| 1. |
- Ellegård, Rada, et al.
(author)
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Targeting HIV-1 innate immune responses therapeutically
- 2011
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In: Current Opinion in HIV & AIDS. - : Lippincott, Williams and Wilkins. - 1746-630X. ; 6:5, s. 435-443
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Journal article (peer-reviewed)abstract
- Purpose of review less thanbrgreater than less thanbrgreater thanThe early stage of HIV-1 infection is when the virus is most vulnerable, and should therefore offer the best opportunity for therapeutic interventions. This review addresses the recent progress in the understanding of innate immune responses against HIV-1 with focus on the potential targets for prevention of viral acquisition, replication and dissemination. less thanbrgreater than less thanbrgreater thanRecent findings less thanbrgreater than less thanbrgreater thanResearch indicates that the host-derived factor trappin-2/elafin is protective against HIV, whereas semen-derived enhancer of viral infection and defensins 5 and 6 enhance viral transmission. Further, studies suggest that stimulation of TLR4 and inhibition of TLR7-9 pathways may be HIV suppressive. The regulation and function of viral restriction factors tetherin and APOBEC3G have been investigated and a molecule mimicking the premature uncoating achieved by TRIM5 alpha, PF74, has been identified. Chloroquine has been shown to inhibit plasmacytoid dendritic cell activation and suppress negative modulators of T-cell responses. Blockade of HMBG1 has been found to restore natural-killer-cell-mediated killing of infected dendritic cells, normally suppressed by HIV-1. Interestingly, when used as adjuvants, EAT-2 and heat shock protein gp96 reportedly enhance innate immune responses. less thanbrgreater than less thanbrgreater thanSummary less thanbrgreater than less thanbrgreater thanSeveral targets for innate immunity-mediated therapeutics have been identified. Nonetheless, more research is required to unveil their underlying mechanisms and interactions before testing these molecules in clinical trials.
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| 2. |
- Shankar, Esakimuthu, et al.
(author)
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Expression of a Broad Array of Negative Costimulatory Molecules and Blimp-1 in T Cells following Priming by HIV-1 Pulsed Dendritic Cells
- 2011
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In: MOLECULAR MEDICINE. - : Feinstein Institute for Medical Research. - 1076-1551 .- 1528-3658. ; 17:3-4, s. 229-240
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Journal article (peer-reviewed)abstract
- Accumulating evidence indicates that immune impairment in persistent viral infections could lead to T-cell exhaustion. To evaluate the potential contribution of induction of negative costimulatory molecules to impaired T-cell responses, we primed naive T cells with mature monocyte-derived dendritic cells (MDDCs) pulsed with HIV-1 in vitro. We used quantitative real-time polymerase chain reaction and flow cytometry, respectively, to compare the gene and surface-protein expression profiles of naive T cells primed with HIV-pulsed or mock-pulsed DCs. We detected elevated expressions of negative costimulatory molecules, including lymphocyte activation gene-3 (LAG-3). CD160, cytolytic T-lymphocyte antigen-4 (CTLA-4). T-cell immunoglobulin mucin-containing domain-3 (TIM-3), programmed death-1 (PD-1) and TRAIL (tumor necrosis-factor-related apoptosis-inducing ligand) in T cells primed by HIV-pulsed DCs. The PD-1(+) T-cell population also coexpressed TIM-3, LAG-3, and CTLA-4. Interestingly, we also found an increase in gene expression of the transcriptional repressors Blimp-1 (B-lymphocyte-induced maturation protein-1) and Foxp3 (forkhead transcription factor) in T-cells primed by HIV-pulsed DCs; Blimp-1 expression was directly proportional to the expression of the negative costimulatory molecules. Furthermore, levels of the effector cytokines interleukin-2, tumor necrosis factor-alpha and interferon-gamma, and perforin and granzyme B were decreased in T-cell populations primed by HIV-pulsed DCs. In conclusion, in vitro priming of halve T-cells with HIV-pulsed DC leads to expansion of T cells with coexpression of a broad array of negative costimulatory mclecules and Blimp-1, with potential deleterious consequences for T-cell responses.
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