4 counts in the seropositive group. HIV RNA was detected in 29% of saliva samples from seropositives and there was a significant correlation between saliva and plasma HIV RNA levels. However, HIV RNA levels in saliva were not significantly associated with any of the saliva or plasma cytokine levels or with CD4 cell numbers. This study shows no association between inflammatory cytokine levels and HIV levels in saliva and suggests that saliva HIV levels are more influenced by blood HIV RNA levels than oral inflammation. [Copyright &y& Elsevier]

We measured levels of six cytokines and human immunodeficiency virus (HIV) RNA in saliva from HIV-seropositive individuals and compared salivary cytokine levels in HIV-seropositives and seronegatives. All of the six tested cytokines were detected in saliva although interleukin-1β, interferon-γ and interleukin-10 were detected more frequently (90%, 68% and 61% of samples, respectively) than interleukin-6, tumor necrosis factor-a and tumor necrosis factor-a receptor II (2-17%). There was no significant association between cytokine levels in saliva and plasma suggesting that cytokines were produced locally. Interferon-c levels were significantly higher in saliva from HIV-seropositives when compared to seronegatives while interleukin-10 levels were lower in seropositive saliva. Interleukin-10 levels were higher in individuals with low CD4 counts in the seropositive group. HIV RNA was detected in 29% of saliva samples from seropositives and there was a significant correlation between saliva and plasma HIV RNA levels. However, HIV RNA levels in saliva were not significantly associated with any of the saliva or plasma cytokine levels or with CD4 cell numbers. This study shows no association between inflammatory cytokine levels and HIV levels in saliva and suggests that saliva HIV levels are more influenced by blood HIV RNA levels than oral inflammation. [ABSTRACT FROM AUTHOR]

There is a vigorous change in cytokine response in individuals with HIV infection. Although this is mitigated by highly active antiretroviral therapy (HAART) and natural control of virus, cytokine levels remain perturbed. To identify and investigate serum cytokines that may play a role in control of viremia or immune-related pathogenesis, we compared four groups from the Women’s Interagency HIV Study defined by HIV clinical status: ELITE controllers (viral load <50 copies/ml; n =48), HAART treated (n =43), untreated HIV viremic non-controllers (NC; n =42), and HIV-uninfected (NEG; n =49). Millipore multiplex assays were used to measure 86 cytokines and other soluble mediators in a cross-sectional study; p-values for group comparisons were calculated by Mann–Whitney. There were higher levels of biomarkers in NC compared to NEG, including IP-10, MCP-2, TRAIL, MIG, BCA-1, ITAC-1, MIP-3b and TNF-α (all p <0.005). The NC had decreased levels of additional cytokines, including IL-17 and FGF-2. IL-21, SDF-1α + β, HCC-1, lymphotactin, 6CKine and CTACK were elevated in ELITE compared to NEG or HAART and not in NC. To explore the properties of viremic control of these cytokines, CD8-depleted cells were infected in vitro with CCR5-tropic HIV 81-A or with CXCR4 tropic HIV NL4-3 in the presence of SDF-1, HCC-1, CTACK or in combination of all six cytokines. This showed significant suppression of virus replication for both 81-A (42%, 73%, 66%, 85% respectively) and NL4-3 (69%, 36%, 54%, 97% respectively). In conclusion, in NC compared to NEG women there were higher levels of pro-inflammatory cytokines and lower levels of cytokines required for homeostasis and differentiation. Cytokines that were differentially elevated in the ELITE were used in infectivity studies and showed that these cytokines may play a role in viral blocking and immunological control. The pattern of cytokine levels studied in these groups may provide insights into HIV pathogenesis and control of viremia. [Copyright &y& Elsevier]