title: Could DNA-reactive B lymphocytes be activated through HIV-1 DNA-stimulation involving BCR/TLR-9 pathway to yield antibodies targeting viral DNA?
abstract: This paper discusses potential avenues to abate the last bulwark to the HIV-1 eradication i.e. viral reservoirs in the body, consisting mainly of viral DNA hidden, in latent form, into long-lived memory CD4+ T-cells, resulting unaffected by either drugs or immune system. Activation of the innate immune system is necessary for the induction of adaptive immune responses against invading pathogens. In part, this is achieved by recognition of molecules associated with infection by a plethora of pattern recognition receptors comprising Toll-like receptors (TLRs) which are express on numerous cells of immune system such as, dendritic cells and B cells, and are activated by some TLR ligands. TLR-9, localized in endosomal compartment, specifically recognizes unmethylated oligonucleotide sequences containing CpG motifs which are particularly abundant in microbial genome, including HIV-1 DNA. Naïve B cells are activated following antigen binding to the B cell receptor (BCR). The complex antigen/BCR, internalises and synergises with TLR leading to hyper activation of B cells and antibodies production. Cross-link of the BCR with TLR9, followed by upregulation of TLR-9, in response to self DNA-containing antigens, on DNA-specific B lymphocytes lead to the development of DNA-specific autoantibodies. This occur in systemic autoimmune disorders, such as, systemic lupus erythematosus (SLE). Although such DNA-specific B lymphocytes, are usually present in B cell repertoire at low frequency, they normally do not produce autoantibodies, they can be activated by antigen BCR ligation, with plasmacytoid dendritic cells (pDCs) providing helper signals. The hypothesis here derives by insight that stimulation of BCR, by exogenously added HIV-1 DNA, on potentially reactive HIV-1 DNA-specific B cells, from HIV-1 and/or HIV-1/SLE patients, co-cultured with autologous viral DNA-stimulated pDCs, could lead to desirable in vitro production of antibodies direct against HIV-1 DNA by involving BCR/TLR9 pathway. These antibodies, suitably delivered into infected or uninfected CD4(+) T-cells, by a carrier, such as, peptide transduction domain of Tat, could selectively recognize viral nucleic acid, rich in CpG motifs, respect to host DNA, both in productively than latently infected T cells. Because HIV-1 DNA into latently infected cells is heavily methylated and deacetylated, co-treatment with a small molecule inhibitor of DNA methylation, such as 5-aza-2'-deoxycytidine (aza-Cdr), and histone deacetylase inhibitors (HDACi), they would favor higher accessibility by antibodies to viral DNA, which is harbored into human chromosomes. The in vitro production of anti-HIV-1 DNA antibodies and their in vivo reintroduction, could find future application as interesting strategy to pave the way to an eventual cure to decrease and/or eliminate viral reservoirs from the body, and providing possible therapeutic applications not only for HIV-1/AIDS, but also for other infectious diseases.
authors.affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome 00161, Italy. Electronic address: sandro.norelli@iss.it.
authors.forename: Sandro
authors.initials: S
authors.lastname: Norelli
mesh_terms: D056704:Adaptive Immunity; D000906:Antibodies / Q000737:chemistry; D001402:B-Lymphocytes / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology; D016679:Genome, Viral; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D008024:Ligands; D010641:Phenotype; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016207:Cytokines; D004279:DNA, Viral; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9