Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)
. However, eradication of the virus in individuals with HIV has not been possible to date
. Given that HIV ...suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication
. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
Abstract
Persistent exposure to antigen leads to T-cell exhaustion and immunologic dysfunction. We examined the immune exhaustion markers T cell immunoglobulin and ITIM domain (TIGIT) and programmed ...cell death protein 1 (PD-1) in human immunodeficiency virus (HIV)–infected and healthy individuals and the relationship with cytotoxic CD8+ T-lymphocyte activity. Frequencies of TIGIT but not PD-1 were positively correlated with CD8+ T-lymphocyte activity in HIV-aviremic and healthy individuals; however, there was no correlation in HIV-viremic individuals. Transcriptome analyses revealed up-regulation of genes associated with antiviral immunity in TIGIT+CD8+ versus TIGIT−CD8+ T cells. Our data suggest that TIGIT+CD8+ T cells do not necessarily represent a state of immune exhaustion and maintain an intrinsic cytotoxicity in HIV-infected individuals.
Our data suggest that subsets of TIGIT+CD8+ T cells do not represent a state of immune exhaustion and maintain an intrinsic capacity to kill targets in human immunodeficiency virus–infected individuals in the absence of active viral replication.
Certain infected individuals suppress human immunodeficiency virus (HIV) in the absence of anti-retroviral therapy (ART). Elucidating the underlying mechanism(s) is of high interest. Here we present ...two contrasting case reports of HIV-infected individuals who controlled plasma viremia for extended periods after undergoing analytical treatment interruption (ATI). In Participant 04, who experienced viral blips and initiated undisclosed self-administration of suboptimal ART detected shortly before day 1,250, phylogenetic analyses of plasma HIV env sequences suggested continuous viral evolution and/or reactivation of pre-existing viral reservoirs over time. Antiviral CD8
T cell activities were higher in Participant 04 than in Participant 30. In contrast, Participant 30 exhibited potent plasma-IgG-mediated neutralization activity against autologous virus that became ineffective when he experienced sudden plasma viral rebound 1,434 d after ATI due to HIV superinfection. Our data provide insight into distinct mechanisms of post-treatment interruption control and highlight the importance of frequent monitoring of undisclosed use of ART and superinfection during the ATI phase.
Abstract
Background
A better understanding of the dynamics of human immunodeficiency virus (HIV) reservoirs in CD4+ T cells of people with HIV (PWH) receiving antiretroviral therapy (ART) is crucial ...for developing therapies to eradicate the virus.
Methods
We conducted a study involving 28 aviremic PWH receiving ART with high and low levels of HIV DNA. We analyzed immunologic and virologic parameters and their association with the HIV reservoir size.
Results
The frequency of CD4+ T cells carrying HIV DNA was associated with higher pre-ART plasma viremia, lower pre-ART CD4+ T-cell counts, and lower pre-ART CD4/CD8 ratios. During ART, the High group maintained elevated levels of intact HIV proviral DNA, cell-associated HIV RNA, and inducible virion-associated HIV RNA. HIV sequence analysis showed no evidence for preferential accumulation of defective proviruses nor higher frequencies of clonal expansion in the High versus Low group. Phenotypic and functional T-cell analyses did not show enhanced immune-mediated virologic control in the Low versus High group. Of considerable interest, pre-ART innate immunity was significantly higher in the Low versus High group.
Conclusions
Our data suggest that innate immunity at the time of ART initiation may play an important role in modulating the dynamics and persistence of viral reservoirs in PWH.
HIV induces immunologic dysfunction in T cells of infected individuals. However, the impact of aging on T cell phenotypes in HIV-infected individuals receiving antiretroviral therapy (ART) has not ...been fully delineated. We evaluated the relationship between aging and the expression of immune activation and exhaustion markers on CD8 + T cells of age-matched HIV-infected and -uninfected male participants.
Levels of immune activation and exhaustion markers on peripheral blood CD8 + T cells of HIV-infected and -uninfected participants were examined.
110 HIV-infected aviremic male participants receiving ART and 146 HIV-uninfected male participants were studied. The levels of TIGIT, PD-1, CD38, and CD226 on CD8 + T cells of the study participants were determined by flow cytometry.
The level of TIGIT on CD8 + T cells was higher in aviremic HIV-infected compared to uninfected participants ( P < 0.0001). In contrast, no significant differences were found in the levels of PD-1 and CD38 on CD8 + T cells between the two groups. Statistically significant correlations were observed between age and the levels of TIGIT + and CD38 + CD8 + T cells in both groups; however, no correlation was found between age and the level of PD-1 + CD8 + T cells in HIV-infected participants. Age-stratification of HIV-infected and -uninfected groups did not show any significant differences in the level of PD-1 expression on CD8 + T cells.
The findings of our study highlight the role of aging in the expression of immune markers on CD8 + T cells and have important implications for therapies that target immune checkpoints in HIV-infected individuals.
Abstract
Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were ...collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission.
Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.
The colonic epithelium is composed of a polarized monolayer sheathed by a layer of pericryptal myofibroblasts (PCMFs). We mimicked these cellular compartments in vitro to assess the effects of ...paracrine-acting PCMF-derived factors on tight junction (TJ) integrity, as measured by transepithelial electrical resistance (TER). Coculture with 18Co PCMFs, or basolateral administration of 18Co conditioned medium, significantly reduced TER of polarized Caco-2 cells. Among candidate paracrine factors, only keratinocyte growth factor (KGF) reduced Caco-2 TER; basolateral KGF treatment led to time- and concentration-dependent increases in claudin-2 levels. We also demonstrate that amphiregulin (AREG), produced largely by Caco-2 cells, increased claudin-2 levels, leading to epidermal growth factor receptor-mediated TER reduction. We propose that colonic epithelial TJ integrity can be modulated by paracrine KGF and autocrine AREG through increased claudin-2 levels. KGF-regulated claudin-2 induction may have implications for inflammatory bowel disease, where both KGF and claudin-2 are upregulated.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Antiretroviral therapy (ART) is highly effective in suppressing human immunodeficiency virus (HIV)
1
; however, eradication of the virus in infected individuals has not been possible thus far
2
. ...Given that HIV suppression requires life-long ART, predominantly on a daily basis, there is a need to develop clinically effective alternatives that utilize long-acting antiviral agents to inhibit viral replication
3
. Here, we report the results of a two-component clinical trial involving passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies (bNAbs) 3BNC117 and 10–1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated ART during the acute/early phase of HIV infection. The second component was an open-label single arm trial that enrolled ART-naive viremic controllers. Up to 8 infusions of 3BNC117 and 10–1074, administered over a period of 24 weeks, were well-tolerated without any serious adverse events related to the infusions. Compared with placebo, the combination bNAbs maintained complete suppression of plasma viremia (up to 43 weeks) following analytical treatment interruption (ATI), provided that no antibody-resistant HIV was detected at baseline in the study participants. Similarly, potent HIV suppression was seen in the ART-naïve, viremic study participants carrying sensitive virus at baseline. Our data demonstrate that combination bNAb therapy can provide long-term ART-free virologic suppression in infected individuals and our experience offers guidance for future clinical trials involving next generation antibodies with long half-lives.
A major water quality issue in urban areas underlain by a productive aquifer is the impact of modern recharge. Using a variety of sample sources including multi-level boreholes, detectable ...concentrations of CFCs and SF^sub 6^ have been found throughout the upper 50 m of the saturated aquifer beneath a suburb of Doncaster, UK, indicating that modern (<50-year old) recharge has penetrated to at least this depth. Additional support for this deep penetration is provided by the detection of sulphite-reducing clostridia and faecal streptococci. Despite the upper aquifer being a poorly cemented sandstone, the residence time indicators suggest that some modern recharge is travelling via fracture systems in addition to that moving down by simple piston flow. However, the overall impact of 80 years of steady urbanisation on water quality in the aquifer beneath this suburb has in general been limited. This is attributed to a combination of factors including previous land use, dilution by direct recharge of rainfall through green-space areas including gardens, and locally high storage in the friable upper aquifer.PUBLICATION ABSTRACT
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