Serial Analysis of the T-Cell Receptor ß-Chain Repertoire in People Living With HIV Reveals Incomplete Recovery After Long-Term Antiretroviral Therapy.

Long-term antiretroviral therapy (ART) in people living with HIV (PLHIV) is associated with sustained increases in CD4+ T-cell count, but its effect on the peripheral blood T-cell repertoire has not been comprehensively evaluated. In this study, we performed serial profiling of the composition and diversity of the T-cell receptor ß-chain (TRB) repertoire in 30 adults with HIV infection before and after the initiation of ART to define its long-term impact on the TRB repertoire. Serially acquired blood samples from 30 adults with HIV infection collected over a mean of 6 years (range, 1-12) years, with 1-4 samples collected before and 2-8 samples collected after the initiation of ART, were available for analysis. TRB repertoires were characterized via high-throughput sequencing of the TRB variable region performed on genomic DNA extracted from unsorted peripheral blood mononuclear cells. Additional laboratory and clinical metadata including serial measurements of HIV viral load and CD4 + T-cell count were available for all individuals in the cohort. A previously published control group of 189 TRB repertoires from peripheral blood samples of adult bone marrow transplant donors was evaluated for comparison. ART initiation in PLHIV was associated with a sustained reduction in viral load and a significant increase in TRB repertoire diversity. However, repertoire diversity in PLHIV remained significantly lower than in the control group even after long-term ART. The composition of TRB repertoires of PLHIV after ART also remained perturbed compared to the control cohort, as evidenced by large persistent private clonal expansions, reduced efficiency in the generation of TRB CDR3 amino acid sequences, and a narrower range of CDR3 lengths. Network analysis revealed an antigen-experienced structure in the TRB repertoire of PLHIV both before and after ART initiation that was quite distinct from the structure of control repertoires, with a slight shift toward a more naïve structure observed after ART initiation. Though we observe significant improvement in TRB repertoire diversity with durable viral suppression in PLHIV on long-term ART, the composition and structure of these repertoires remain significantly perturbed compared to the control cohort of adult bone marrow transplant donors.

Immunotherapy in People With HIV and Cancer.

HIV infection alters the natural history of several cancers, in large part due to its effect on the immune system. Immune function in people living with HIV may vary from normal to highly dysfunctional and is largely dependent on the timing of initiation (and continuation) of effective antiretroviral therapy (ART). An individual's level of immune function in turn affects their cancer risk, management, and outcomes. HIV-associated lymphocytopenia and immune dysregulation permit immune evasion of oncogenic viruses and premalignant lesions and are associated with inferior outcomes in people with established cancers. Various types of immunotherapy, including monoclonal antibodies, interferon, cytokines, immunomodulatory drugs, allogeneic hematopoietic stem cell transplant, and most importantly ART have shown efficacy in HIV-related cancer. Emerging data suggest that checkpoint inhibitors targeting the PD-1/PD-L1 pathway can be safe and effective in people with HIV and cancer. Furthermore, some cancer immunotherapies may also affect HIV persistence by influencing HIV latency and HIV-specific immunity. Studying immunotherapy in people with HIV and cancer will advance clinical care of all people living with HIV and presents a unique opportunity to gain insight into mechanisms for HIV eradication.

Long-Term Follow-Up of 90Y-Ibritumomab Tiuxetan, Fludarabine, and Total Body Irradiation-Based Nonmyeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B Cell Lymphoma.

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392.

Acquired von Willebrand syndrome in a patient with monoclonal gammopathy of undetermined significance.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that typically presents as mucocutaneous bleeding in individuals with no personal or family history of bleeding disorder. Here we present a case in which a patient presented with profound epistaxis and was found to have AVWS in the setting of monoclonal gammopathy of undetermined significance (MGUS).

Decreased interleukin 7 responsiveness of T lymphocytes in patients with idiopathic CD4 lymphopenia.

BACKGROUND: Elevated serum interleukin 7 (IL-7) levels are observed in lymphopenic conditions, including idiopathic CD4 lymphopenia (ICL), which is characterized by CD4 lymphopenia in the absence of human immunodeficiency virus infection or other known immunodeficiency. METHODS: To test whether defective IL-7 signaling could be an etiologic or contributing factor in ICL, peripheral blood mononuclear cells from patients with ICL (median CD4 T-cell count, 160 cells/µL) and healthy controls (median CD4 T-cell count, 582 cells/µL) were evaluated for expression of IL-7Rα chain (CD127) and intracellular phosphorylated STAT-5 (a marker of γc cytokine signaling) after cytokine stimulation. Gene expression was analyzed by real-time polymerase chain reaction following IL-7 stimulation. RESULTS: The percentage of CD4+CD127+ T cells was lower in patients with ICL, compared with controls (P < .001). Lower levels of STAT-5 phosphorylation after IL-7 stimulation were observed in both CD4 and CD8 T cells from patients with ICL, compared with controls (P < .001 and P = .017, respectively), that inversely correlated in CD4 T cells with serum IL-7 levels (r = -0.734, P = .013). Destabilization of p27(kip1), a critical step for IL-7-induced T-cell cycling, was decreased in patients with ICL, compared with controls (P = .004), after IL-7 stimulation. CONCLUSIONS: These data suggest that diminished responsiveness to IL-7 in CD4 and CD8 T cells during ICL may be contributing to the dysregulation of T-cell homeostasis.

Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death.

BACKGROUND: Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups. METHODS: Pre-ART and 1-month samples from an initial ART trial were evaluated for biomarkers associated with AIDS events or death within 1-12 months. Case patients (n = 63) and control patients (n = 126) were 1:2 matched on baseline CD4 cell count, hepatitis status, and randomization date. All had ≥ 1 log(10) HIV RNA level decrease at 1 month. RESULTS: Case patients had more frequent prior AIDS events, compared with control patients (P = .004), but similar HIV RNA levels at baseline. Pre-ART and 1-month C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) levels and pre-ART hyaluronic acid (HA) levels were associated with new AIDS events or death (P ≤ .01). Patients who experienced immune reconstitution inflammatory syndrome (IRIS) events had higher pre-ART tumor necrosis factor α (TNF-α) and HIV RNA levels and significant 1-month increases in CRP, D-dimer, IL-6, interleukin 8, CXCL10, TNF-α, and interferon-γ levels, compared with patients who experienced non-IRIS events (P ≤ .03). Individuals with baseline CRP and HA levels above the cohort median (>2.1 mg/L and >50.0 ng/mL, respectively) had increased risk of AIDS or death (OR, 4.6 [95% CI, 2.0-10.3]; P < .001) and IRIS (OR, 8.7 [95% CI, 2.2-34.8] P = .002). CONCLUSIONS: Biomarkers of Inflammation (CRP, IL-6), coagulation (D-dimer), and tissue fibrosis (HA) measured pre-ART and at 1 month are associated with higher risk of AIDS events, IRIS, or death, warranting additional study as risk stratification strategies.

Immunopathogenesis of asymptomatic chronic HIV Infection: the calm before the storm.

PURPOSE OF REVIEW: HIV and pathogenic simian immunodeficiency virus infection are characterized by chronic immune activation. This review addresses the factors that influence immune activation and may thus determine the rate of disease progression during the asymptomatic period of HIV. RECENT FINDINGS: Immune activation stems from foreign antigen stimulation, including HIV, microbial products and coinfections and compensatory homeostatic mechanisms. Continuous immune stimulation creates a permissive environment for further viral replication, while temporarily allowing successful replenishment of the T-cell pool. Type I interferon, microbial translocation, activated (but ineffective) effector T cells, unruly regulatory T cells and inadequate T helper 17 cells all play important roles in the cycle of activation, functional exhaustion and T-cell death that leads to immunodeficiency. SUMMARY: The asymptomatic chronic phase of HIV infection is a dynamic balance between host and virus, the outcome of which determines an individual's course of disease. Evaluation of the factors that determine the immunologic threshold of disease progression could assist in designing therapeutic strategies, including individualized timing of ART.