Brief Report: Recurrence of Anal High-Grade Squamous Intraepithelial Lesions Among Women Living With HIV.

BACKGROUND: Women living with HIV (WLHIV) have a high risk of developing invasive anal cancer. Anal cancer may be prevented with early detection and treatment of anal histologic high-grade squamous intraepithelial lesions (HSIL). However, there are limited data on the efficacy of anal HSIL treatment in WLHIV. STUDY DESIGN: We conducted a retrospective study of WLHIV treated for anal HSIL under high-resolution anoscopy (HRA) guidance from January 1, 2007 to December 31, 2017 with at least one post-treatment visit at an urban tertiary care hospital. RESULTS: Forty-five WLHIV women with at least 1 follow-up evaluation after treatment for anal HSIL were identified. The median age was 46 years (range 35-66 years), 63% were African American, 27% were Hispanic/Latino, and 53% were current smokers. The mean absolute CD4 T-cell count was 516 cells/mm; 50% and 24% of the cohort had a history of cervical or vulvar HSIL respectively. The cumulative probability of anal HSIL recurrence was 29% at 12 months, 52% at 24 months, and 79% at 36 months post-treatment. CONCLUSION: Most WLHIV treated for anal HSIL recurred within 3 years, suggesting need for continued surveillance after treatment. Our data contribute to the information needed to develop effective anal cancer prevention guidelines in WLHIV.

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond.

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of "self-eating" where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.

Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner.

The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs.

SAP expression in invariant NKT cells is required for cognate help to support B-cell responses.

One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in T, invariant natural killer T (NKT) cells and NK cells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP(-/-).B6 mice that completely lack NKT cells, the small number of SAP-deficient NKT cells in SAP(-/-).BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP(fl/fl).tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell-mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.

Predictors for hematopoietic growth factors use in HIV/HCV-coinfected patients treated with peginterferon alfa 2b and ribavirin.

HIV/hepatitis C virus (HCV)-coinfected individuals have accelerated liver disease, increased drug toxicities, and modest responses to peginterferon and ribavirin. Hematologic toxicities necessitating dose reduction or discontinuation are limiting factors to HCV treatment in the coinfected patient. This study aimed to identify predictors for the need of filgrastim and darbepoetin to manage hematologic toxicities so as to maintain patients on full doses of study drugs for the duration of study. The primary study was a single-center, open-label, prospective study to evaluate the safety, efficacy, and viral kinetics of 48-week peginterferon alfa 2b and ribavirin in HIV/HCV-coinfected patients. Complete blood count was monitored at baseline, days 3, 7, 10, 14, and then weekly for the first month, fortnightly until week 8, then monthly from week 12 to 48. Filgrastim was initiated when absolute neutrophil count (ANC) fell below 750 cells/mm(3) and darbepoetin was used when hemoglobin dropped to less than 10 g/dL. All patients experienced decrease in ANC and hemoglobin. Twenty of 30 (66.6%) of patients required hematopoeitic growth factors, 15 (50%) received filgrastim, and 12 (40%) received darbepoetin. Seven (23.3%) required both. Baseline ANC of less than 2250 cells per millimeter and negative rate of change of hemoglobin on day 3 of therapy were excellent predictors for filgrastim and darbepoetin use, respectively. Supplemental growth factors were associated with substantial increase in overall cost for HCV treatment. Larger clinical trials will be needed to address the cost effectiveness of supplemental growth factor use in the HIV/HCV-coinfected patients.

Five-year follow-up of a cohort of profoundly immunosuppressed patients discontinuing therapy for cytomegalovirus retinitis.

Potent antiretroviral therapy stimulates robust and durable immune reconstitution among profoundly immunosuppressed patients that is clinically important. Fifteen patients with cytomegalovirus retinitis (CMVR) were followed after discontinuing anti-cytomegalovirus therapy. No patients had progression or relapse for a median of 51 months. Survival from the diagnosis of CMVR was universal for up to 95 months, with an observation period averaging more than 6 years. The CD4 cell count continued to rise through the fourth year of follow-up.