Previous studies identified clones of the U937 promonocytic cell line that were either permissive or nonpermissive for human immunodeficiency virus type 1 (HIV-1) replication. These clones were investigated further in the search for host restriction factors that could explain their differential capacity to support HIV-1 replication. Among known HIV-1 restriction factors screened, tripartite motif-containing protein 22 (TRIM22) was the only factor constitutively expressed in nonpermissive and absent in permissive U937 cells. Stable TRIM22 knockdown (KD) rescued HIV-1 long-terminal-repeat (LTR)-driven transcription in KD-nonpermissive cells to the levels observed in permissive cells. Conversely, transduction-mediated expression of TRIM22 in permissive cells reduced LTR-driven luciferase expression by ϳ7-fold, supporting a negative role of TRIM22 in HIV-1 transcription. This finding was further confirmed in the human T cell line A3.01 expressing TRIM22. Moreover, overexpression of TRIM22 in 293T cells significantly impaired basal and phorbol myristate acetate-ionomycin-induced HIV-1 LTR-driven gene expression, whereas inhibition of tumor necrosis factor alpha-induced viral transcription was a consequence of lower basal expression. In agreement, TRIM22 equally inhibited an LTR construct lacking the tandem NF-B binding sites. In addition, TRIM22 did not affect Tat-mediated LTR transactivation. Finally, these effects were independent of TRIM22 E3 ubiquitin-ligase activity. In the context of replication-competent virus, significantly higher levels of HIV-1 production were observed in KD-nonpermissive versus control nonpermissive U937 cells after infection. In contrast, lower peak levels of HIV-1 replication characterized U937 and A3.01 cells expressing TRIM22 versus their control transduced counterpart. Thus, nuclear TRIM22 significantly impairs HIV-1 replication, likely by interfering with Tat-and NF-B-independent LTR-driven transcription.

The CpG island methylator phenotype (CIMP) in colorectal tumours can be recognized by an increased frequency of aberrant methylation in a specific set of genomic loci. Because of the strong association of CIMP with high microsatellite instability (MSI-H), the identification of CIMP+ tumours within microsatellite stable (MSS) colorectal cancers may not be straightforward. To overcome this potential limitation, we have built an improved seven-locus set of methylation markers that includes CACNA1G, IGF2, RUNX3, HTR6, RIZ1, MINT31, and MAP1B. This new set of CIMP markers revealed a bimodal distribution of methylation frequencies in a group of 95 MSS colorectal cancers, which allowed a clearer separation between CIMP classes. Correlation of MSS CIMP+ tumours with bio-pathological traits revealed significant associations with location to the proximal colon, mucinous histology, BRAF mutation, and chromosomal stability. A potential trend towards an adverse prognosis of CIMP+ cases was associated with the high frequency of BRAF mutations present within this cohort of tumours. Microarray analysis revealed that CIMP+ tumours are characterized by a unique expression profile, a result that confirms that CIMP+ tumours represent a truly distinct molecular class within MSS colorectal cancers.

Polymorphisms in the 3′ untranslated region (3′UTR) of HLA‐G, an important player in immunological tolerance, could be involved in post‐transcriptional expression control, and their association with different clinical immune‐related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single‐nucleotide polymorphisms (SNPs) in the HLA‐G 3′UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3′UTR haplotypes of HLA‐G, or the 14 bp ins/del, with clinical outcome of HLA‐identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta‐thalassemia patients. Sequence based typing of 3′UTR HLA‐G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3′UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation‐maximization studies, with four predominant haplotypes (UTRs1–4). After HSCT, we found a moderate though not significant association between the presence of UTR‐2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14–1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16–1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3′UTR HLA‐G haplotypes for risk prediction after allogeneic HSCT for beta‐thalassemia.

No abstract

Viral tropism, replication, and pathogenesis are determined by multiple interactions between the pathogen and the host. In the case of retroviruses, and in particular, the human immunodeficiency virus, the specific interaction of the envelope protein with the host receptors and co-receptors is essential to gain entry in the cells. After entry, the success of retroviruses to complete their life cycle depends on a complex interplay between the virus and host proteins. Indeed, the cell environment is endowed with a number of factors that actively block distinct stage(s) in the microbial life cycle. Among these restriction factors, Tripartite Motif-5 alpha (TRIM5 alpha) has been extensively studied; however, other TRIM family members have been demonstrated to be anti-retroviral effector proteins. This article reviews, in particular, the current knowledge on the anti-retroviral effects of TRIM5 alpha and TRIM22.