Hela Saidi

Publications (33) View all

• Article: Understanding Factors That Modulate HIV Infection at the Female Genital Tract Mucosae for the Rationale Design of Microbicides.

  Hela Saidi, Mohammad-Ali Jenabian, Laurent Belec
  [show abstract] [hide abstract]
  ABSTRACT: Abstract Women are now becoming the pivot of the epidemiological spread of HIV infection worldwide, especially in developing countries. Therefore, research to develop an efficient microbicide is now a priority for the prevention of HIV-1 acquisition in exposed women. However, recent disappointing failures in microbicide clinical trials revealed major gaps in basic and applied knowledge that hinder the development of effective microbicide formulations. Indeed, the inhibitory power of microbicide molecules may be affected by several physiological and immunological factors present in male and female genital tracts. Furthermore, mucosal crossing of HIV-1 to increase the ability to reach the submucosal target cells (macrophages, lymphocytes, and dendritic cells) may be modulated by supraepithelial factors such as seminal complement components (opsonized HIV-1), by epithelial factors released in the submucosal microenvironment such as antimicrobial soluble factors, cytokines, and chemokines, and by potent intraepithelial and submucosal innate immunity. The design of vaginal microbicide formulations should take into account an understanding of the intimate mechanisms involved in the crossing of HIV through the female genital mucosae, in the context of a mixture of both male and female genital fluids.
  AIDS research and human retroviruses 08/2012; · 2.18 Impact Factor
• Article: Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques.

  Annette E Sköld, Maroof Hasan, Leonardo Vargas, Hela Saidi, Nathalie Bosquet, Roger Le Grand, C I Edvard Smith, Anna-Lena Spetz
  [show abstract] [hide abstract]
  ABSTRACT: TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virus-induced asthma. Strategies to prevent TLR3-mediated pathology are therefore desired. We investigated the effect of single-stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte-derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine-polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA-ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA-ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA-ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNA-ODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. Our results demonstrate that TLR3-triggered immune activation can be modulated by ssDNA-ODNs and provide evidence of dampening proinflammatory cytokine release in the airways of cynomolgus macaques. These findings may open novel perspectives for clinical strategies to prevent or treat inflammatory conditions exacerbated by TLR3 signaling.
  Blood 06/2012; 120(4):768-77. · 9.90 Impact Factor
• Article: HMGB1, an alarmin promoting HIV dissemination and latency in dendritic cells.

  M-L Gougeon, M-T Melki, H Saïdi
  [show abstract] [hide abstract]
  ABSTRACT: Dendritic cells (DCs) initiate immune responses by transporting antigens and migrating to lymphoid tissues to initiate T-cell responses. DCs are located in the mucosal surfaces that are involved in human immunodeficiency virus (HIV) transmission and they are probably among the earliest targets of HIV-1 infection. DCs have an important role in viral transmission and dissemination, and HIV-1 has evolved different strategies to evade DC antiviral activity. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein that can act as an alarmin, a danger signal to alert the innate immune system for the initiation of host defense. It is the prototypic damage-associated molecular pattern molecule, and it can be secreted by innate cells, including DCs and natural killer (NK) cells. The fate of DCs is dependent on a cognate interaction with NK cells, which involves HMGB1 expressed at NK-DC synapse. HMGB1 is essential for DC maturation, migration to lymphoid tissues and functional type-1 polarization of naïve T cells. This review highlights the latest advances in our understanding of the impact of HIV on the interactions between HMGB1 and DCs, focusing on the mechanisms of HMGB1-dependent viral dissemination and persistence in DCs, and discussing the consequences on antiviral innate immunity, immune activation and HIV pathogenesis.
  Cell death and differentiation 01/2012; 19(1):96-106. · 8.24 Impact Factor
• Article: The suppression of immune activation during enfuvirtide-based salvage therapy is associated with reduced CCR5 expression and decreased concentrations of circulating interleukin-12 and IP-10 during 48 weeks of longitudinal follow-up.

  H Carsenti-Dellamonica, H Saïdi, M Ticchioni, F Guillouet de Salvador, J Dufayard Cottalorda, R Garraffo, P Dellamonica, J Durant, M-L Gougeon
  [show abstract] [hide abstract]
  ABSTRACT: It has been suggested that patients who initiate highly active antiretroviral therapy (HAART) late in their course of infection may have suboptimal CD4 T-cell gains, persistent alterations in T-cell subsets and residual inflammation. To address this issue, we carried out a comprehensive 48-week immunological study in HIV-infected patients who had experienced failures of prior therapies, had low CD4 cell counts, and were receiving enfuvirtide-based salvage therapy. Immunological monitoring of peripheral lymphocytes from enfuvirtide-responder patients was performed over a 48-week period. A detailed assessment of immune cell subsets, their activation state [CD38 and human leucocyte antigen (HLA)-DR expression] and homeostasis [activation-induced cell death (AICD) and Ki67 expression], and the expression of co-receptors was performed by flow cytometry. Cytokine and chemokine signatures were assessed using multianalyte profiling technology. Enfuvirtide-based salvage therapy induced a progressive restoration of naïve and central memory CD4 T cells, associated with a decrease in their activation state, suppression of premature priming for AICD and increased expression of Ki67. In addition, a significant decrease in C-C chemokine receptor 5 (CCR5) expression was detected on CD4 T cells, which was strongly correlated with the suppression of immune activation. Changes in circulating proinflammatory molecules occurred; i.e. there were decreases in the concentrations of interleukin (IL)-12, macrophage inflammatory protein MIP-1α, MIP-1β, monokine induced by IFNγ (MIG) and interferon-γ-inducible protein-10 (IP-10). The decline in circulating IL-12 and IP-10 was correlated with both the reduction in the viral load and CD4 T-cell restoration. This study shows that suppression of HIV-1 replication with enfuvirtide-based salvage therapy in patients with low CD4 cell counts may result in an immunological benefit, characterized by the restoration of CD4 T-cell subsets associated with decreased immune activation and suppression of inflammation.
  HIV Medicine 02/2011; 12(2):65-77. · 3.01 Impact Factor
• Article: Combinatorial prevention of HIV transmission in women: the case for a vaginal microbicide.

  Laurent Bélec, Mohammad-Ali Jenabian, Charlotte Charpentier, Hela Saïdi
  [show abstract] [hide abstract]
  ABSTRACT: Women are now becoming pivotal in the epidemiological spread of HIV infection throughout the world, especially in developing countries, where heterosexual transmission accounts for more than 80% of all new HIV infections. Recently, significant but partial successes have occurred in the field of HIV prevention, including male circumcision, preventive HIV vaccines, vaginal microbicides and oral pre-exposure prophylaxis, and there is increasingly widespread access to antiretroviral treatment. However, none of the currently available tools for HIV intervention are sufficiently effective, particularly for women, and all require further development. Among all biomedical approaches, microbicides could hold the greatest hope of curtailing AIDS worldwide, especially if used by women in Africa. Research for an efficacious microbicide constitutes a priority in the global agenda to prevent HIV infection. Finally, the combination of existing partially effective strategies for HIV prevention should be promoted, scaled-up and evaluated.
  Future Microbiology 07/2011; 6(7):731-7. · 3.82 Impact Factor