Abstract
BackgroundThe mechanism by which HIV-1 induces AIDS is still unknown. Previously, synthetic peptides corresponding to the conserved immunosuppressive (isu) domain in gp41 of HIV-1 had been shown to inhibit proliferation and to modulate cytokine expression of immune cells. The question is, whether the viral gp41 can do the same.ResultsWe show for the first time that two trimeric forms of glycosylated gp41 released from transfected human cells modulated expression of cytokines and other genes in human PBMCs in the same manner, but at least seven hundred-fold stronger compared to that induced by the isu peptide. Single amino acid substitutions in the isu domain of gp41 introduced by site-directed mutagenesis abrogated this property. Furthermore, replication-competent HIV-1 with a mutation in the isu domain of gp41 did not modulate the cytokine expression, while wild-type virus did. Interestingly, most of the abrogating mutations were not reported in viral sequences derived from infected individuals, suggesting that mutated non-immunosuppressive viruses were eliminated by immune responses. Finally, immunisation of rats with gp41 mutated in the isu domain resulted in increased antibody responses compared with the non-mutated gp41. These results show that non-mutated gp41 is immunosuppressive in immunisation experiments, i.e. in vivo, and this has implications for the vaccine development.ConclusionsThese findings indicate that the isu domain of gp41 modulates cytokine expression in vitro and suppresses antibody response in vivo and therefore may contribute to the virus induced immunodeficiency.
Highlights
The mechanism by which Human immunodeficiency virus type 1 (HIV-1) induces acquired immunodeficiency syndrome (AIDS) is still unknown
IL-10 released from donor peripheral blood mononuclear cells (PBMCs) was completely abrogated when an infectious virus with a single mutation in the core region was tested, while nonmutated virus efficiently modulated cytokine release
Vectors encoding gp41 variants and characterisation of the gp41 released from transfected human cells Two expression vectors were designed, one coding for the nearly entire wild-type gp41 with 25 residues deleted at the C-terminus [amino acids 512–831, GenBank: K03455] and another coding for the ectodomain of gp41 lacking the intracytoplasmic tail and the membrane spanning domain, gp41ΔCT [amino acids 512–695, GenBank: K03455]
Summary
Synthetic peptides corresponding to the conserved immunosuppressive (isu) domain in gp of HIV-1 had been shown to inhibit proliferation and to modulate cytokine expression of immune cells. The mechanism by which HIV-1 induces the immunodeficiency is still unclear, but it was shown that progression to AIDS correlates with virus load [1]. Whereas mutations of six amino acids forming a core region in the isu domain completely abrogated the IL-10 release, amino acids outside the core contributed differently in a donor dependent manner. Gp with a single mutation in the core region induced a better immune response in rats immunised with this protein compared to the wt gp. IL-10 released from donor PBMCs was completely abrogated when an infectious virus with a single mutation in the core region was tested, while nonmutated virus efficiently modulated cytokine release
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