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CURATOR
A pinboard by
Endre Szvetnik

I cover science and tech news for Sparrho and work with Sparrho Heroes to curate, translate and disseminate scientific research to the wider public.

PINBOARD SUMMARY

Researchers discovered that HIV makes some vital immune cells behave in an unexpected way.

Researchers discovered that when HIV infects people, it makes some vital immune cells behave in an unexpected way. The discovery helps to better understand how HIV works and offers strategies to defeat it.

In 10 seconds? Immune cells called Tfh fail to help mount a defence in HIV-infected people, while they perform their proper role with other infections. Finding out the root cause of this dysfunction can help to better understand and eventually defeat the mutating virus.

What did researchers find out? That a certain type of immune cell multiplies in HIV-infected patients. There is a contradiction though: while its numbers increase, it stops perfoming the job of mobilising other immune cells. Crucially, this only happens during HIV-infections and they work normal for example with common colds.

Which cells are we talking about? Tfh or follicular helper T cells. For some reason their numbers are much more elevated in HIV-positive people, then in healthy individuals. This occurs despite the fact that HIV-infection decimates their parent group, CD4+ T cells. Patients end up with a large count of Tfh cells, who sit idly instead of helping defend against HIV.

What do they do normally? They activate B-cells, the production line for specific antibodies that go into battle with viruses. Additionally, they generate lasting ‘immune memory’, which helps fight off the same infection in the future. But in case of a HIV-patients, Tfh cells become a key reservoir and replication centre for the virus instead of promoting antibody production.

And why does this advance the search for a cure? Because it’s one more piece in the incomplete jigsaw of what HIV is. It points the investigation in the direction of the immune system’s way of defence, which is generating antibodies.

So, what are the next steps? We know the next question, which is: what is the cause of Tfh dysfunction during HIV-infection and how are their signals lost, that would normally instruct B-cells to mount a defence? Researchers are also looking at cancer trials investigating ways to improve the interaction between Tfh and B-cells. Their results could point towards new therapies against HIV-infection.

14 ITEMS PINNED

Comparative biology and pathogenesis of AIDS and hepatitis B viruses: related but different.

Abstract: AIDS (HIV) and hepatitis B viruses are remarkably similar in their sharing of reverse transcription, in their ancestral origins and common genetic elements, and in their modes of transmission. Both are hypermutable and exist as quasispecies due primarily to errors in reverse transcription, though there is severe restriction in the replicative competence of most hepatitis B mutants. They differ in the lack of an integrase in hepatitis B virus and in their pathogenesis in the infected host. HIV survives mainly by antigenic variability, immune evasion, and impairment of immune function though viral regulatory control elements seek to restrict fatal damage to the host. Hepatitis B virus survives primarily by mutation of e antigen/core genes that directly obviates cytotoxic T cell destruction of infected liver cells, or indirectly limits destruction of infected cells through induction of anergy in the cytotoxic T cell response. Most persons infected with hepatitis B virus recover completely while recovery from HIV infection is rare if ever. Hepatitis B is highly preventable by vaccine while HIV vaccine is still seeking a meaningful immunoprophylactic target. AIDS and hepatitis B represent an extreme example, among the viruses of man, in their close similarities but distinct differences. In depth details and perspectives are presented in this review.

Pub.: 01 Nov '94, Pinned: 14 Apr '18

An OX40/OX40L interaction directs successful immunity to hepatitis B virus.

Abstract: Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Pub.: 23 Mar '18, Pinned: 13 Apr '18

T follicular helper cells and antibody response to Hepatitis B virus vaccine in HIV-1 infected children receiving ART.

Abstract: HBV vaccine has 95% efficacy in children to prevent HBV infection and related cancer. We conducted a prospective study in HIV-1 infected children receiving ART (n = 49) and controls (n = 63) to assess humoral and cellular responses to HBV vaccine provided with three doses under an accelerated schedule of 4 weeks apart. At 1 month post-vaccination all children, except 4 HIV-1 infected, displayed protective antibody (ab) titers to HBV vaccine; ab titers were lower in infected children (P < 0.0001). Ab titers decreased (P < 0.0001) in both HIV-1 infected and control children at 6 months. The frequency of circulating Tfh (cTFh) cells was 20.3% for controls and 20.8% for infected children prior to vaccination and remained comparable post-vaccination. Cytokine expression by cTfh cells upon activation with HBV antigen was comparable in the two groups at baseline and 1 month post-vaccination. Higher plasma levels (P < 0.0001) of CXCL13 were found in infected children which correlated with cTfh cell frequency at baseline. In conclusion, a lower ab response to HBV vaccine was measured in HIV-1 infected children. The frequency and activation profile of cTfh cells was comparable in infected children and controls suggesting that cells other than Tfh cells are responsible for impaired ab response to HBV vaccine.

Pub.: 23 Aug '17, Pinned: 13 Apr '18

Expansion of circulating T follicular helper cells is associated with disease progression in HIV-infected individuals.

Abstract: T follicular helper (Tfh) cells within germinal centers (GC) of lymphoid tissue play an important role in HIV infection. Recently, circulating Tfh cells have been described, which share phenotypic and functional characteristics with GC Tfh cells. This study aimed to investigate the effect of HIV infection on four circulating Tfh subsets, including CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+PD-1+ cells.Peripheral blood samples were collected from 33 HIV-infected individuals and 21 healthy controls. The frequency and absolute number of CD3, CD4 and CD8 cells were detected by flow cytometry. The frequency of circulating Tfh cell subsets was also determined by flow cytometry. The correlation between the frequency of Tfh subsets and CD4 T cells counts was assessed by Pearson correlation analysis.There was no significant difference in the frequency of peripheral CD4+CXCR5+ Tfh cells between HIV-infected individuals and healthy controls. However, the percentages of circulating CD4+CXCR5+ICOS+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+PD-1+ Tfh cells were significantly higher in individuals with HIV infection than those of healthy controls. Furthermore, the percentage of CD4+CXCR5+PD-1+ Tfh cells showed negative correlation with CD4 T cell counts in HIV-infected individuals.Our results suggested the potential involvement of circulating CD4+CXCR5+PD-1+ Tfh cells during the development of HIV infection.

Pub.: 08 Feb '18, Pinned: 11 Apr '18

Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes

Abstract: by Dionysios C. Watson, Eirini Moysi, Antonio Valentin, Cristina Bergamaschi, Santhi Devasundaram, Sotirios P. Fortis, Jenifer Bear, Elena Chertova, Julian Bess Jr., Ray Sowder, David J. Venzon, Claire Deleage, Jacob D. Estes, Jeffrey D. Lifson, Constantinos Petrovas, Barbara K. Felber, George N. Pavlakis B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry) of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals. Trial registration: ClinicalTrials.gov NCT02452268

Pub.: 23 Feb '18, Pinned: 11 Apr '18

Associations of Simian Immunodeficiency Virus (SIV)-Specific Follicular CD8 + T Cells with Other Follicular T Cells Suggest Complex Contributions to SIV Viremia Control.

Abstract: Follicular CD8T (fCD8) cells reside within B cell follicles and are thought to be immune-privileged sites of HIV/SIV infection. We have observed comparable levels of fCD8 cells between chronically SIV-infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. In this study, we sought to clarify the role of SIV-specific fCD8 cells in lymph nodes during the course of SIV infection in rhesus macaques. We observed that fCD8 cells, T follicular helper (Tfh) cells, and T follicular regulatory cells (Tfreg) were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than did HVL animals, and their cell frequencies were negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfreg via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to be negatively correlated, and a positive correlation was seen between Tfreg number and viremia, suggesting possible dysfunction and suppression of an effective fCD8 cell immune response. Our data suggest that control of virus-infected cells in B cell follicles not only depends on fCD8 cell cytotoxicity but also on complex fCD8 cell associations with Tfh cells and Tfreg. Copyright © 2018 by The American Association of Immunologists, Inc.

Pub.: 07 Mar '18, Pinned: 11 Apr '18

Simian Immunodeficiency Virus (SIV)-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication.

Abstract: There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh) located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV)-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh) cells using antiviral chimeric antigen receptor (CAR) T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured, and CXCR5-mediated migration was evaluated using both antranswell migration assay, as well as a noveltissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVand SIVreplication inand migration to the ligand CXCL13, and concentration in B cell follicles in tissues. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure) of HIV and SIV infections.

Pub.: 05 Apr '18, Pinned: 11 Apr '18

Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers.

Abstract: T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 (Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6-expressing CD4(+) T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5(lo)ICOS(lo)), and it was found exclusively outside GCs. CXCR5(lo)ICOS(lo) CD4(+) T cells secreted larger amounts of IL-21 and IL-10 than CXCR5(hi)ICOS(hi) GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS-ligand interaction. CXCR5(lo)ICOS(lo) CD4(+) T cells expressed equivalent amounts of BCL6 transcript with CXCR5(hi)ICOS(hi) GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5(lo)ICOS(lo) CD4(+) T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs.

Pub.: 03 Aug '11, Pinned: 11 Apr '18