Background

Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome.

Methods

AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies.

Results

Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation.

Conclusions

Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.

Purpose

The recent approval of anti-programmed death-ligand 1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor immune microenvironment (TIME).

Experimental design

We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). In addition, we sought to characterize the systemic effects of NAC through single-cell analysis (RNAseq and cytokine secretion) of programmed death-1-high (PD-1^HI) CD8⁺ peripheral T cells and examination of a cytolytic gene signature in whole blood.

Results

In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T-cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active antitumor immunity that may indicate ongoing disease burden.

Conclusions

We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

Background

Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.

Methods

We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.

Results

The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.

Conclusions

The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.