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Abstract: Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host. [Copyright &y& Elsevier]

Abstract: T-regulatory cell (T-reg) frequency is increased in HIV infection and with aging. We evaluated the effect of age on total, memory and naïve T-reg percentages in untreated HIV infection. Older HIV+ subjects had a total T-reg percent that is 2.8% (p =0.02) higher than among younger HIV+, older HIV− and younger HIV− subjects. In HIV+ subjects, the total T-reg percentage is inversely correlated with the lymphocyte proliferative responses to tetanus (r =−0.45, p =0.002) and Candida (r =−0.43, p =0.003) antigens. Similar correlations were seen between memory T-reg percentages and the lymphocyte proliferative response to tetanus and Candida in HIV+ subjects. T-reg percentages did not correlate consistently with markers of immune activation. T-reg percentages are increased in the older HIV+ population and may play a role in the accelerated disease progression seen in older HIV-infected persons. [Copyright &y& Elsevier]

Abstract: The frequency, subsets and activation status of peripheral blood invariant NKT (iNKT) cells were evaluated in pulmonary tuberculosis (TB) patients and in chronically HIV-1-infected subjects. The absolute numbers of iNKT cells were significantly decreased in TB patients and in HIV-1+ individuals who were antiretroviral therapy naive or had detectable viremia despite receiving HAART. iNKT cell subset analysis demonstrated a decreased percentage of CD4+ iNKT cells in HIV-1+ subjects, and a decreased percentage of double negative iNKT cells in TB patients. Peripheral blood iNKT cells from HIV-1+ and TB patients had significantly increased expression of CD69, CD38, HLA-DR, CD16, CD56, and CD62L. The expression of CD25 was significantly increased only on iNKT cells from TB patients. These findings indicate that peripheral blood iNKT cells in these two chronic infections show an up-regulated expression of activation markers, suggesting their role in the immune response to infection. [Copyright &y& Elsevier]

Abstract: We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002), and TLR7/8 (3M-011). Activation and maturation of plasmacytoid dendritic cells (pDC) were measured by evaluating CD86, CD40, and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV+ and HIV− individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV+ individuals. Quantitative assessment of secreted IFN-α and pro-inflammatory cytokines at the single cell level showed that pDC from HIV+ individuals stimulated with TLR7 and TLR7/8 induced IFN-α. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV+ and HIV− individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1. [Copyright &y& Elsevier]

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]

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]