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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]