2 research outputs found
Disulfide Sensitivity in the Env Protein Underlies Lytic Inactivation of HIV‑1 by Peptide Triazole Thiols
We investigated the mode of action
underlying lytic inactivation
of HIV-1 virions by peptide triazole thiol (PTT), in particular the
relationship between gp120 disulfides and the C-terminal cysteine-SH
required for virolysis. Obligate PTT dimer obtained by PTT SH cross-linking
and PTTs with serially truncated linkers between pharmacophore isoleucine–ferrocenyltriazole-proline–tryptophan
and cysteine-SH were synthesized. PTT variants showed loss of lytic
activity but not binding and infection inhibition upon SH blockade.
A disproportionate loss of lysis activity vs binding and infection
inhibition was observed upon linker truncation. Molecular docking
of PTT onto gp120 argued that, with sufficient linker length, the
peptide SH could approach and disrupt several alternative gp120 disulfides.
Inhibition of lysis by gp120 mAb 2G12, which binds at the base of
the V3 loop, as well as disulfide mutational effects, argued that
PTT-induced disruption of the gp120 disulfide cluster at the base
of the V3 loop is an important step in lytic inactivation of HIV-1.
Further, PTT-induced lysis was enhanced after treating virus with
reducing agents dithiothreitol and tris (2-carboxyethyl)Âphosphine.
Overall, the results are consistent with the view that the binding
of PTT positions the peptide SH group to interfere with conserved
disulfides clustered proximal to the CD4 binding site in gp120, leading
to disulfide exchange in gp120 and possibly gp41, rearrangement of
the Env spike, and ultimately disruption of the viral membrane. The
dependence of lysis activity on thiol–disulfide interaction
may be related to intrinsic disulfide exchange susceptibility in gp120
that has been reported previously to play a role in HIV-1 cell infection
DataSheet_1_T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults.pdf
IntroductionThe immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract.MethodsThis study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017–2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated–) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups.ResultsPre–RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+).ConclusionThe evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults.</p