Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.     

Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle

Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage. While Cdc6 overexpression did not promote skin tumors, it facilitated the formation of papillomas in cooperation with mutagenic agents such as DMBA. In addition, the elevated levels of CDC6 protein in the skin extended the resting stage of the hair growth cycle, leading to better fur preservation in older mice.     

Are there links between responses of soil microbes and ecosystem functioning to elevated CO2, N deposition and warming? A global perspective

In recent years, there has been an increase in research to understand how global changes’ impacts on soil biota translate into altered ecosystem functioning. However, results vary between global change effects, soil taxa, and ecosystem processes studied, and a synthesis of relationships is lacking. Therefore, here we initiate such a synthesis to assess whether the effect size of global change drivers (elevated CO₂, N deposition, and warming) on soil microbial abundance is related with the effect size of these drivers on ecosystem functioning (plant biomass, soil C cycle, and soil N cycle) using meta‐analysis and structural equation modeling. For N deposition and warming, the global change effect size on soil microbes was positively associated with the global change effect size on ecosystem functioning, and these relationships were consistent across taxa and ecosystem processes. However, for elevated CO₂, such links were more taxon and ecosystem process specific. For example, fungal abundance responses to elevated CO₂ were positively correlated with those of plant biomass but negatively with those of the N cycle. Our results go beyond previous assessments of the sensitivity of soil microbes and ecosystem processes to global change, and demonstrate the existence of general links between the responses of soil microbial abundance and ecosystem functioning. Further we identify critical areas for future research, specifically altered precipitation, soil fauna, soil community composition, and litter decomposition, that are need to better quantify the ecosystem consequences of global change impacts on soil biodiversity.     

Changes in muscle proteomics in the course of the Caudwell Research Expedition to Mt. Everest

This study employed differential proteomic and immunoassay techniques to elucidate the biochemical mechanisms utilized by human muscle (vastus lateralis) in response to high altitude hypoxia exposure. Two groups of subjects, participating in a medical research expedition (A, n = 5, 19d at 5300 m altitude; B, n = 6, 66d up to 8848 m) underwent a ≈ 30% drop of muscular creatine kinase and of glycolytic enzymes abundance. Protein abundance of most enzymes of the tricarboxylic acid cycle and oxidative phosphorylation was reduced both in A and, particularly, in B. Restriction of α‐ketoglutarate toward succinyl‐CoA resulted in increased prolyl hydroxylase 2 and glutamine synthetase. Both A and B were characterized by a reduction of elongation factor 2alpha, controlling protein translation, and by an increase of heat shock cognate 71 kDa protein involved in chaperone‐mediated autophagy. Increased protein levels of catalase and biliverdin reductase occurred in A alongside a decrement of voltage‐dependent anion channels 1 and 2 and of myosin‐binding protein C, suggesting damage to the sarcomeric structures. This study suggests that during acclimatization to hypobaric hypoxia the muscle behaves as a producer of substrates activating a metabolic reprogramming able to support anaplerotically the tricarboxylic acid cycle, to control protein translation, to prevent energy expenditure and to activate chaperone‐mediated autophagy.     

Nocturnal migratory songbirds adjust their travelling direction aloft: evidence from a radiotelemetry and radar study

In order to fully understand the orientation behaviour of migrating birds, it is important to understand when birds set their travel direction. Departure directions of migratory passerines leaving stopover sites are often assumed to reflect the birds'' intended travel directions, but this assumption has not been critically tested. We used data from an automated radiotelemetry system and a tracking radar at Falsterbo peninsula, Sweden, to compare the initial orientation of departing songbirds (recorded by radiotelemetry) with the orientation of songbird migrants in climbing and level flight (recorded by radar). We found that the track directions of birds at high altitudes and in level flight were more concentrated than the directions of departing birds and birds in climbing flight, which indicates that the birds adjust their travelling direction once aloft. This was further supported by a wide scatter of vanishing bearings in a subsample of radio-tracked birds that later passed an offshore radio receiver station 50 km southeast of Falsterbo. Track directions seemed to be more affected by winds in climbing compared with level flights, which may be explained by birds not starting to partially compensate for wind drift until they have reached cruising altitudes.     

Targeting Protein for Xenopus Kinesin-like Protein 2 (TPX2) Regulates γ-Histone 2AX (γ-H2AX) Levels upon Ionizing Radiation

The microtubule-associated protein targeting protein for Xenopus kinesin-like protein 2 (TPX2) plays a key role in spindle assembly and is required for mitosis in human cells. In interphase, TPX2 is actively imported into the nucleus to prevent its premature activity in microtubule organization. To date, no function has been assigned to nuclear TPX2. We now report that TPX2 plays a role in the cellular response to DNA double strand breaks induced by ionizing radiation. Loss of TPX2 leads to inordinately strong and transient accumulation of ionizing radiation-dependent Ser-139-phosphorylated Histone 2AX (γ-H2AX) at G₀ and G₁ phases of the cell cycle. This is accompanied by the formation of increased numbers of high intensity γ-H2AX ionizing radiation-induced foci. Conversely, cells overexpressing TPX2 have reduced levels of γ-H2AX after ionizing radiation. Consistent with a role for TPX2 in the DNA damage response, we found that the protein accumulates at DNA double strand breaks and associates with the mediator of DNA damage checkpoint 1 (MDC1) and the ataxia telangiectasia mutated (ATM) kinase, both key regulators of γ-H2AX amplification. Pharmacologic inhibition or depletion of ATM or MDC1, but not of DNA-dependent protein kinase (DNA-PK), antagonizes the γ-H2AX phenotype caused by TPX2 depletion. Importantly, the regulation of γ-H2AX signals by TPX2 is not associated with apoptosis or the mitotic functions of TPX2. In sum, our study identifies a novel and the first nuclear function for TPX2 in the cellular responses to DNA damage.     

Haemoglobin modulates salicylate and jasmonate/ethylene-mediated resistance mechanisms against pathogens

Nitric oxide (NO) plays a role in defence against hemibiotrophic pathogens mediated by salicylate (SA) and also necrotrophic pathogens influenced by jasmonate/ethylene (JA/Et). This study examined how NO-oxidizing haemoglobins (Hb) encoded by GLB1, GLB2, and GLB3 in Arabidopsis could influence both defence pathways. The impact of Hb on responses to the hemibiotrophic Pseudomonas syringae pathovar tomato (Pst) AvrRpm1 and the necrotrophic Botrytis cinerea were investigated using glb1, glb2, and glb3 mutant lines and also CaMV 35S GLB1 and GLB2 overexpression lines. In glb1, but not glb2 and glb3, increased resistance was observed to both pathogens but was compromised in the 35S-GLB1. A quantum cascade laser-based sensor measured elevated NO production in glb1 infected with Pst AvrRpm1 and B. cinerea, which was reduced in 35S-GLB1 compared to Col-0. SA accumulation was increased in glb1 and reduced in 35S-GLB1 compared to controls following attack by Pst AvrRpm1. Similarly, JA and Et levels were increased in glb1 but decreased in 35S-GLB1 in response to attack by B. cinerea. Quantitative PCR assays indicated reduced GLB1 expression during challenge with either pathogen, thus this may elevate NO concentration and promote a wide-ranging defence against pathogens.