Mogamulizumab-Associated Myositis With and Without Myasthenia Gravis and/or Myocarditis in Patients With T-Cell Lymphoma.

Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.

Clinical features and treatment outcomes for primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder: a retrospective cohort study from the Dana-Farber Cancer Institute and updated literature review.

Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) was reclassified in 2016 as a rare benign entity with an excellent prognosis, yet its clinical features and best treatments remain poorly defined. We collected clinical data, treatments, and treatment-responses from our institution's patients with PCSM-TCLPD through September 2018 and an identical PubMed review through June 2021. Among 36 cases (median-age 54 years; 58.3% head/neck), diagnostic biopsy resulted in sustained complete remission (CR) in 13/33 punch/shave biopsies and 3/3 excisional biopsies. The remaining 20 patients further required topical corticosteroids (n = 5); intralesional corticosteroids (n = 1); surgical-excision (n = 5); electron-beam-radiation (n = 6); or brachytherapy (n = 3). All patients ultimately achieved CR, excluding one patient continuing treatment at end-of-study. 57/59 (96.6%) of institutional and literature-reported radiation-treated patients experienced CR. No institutional cases progressed beyond skin; 5/209 (2.4%) literature-reported cases progressed to systemic/extracutaneous involvement, all pre-reclassification. PCSM-TCLPD responds well to local-directed therapy including radiation, and only rarely if ever progresses.

Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species.

The host range of retroviruses is influenced by antiviral proteins such as TRIM5, a restriction factor that recognizes and inactivates incoming retroviral capsids. Remarkably, in Owl monkeys (omk), a cyclophilin A (CypA) cDNA has been transposed into the TRIM5 locus, resulting in the expression of a TRIM5-CypA fusion protein (TRIMCyp) that restricts retroviral infection based on the retroviral capsid-binding specificity of CypA. Here, we report that the seemingly improbable genesis of TRIMCyp has, in fact, occurred twice, and pigtailed macaques (pgt) express an independently generated TRIMCyp protein. The omkTRIMCyp and pgtTRIMCyp proteins restrict infection by several lentiviruses, but their specificities are distinguishable. Surprisingly, pgtTRIMCyp cannot bind to or restrict HIV-1 capsids as a consequence of a point mutation close to the Cyp:capsid-binding interface that was acquired during or after transposition of pgtCypA. However, the same mutation confers on pgtTRIMCyp the ability to restrict FIV in the presence of cyclosporin A, a drug that normally abolishes the interaction between pgtTRIMCyp or omkTRIMCyp and lentiviral capsids. Overall, an intuitively unlikely evolutionary event has, in fact, occurred at least twice in primates and represents a striking example of convergent evolution in divergent species.

Plasma membrane is the site of productive HIV-1 particle assembly.

Recently proposed models that have gained wide acceptance posit that HIV-1 virion morphogenesis is initiated by targeting the major structural protein (Gag) to late endosomal membranes. Thereafter, late endosome-based secretory pathways are thought to deliver Gag or assembled virions to the plasma membrane (PM) and extracellular milieu. We present several findings that are inconsistent with this model. Specifically, we demonstrate that HIV-1 Gag is delivered to the PM, and virions are efficiently released into the extracellular medium, when late endosome motility is abolished. Furthermore, we show that HIV-1 virions are efficiently released when assembly is rationally targeted to the PM, but not when targeted to late endosomes. Recently synthesized Gag first accumulates and assembles at the PM, but a proportion is subsequently internalized via endocytosis or phagocytosis, thus accounting for observations of endosomal localization. We conclude that HIV-1 assembly is initiated and completed at the PM, and not at endosomal membranes.