An open label randomized controlled trial of atorvastatin versus aspirin in elite controllers and antiretroviral-treated people with HIV.

BACKGROUND: Residual inflammation in people with HIV (PWH) despite suppression of HIV replication is associated with many comorbidities including cardiovascular disease. Targeting inflammation may decrease the risk of cardiovascular disease. METHODS: An open label randomized study was conducted to evaluate the effect of nine months of 81 mg aspirin versus 40 mg atorvastatin in antiretroviral therapy (ART) treated PWH and elite controllers (EC), not on ART. Biomarkers associated with inflammation and virologic indices were measured and analyzed using nonparametric and linear mixed effect models. RESULTS: Fifty-three participants were randomized and 44 were included in the final analysis. Median age was 54 years, 72% were male, 59% were Black. Median CD4 + count was 595 cells/µl in the aspirin and 717 cells/µl in the atorvastatin arm. After 9 months of treatment, plasma soluble (s) CD14 + was reduced in the aspirin group within both treated PWH and EC ( P  = 0.0229), yet only within treated PWH in the atorvastatin group ( P  = 0.0128). A 2.3% reduction from baseline in tissue factor levels was also observed in the aspirin arm, driven by the EC group. In the atorvastatin arm, there was a 4.3% reduction in interleukin-8 levels ( P  = 0.02) and a small decrease of activated CD4 + T cells ( P  < 0.001). No statistically significant differences were observed in the plasma HIV viral load and cell-associated (CA) HIV DNA and RNA. CONCLUSIONS: Aspirin and atorvastatin could play a role in targeting HIV-associated inflammation. Elite controllers may warrant special consideration for anti-inflammatory strategies.

A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity.

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).

Prolonged Posttreatment Virologic Control and Complete Seroreversion After Advanced Human Immunodeficiency Virus-1 Infection.

BACKGROUND: Possible human immunodeficiency virus (HIV)-1 clearance has rarely been reported. In this study, we describe a unique case of an HIV-positive, combination antiretroviral therapy (cART)-experienced woman with prior acquired immunodeficiency syndrome (AIDS) who has not experienced viral rebound for over 12 years since discontinuing cART. METHODS: Leukapheresis, colonoscopy, and lymph node excision were performed for detailed examination of virologic (including HIV reservoir) and immunologic features. Comparisons were made with chronically infected patients and healthy controls. RESULTS: No HIV-specific antibodies were detected in serum. Plasma HIV ribonucleic acid (RNA) levels were <0.2 copies/mL, and, except for low-frequency HIV deoxyribonucleic acid (DNA)+ cells in lymph node tissue (1 copy/3 × 106 cells), HIV antigen could not be detected by quantitative virus outgrowth (<0.0025 infectious units/106 CD4+ T cells) or by most measurements of HIV RNA or DNA in blood, lymph node, or gut-associated mononuclear cells. Human immunodeficiency virus-specific T-cell responses were detectable but low. Brain imaging revealed a prior biopsy site and persistent white matter disease since 1996. Human immunodeficiency virus DNA+ cells in the 1996 brain biopsy specimen confirmed her identity and initial HIV diagnosis. CONCLUSIONS: This represents the first report of complete seroreversion, prolonged posttreatment virus suppression, a profoundly small HIV reservoir, and persistent HIV-specific T cells in an adult with prior AIDS.

Antigenic Restimulation of Virus-Specific Memory CD8+ T Cells Requires Days of Lytic Protein Accumulation for Maximal Cytotoxic Capacity.

In various infections or vaccinations of mice or humans, reports of the persistence and the requirements for restimulation of the cytotoxic mediators granzyme B (GrB) and perforin (PRF) in CD8+ T cells have yielded disparate results. In this study, we examined the kinetics of PRF and GrB mRNA and protein expression after stimulation and associated changes in cytotoxic capacity in virus-specific memory cells in detail. In patients with controlled HIV or cleared respiratory syncytial virus (RSV) or influenza virus infections, all virus-specific CD8+ T cells expressed low PRF levels without restimulation. Following stimulation, they displayed similarly delayed kinetics for lytic protein expression, with significant increases occurring by days 1 to 3 before peaking on days 4 to 6. These increases were strongly correlated with, but were not dependent upon, proliferation. Incremental changes in PRF and GrB percent expression and mean fluorescence intensity (MFI) were highly correlated with increases in HIV-specific cytotoxicity. mRNA levels in HIV-specific CD8+ T-cells exhibited delayed kinetics after stimulation as with protein expression, peaking on day 5. In contrast to GrB, PRF mRNA transcripts were little changed over 5 days of stimulation (94-fold versus 2.8-fold, respectively), consistent with posttranscriptional regulation. Changes in expression of some microRNAs, including miR-17, miR-150, and miR-155, suggested that microRNAs might play a significant role in regulation of PRF expression. Therefore, under conditions of extremely low or absent antigen levels, memory virus-specific CD8+ T cells require prolonged stimulation over days to achieve maximal lytic protein expression and cytotoxic capacity.IMPORTANCE Antigen-specific CD8+ T cells play a major role in controlling most virus infections, primarily by perforin (PRF)- and granzyme B (GrB)-mediated apoptosis. There is considerable controversy regarding whether PRF is constitutively expressed, rapidly increased similarly to a cytokine, or delayed in its expression with more prolonged stimulation in virus-specific memory CD8+ T cells. In this study, the degree of cytotoxic capacity of virus-specific memory CD8+ T cells was directly proportional to the content of lytic molecules, which required antigenic stimulation over several days for maximal levels. This appeared to be modulated by increases in GrB transcription and microRNA-mediated posttranscriptional regulation of PRF expression. Clarifying the requirements for maximal cytotoxic capacity is critical to understanding how viral clearance might be mediated by memory cells and what functions should be induced by vaccines and immunotherapies.

A Phase I, Randomized, Controlled Clinical Study of CC-11050 in People Living With HIV With Suppressed Plasma Viremia on Antiretroviral Therapy (APHRODITE).

OBJECTIVE: Phosphodiesterase 4 inhibitors (PDE4i) are novel anti-inflammatory medications that have been approved for rheumatologic diseases and have been tested as host-directed therapy in tuberculosis. We examined the safety of CC-11050, a potent PDE4i in people living with HIV (PLWH) with suppressed HIV plasma viremia. We hypothesized that CC-11050 could be used to modulate HIV-related inflammation. METHOD: Thirty PLWH on antiretroviral therapy (ART) ≥ 1 year with suppressed HIV viremia were enrolled and randomized 2:1 to 12 weeks of CC-11050 200mg twice daily or placebo with follow-up at weeks 2, 4, 8, 12, and 16. Primary endpoint was safety. Secondary endpoints were the effect of CC-11050 on cytokines, monocyte, and T-cell activation and potential pharmacokinetic interaction between CC-11050 and Efavirenz (EFV). RESULTS: At baseline, median age was 49.5 years and CD4 count 459 cells/µL. Most frequent adverse events (grade 1 and 2 only) in CC-11050 group were headache, diarrhea, nausea, cough, nasal congestion, and restlessness. Over a 12-week period, the CC-11050 group had lower level of IL-8, adjusted for baseline level, group, and week (0.72-fold, P = .02), lower percentage of NK cells (0.87-fold, P = .02) and higher IL-6 level (1.48-fold, P = .03) compared to placebo (0.87-fold, P = .02). CC-11050 and EFV co-administration did not reveal any pharmacokinetic interaction. CONCLUSIONS: CC-11050 was well tolerated in PLWH, without affecting CD4 counts or plasma viremia, and led to a decrease in NK cells and plasma IL-8 level after 12-weeks of administration. Further study will be needed to elucidate the efficacy of CC-11050 as potential anti-inflammatory adjuvant strategy in HIV.

Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine.

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.