Mammalian cells express several factors that act in a cell-autonomous manner to inhibit retrovirus replication. Among these are the Friend virus susceptibility factor 1͞lentivirus susceptibility factor 1͞restriction factor 1 (Ref1) class of restriction factors, which block infection by targeting the capsids of diverse retroviruses. Here we show that lentivirus susceptibility factor 1 and Ref1 are speciesspecific variants of tripartite interaction motif 5␣ (TRIM5␣), a cytoplasmic body component recently shown to block HIV-1 infection in rhesus macaque cells, and can indeed block infection by widely divergent retroviruses. Depletion of TRIM5␣ from human cells relieved restriction of N-tropic murine leukemia virus (N-MLV), and expression of human TRIM5␣ in otherwise nonrestricting cells conferred specific resistance to N-MLV infection, indicating that TRIM5␣ is Ref1 or an essential component of Ref1. TRIM5␣ variants from humans, rhesus monkeys, and African green monkeys displayed different but overlapping restriction specificities that were quite accurately predicted by the restriction properties of the cells from which they were derived. All TRIM5␣ variants could inhibit infection by at least two different retroviruses, and African green monkey TRIM5␣ was able to inhibit infection by no less than four divergent retroviruses of human, non-human primate, equine, and murine origin. However, each TRIM5␣ variant was unable to restrict retroviruses isolated from the same species. These data indicate that TRIM5␣ can confer broad innate immunity to retrovirus infection in primate cells and is likely to be an important natural barrier to cross-species retrovirus transmission.

ObjectiveTo evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials.gov.Study selectionEligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease.Data extractionThree independent investigators extracted data on adverse events from ClinicalTrials.gov and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators.Results13 relevant studies were included; adverse event data were available on ClinicalTrials.gov for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.ConclusionsOrgan specific immune-related adverse events are uncommon with anti-PD-1 drugs but the risk is increased compared with control treatments. General adverse events related to immune activation are largely similar. Adverse events consistent with musculoskeletal problems are inconsistently reported but adverse events may be common.

The tripartite motif 5␣ protein (TRIM5␣) is one of several factors expressed by mammalian cells that inhibit retrovirus replication. Human TRIM5␣ (huTRIM5␣) inhibits infection by N-tropic murine leukemia virus (N-MLV) but is inactive against human immunodeficiency virus type 1 (HIV-1). However, we show that replacement of a small segment in the carboxy-terminal B30.2/SPRY domain of huTRIM5␣ with its rhesus macaque counterpart (rhTRIM5␣) endows it with the ability to potently inhibit HIV-1 infection. The B30.2/ SPRY domain and an additional domain in huTRIM5␣, comprising the amino-terminal RING and B-box components of the TRIM motif, are required for N-MLV restriction activity, while the intervening coiled-coil domain is necessary and sufficient for huTRIM5␣ multimerization. Truncated huTRIM5␣ proteins that lack either or both the N-terminal RING/B-Box or the C-terminal B30.2/SPRY domain form heteromultimers with full-length huTRIM5␣ and are dominant inhibitors of its N-MLV restricting activity, suggesting that homomultimerization of intact huTRIM5␣ monomers is necessary for N-MLV restriction. However, localization in large cytoplasmic bodies is not required for inhibition of N-MLV by huTRIM5␣ or for inhibition of HIV-1 by chimeric or rhTRIM5␣.Several intrinsic immune mechanisms exist in mammalian cells that inhibit the replication of viruses (2, 9). Among these are APOBEC3G and related proteins (26) and zinc-finger antiviral protein (8), which modify and/or destabilize viral nucleic acids (8,11,19,32). Products of the tripartite motif 5 (TRIM5) gene in primates and the Friend virus susceptibility factor 1 (Fv1) gene in mice constitute a class of restriction factors that inhibit retrovirus infection by targeting incoming capsids and preventing the establishment of a provirus in the target cell (1, 28).Naturally occurring variation in TRIM5 and Fv1 sequence impacts the spectrum of retroviruses that are inhibited. For example, two principal Fv1 alleles exist in laboratory mice (Fv1 n and Fv1 b ) that inhibit infection by B-tropic murine leukemia virus (B-MLV) and N-tropic MLV (N-MLV), respectively (16,17,22,24). The differential sensitivity of N-MLV and B-MLV to Fv1 n and Fv1 b is determined by a single amino acid in the MLV capsid (15), whereas the differential specificity of Fv1 n and Fv1 b is governed by sequence variation at three positions within the C-terminal domain of the protein (3, 4). The reciprocal specificity of inhibition of MLV strains by Fv1 variants is the basis of the compelling (albeit unproven) hypothesis that Fv1-based restriction involves direct recognition of the incoming MLV capsid by the Fv1 protein (10, 27).Like Fv1 variants, TRIM5 proteins from different primate species exhibit noticeable variation in the specificity with which they inhibit retrovirus infection (13,14,23,28,30). For example, human immunodeficiency virus type 1 (HIV-1) is strongly blocked by rhesus monkey and African green monkey (AGM) TRIM5␣ (rhTRIM5␣ and AGM TRIM5␣) but not by human TRIM5␣ (huTRIM5␣). Conversely SIV MAC ...