Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials.

In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

Ancestry shapes genetic immune responses Selection for genes affecting the immune system can vary among populations because of selection for local environments. In humans, ancestry has been associated with different responses to infection. Randolph et al . examined the molecular determinants of these observations using single-cell RNA sequencing of immune cells from individuals of European and African descent who were infected with influenza in vitro. The experiments showed that infection-induced gene signatures diverged in a cell-type-specific manner that was correlated with ancestry, and that these observed ancestry-related differences were caused by changes in gene regulation and processes involved in transcription and translation. —LMZ

Abstract. X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the ␣5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for ␣5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With ␣5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.

The deoxycytidine deaminase APOBEC3G (A3G) is expressed in human T cells and inhibits HIV-1 replication. When transfected into A3G-deficient epithelial cell lines, A3G induces catastrophic hypermutation by deaminating the HIV-1 genome. Interestingly, studies suggest that endogenous A3G in T cells induces less hypermutation than would be expected. However, to date, the specific deaminase activity of endogenous A3G in human CD4+ T cells has not been examined directly. Here, we compared deaminase activity of endogenous and exogenous A3G in various human cell lines using a standard assay and a novel, quantitative, high-throughput assay. Exogenous A3G in epithelial cell lysates displayed deaminase activity only following RNase treatment, as expected given that A3G is known to form an enzymatically inactive RNA-containing complex. Surprisingly, comparable amounts of endogenous A3G from T cell lines or from resting or activated primary CD4+ T cells exhibited minimal deaminase activity, despite RNase treatment. Specific deaminase activity of endogenous A3G in H9, CEM, and other T cell lines was up to 36-fold lower than specific activity of exogenous A3G in epithelial-derived cell lines. Furthermore, RNase-treated T cell lysates conferred a dose-dependent inhibition to epithelial cell lysates expressing enzymatically active A3G. These studies suggest that T cells, unlike epithelial-derived cell lines, express an unidentified RNase-resistant factor that inhibits A3G deaminase activity. This factor could be responsible for reduced levels of hypermutation in T cells, and its identification and blockade could offer a means for increasing antiretroviral intrinsic immunity of T cells.

We found seasonal circulation of influenza C with year-to-year variability. Detection was most frequent among young children but occurred in all ages. Some cases that were positive for influenza C, particularly those with comorbid conditions, had severe disease, suggesting a need for further study of the role of influenza C virus in the pathogenesis of respiratory disease.

Background Determining the incidence, disease-associated serotypes and antimicrobial susceptibility of invasive pneumococcal disease (IPD) among children in Africa is essential in order to monitor the impact of these infections prior to widespread introduction of the pneumococcal conjugate vaccine (PCV). Methods To provide updated estimates of the incidence, serotype distribution, and antimicrobial susceptibility profile of Streptococcus pneumoniae causing disease in Africa, we performed a systematic review of articles published from 2000–2015 using Ovid Medline and Embase. We included prospective and surveillance studies that applied predefined diagnostic criteria. Meta-analysis for all pooled analyses was based on random-effects models. Results We included 38 studies consisting of 386,880 participants in 21 countries over a total of 350,613 person-years. The pooled incidence of IPD was 62.6 (95% CI 16.9, 226.5) per 100,000 person-years, including meningitis which had a pooled incidence of 24.7 (95% CI 11.9, 51.6) per 100,000 person-years. The pooled prevalence of penicillin susceptibility was 78.1% (95% CI 61.9, 89.2). Cumulatively, PCV10 and PCV13 included 66.9% (95% CI 55.9, 76.7) and 80.6% (95% CI 66.3, 90.5) of IPD serotypes, respectively. Conclusions Our study provides an integrated and robust summary of incidence data, serotype distribution and antimicrobial susceptibility for S. pneumoniae in children ≤5 years of age in Africa prior to widespread introduction of PCV on the continent. The heterogeneity of studies and wide range of incidence rates across the continent indicate that surveillance efforts should be intensified in all regions of Africa to improve the integrity of epidemiologic data, vaccine impact and cost benefit. Although the incidence of IPD in young children in Africa is substantial, currently available conjugate vaccines are estimated to cover the majority of invasive disease-causing pneumococcal serotypes. These data provide a reliable baseline from which to monitor the impact of the broad introduction of PCV.