Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans

Cold‐season methane fluxes simulated by GCP-CH4 models

Cold-season methane (CH4) emissions may be poorly constrained in wetland models. We examined cold-season CH4 emissions simulated by 16 models participating in the Global Carbon Project model intercomparison and analyzed temporal and spatial patterns in simulation results using prescribed inundation data for 2000–2020. Estimated annual CH4 emissions from northern (>60°N) wetlands averaged 10.0 ± 5.5 Tg CH4 yr−1. While summer CH4 emissions were well simulated compared to in-situ flux measurement observations, the models underestimated CH4 during September to May relative to annual total (27 ± 9%, compared to 45% in observations) and substantially in the months with subzero air temperatures (5 ± 5%, compared to 27% in observations). Because of winter warming, nevertheless, the contribution of cold-season emissions was simulated to increase at 0.4 ± 0.8% decade−1. Different parameterizations of processes, for example, freezing–thawing and snow insulation, caused conspicuous variability among models, implying the necessity of model refinement