Species-specific differences in antagonism of APOBEC3 proteins by HIV-2 and SIVsmm Vif proteins

ABSTRACTSIVsmm infecting sooty mangabeys has been transmitted to humans on at least nine independent occasions, giving rise to HIV-2 groups A to I. SIVsmm isolates replicate in human T cells and seem capable of overcoming major human restriction factors without adaptation. However, only groups A and B are responsible for the HIV-2 epidemic in Sub-Saharan Africa and it is largely unclear whether adaptive changes were associated with significant spread in humans. To address this, we examined the sensitivity of infectious molecular clones (IMCs) of five HIV-2 strains (4 group A and one AB recombinant) and representatives of five different SIVsmm lineages to inhibition by type I interferon (IFN) and various APOBEC3 proteins. We confirmed that SIVsmm strains replicate in primary human CD4+ T cells. However, SIVsmm replication was highly variable, typically lower relative to HIV-2 isolates and almost entirely prevented by type I IFN treatment. Viral propagation was generally dependent on intact vif genes, highlighting the need for efficient counteraction of APOBEC3 proteins. On average, SIVsmm strains were significantly more susceptible to inhibition by human APOBEC3D, F, G and H than HIV-2 IMCs. For example, human APOBEC3F reduced infectious virus yield of SIVsmm by ∼80% but achieved only ∼40% in the case of HIV-2. Functional and mutational analyses of human, sooty mangabey and rhesus macaque derived alleles revealed that an R128T polymorphism in APOBEC3F is important for species-specific counteraction by HIV-2 and SIVsmm Vif proteins. In addition, we found that changes of Y45H and T84S in SIVsmm Vif increase its ability to antagonize human APOBEC3F. Altogether, our results show that SIVsmm Vifs show some intrinsic activity against human ABOBEC3 proteins, but HIV-2 Vifs acquired adaptive changes to efficiently clear this barrier in the human host.AUTHOR SUMMARYSIVs infecting African monkey species do not infect humans, with one notable exception. SIVsmm from sooty mangabeys managed to cross the species barrier to humans on at least nine independent occasions. This is because SIVsmm strains seem capable of overcoming many innate defense mechanisms without adaptation and that their Vif proteins are active against human APOBEC3 proteins. Here, we show that replication of SIVsmm is highly variable in human CD4 T cells and more sensitive to interferon inhibition compared to HIV-2. While different lineages of SIVsmm were capable of counteracting human APOBEC3 proteins in a Vif-dependent manner, they were significantly more susceptible to inhibition by APOBEC3D/F/G/H compared to HIV-2. Mutational analyses revealed an R128T substitution in APOBEC3F and a T84S change in Vif are relevant for species-specific counteraction by HIV-2 and SIVsmm. Altogether, our results support that HIV-2 group A adapted to humans prior to or during epidemic spread.

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APOBEC3F constitutes a barrier to successful cross-species transmission of SIVsmm to humans

Journal of Virology ◽

10.1128/jvi.00808-21 ◽

2021 ◽

Author(s):

Rayhane Nchioua ◽

Dorota Kmiec ◽

Amit Gaba ◽

Christina M. Stürzel ◽

Tyson Follack ◽

...

Keyword(s):

T Cells ◽

Sub Saharan Africa ◽

Intrinsic Activity ◽

Significant Activity ◽

Restriction Factors ◽

Innate Defense ◽

Human T Cells ◽

Sooty Mangabeys ◽

Apobec3 Proteins ◽

Species Specific

SIVsmm infecting sooty mangabeys has been transmitted to humans on at least nine occasions, giving rise to HIV-2 groups A to I. SIVsmm isolates replicate in human T cells and seem capable of overcoming major human restriction factors without adaptation. However, only groups A and B are responsible for the HIV-2 epidemic in Sub-Saharan Africa and it is largely unclear whether adaptive changes were associated with spread in humans. To address this, we examined the sensitivity of infectious molecular clones (IMCs) of five HIV-2 strains and representatives of five different SIVsmm lineages to various APOBEC3 proteins. We confirmed that SIVsmm strains replicate in human T cells, albeit with more variable and frequently lower efficiency than HIV-2 IMCs. Efficient viral propagation was generally dependent on intact vif genes, highlighting the need for counteraction of APOBEC3 proteins. On average, SIVsmm was more susceptible to inhibition by human APOBEC3D, F, G and H than HIV-2. For example, human APOBEC3F reduced infectious virus yield of SIVsmm by ∼80% but achieved only ∼40% in the case of HIV-2. Functional and mutational analyses of human and monkey derived alleles revealed that an R128T polymorphism in APOBEC3F contributes to species-specific counteraction by HIV-2 and SIVsmm Vif proteins. In addition, a T84S substitution in SIVsmm Vif increased its ability to counteract human APOBEC3F. Altogether, our results confirm that SIVsmm Vifs show intrinsic activity against human ABOBEC3 proteins but also demonstrate that epidemic HIV-2 strains evolved an increased ability to counteract this class of restriction factors during human adaptation. IMPORTANCE Viral zoonoses pose a significant threat to human health and it is important to understand determining factors. SIVs infecting great apes gave rise to HIV-1. In contrast, SIVs infecting African monkey species have not been detected in humans, with one notable exception. SIVsmm from sooty mangabeys crossed the species barrier to humans on at least nine independent occasions and seems capable of overcoming many innate defense mechanisms without adaptation. Here, we confirmed that SIVsmm Vif proteins show significant activity against human APOBEC3 proteins. Our analyses also revealed, however, that different lineages of SIVsmm are significantly more susceptible to inhibition by various human APOBEC3 proteins than HIV-2 strains. Mutational analyses suggest that a R128T substitution in APOBEC3F and a T84S change in Vif contribute to species-specific counteraction by HIV-2 and SIVsmm. Altogether, our results support that epidemic HIV-2 strains acquired increased activity against human APOBEC3 proteins to clear this restrictive barrier.

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Faculty Opinions recommendation of Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1091063.544447 ◽

2007 ◽

Author(s):

Claire Chougnet

Keyword(s):

T Cells ◽

Simian Immunodeficiency Virus ◽

Cd4 T Cells ◽

Immunodeficiency Virus ◽

Sooty Mangabeys

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T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8

Nature Communications ◽

10.1038/s41467-021-25404-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mai T. Tran ◽

Pouya Faridi ◽

Jia Jia Lim ◽

Yi Tian Ting ◽

Goodluck Onwukwe ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Type I Diabetes ◽

Binding Motif ◽

Type I ◽

Cell Repertoire ◽

Islet Amyloid ◽

Autoreactive T Cell ◽

Β Chain

AbstractHLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.

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Interferon-inducible miR-128 modulates HIV-1 replication by targeting TNPO3 mRNA

10.1101/195511 ◽

2017 ◽

Author(s):

Aurore Bochnakian ◽

Dimitrios G Zisoulis ◽

Adam Idica ◽

Anjie Zhen ◽

Vineet N KewalRamani ◽

...

Keyword(s):

T Cells ◽

Nuclear Import ◽

Cd4 T Cells ◽

Jurkat Cells ◽

Type I ◽

Coding Region ◽

Aids Pandemic ◽

Mrna And Protein Expression ◽

Dual Mechanism ◽

Hiv 1

ABSTRACTThe HIV/AIDS pandemic remains an important threat to human health. We have recently demonstrated that a novel microRNA (miR-128) represses retrotransposon (LINE-1 or L1) by a dual mechanism, by directly targeting the coding region of the L1 RNA and by repressing a required nuclear import factor (TNPO1). We have further determined that miR-128 represses the expression of all three isoforms of TNPO proteins (transportins, TNPO1,-2 and TNPO3). Here, we establish that miR-128 also controls HIV-1 replication by repressing TNPO3. TNPO3 is well established to regulate HIV-1 nuclear import and viral replication. Here, we report that the type I interferon inducible miR-128 directly targets two sites in the TNPO3 mRNA, significantly down-regulating TNPO3 mRNA and protein expression levels. Manipulation of miR-128 levels in HIV target cell lines and in primary human CD4 T-cells by over-expression or knockdown showed that modulation of TNPO3 by miR-128 affects HIV-1 replication but not MLV infection. In addition, we found that miR-128 modulation of HIV-1 replication is reduced with TNPO3-independent HIV-1 virus and in cells depleted of CPSF6, suggesting that miR-128-indued TNPO3 repression is partly required for miR-128-induced inhibition of HIV-1 replication. Finally, challenging miR-modulated Jurkat cells or primary CD4 T-cells with wildtype, replication-competent HIV-1 shows that miR-128 significantly delays spreading infection. Thus, we have established a novel role of miR-128 in anti-viral defense in human cells, inhibiting HIV-1 replication partly by targeting TNPO3.

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Immune response evaluation in Balb/c mice after crude extract of Anisakis typica sensitization

Veterinary World ◽

10.14202/vetworld.2019.1529-1534 ◽

2019 ◽

Vol 12 (10) ◽

pp. 1529-1534

Author(s):

Linda Haryadi ◽

Eddy Suprayitno ◽

Aulanni'am Aulanni'am ◽

Anik Martinah Hariati

Keyword(s):

Immune Response ◽

T Cells ◽

Crude Extract ◽

Cd4 T Cells ◽

Classical Model ◽

Economic Value ◽

Dependent Manner ◽

T Helper ◽

Food Antigens ◽

Ifn Γ

Background and Aim: Anisakis is a global challenge for a fish product which may lead to a decrease in economic value and consumers' preference. Skipjack (Katsuwonus pelamis) in Kupang, Nusa Tenggara Timur, Indonesia, have important economic value for local fisheries. Anisakis typica is one of the Anisakis species which potent to induce an allergic reaction. However, the study about A. typica involved in the dendritic cells (DCs), T helper 1 (Th1), T helper 2 (Th2), and regulatory T cells (Tregs) is still limited. This study aimed to analyze the dynamic changed of the immune system including DCs, CD4+ T cells, and Tregs after 1 week of A. typica sensitization. Materials and Methods: Twenty-four male Balb/C mice were randomly divided into four groups (n=6), mice treated with crude A. typica extract (CAE) 50, 75, and 100 mg/kg BW, respectively. CAE was given orally per day for a week. At the end of the experiment, the animals were sacrificed and the spleen was collected. DCs were labeled as CD11c+ interleukin-6+ (IL-6+); CD4+ T cells were distinguished as Th1 (CD4+ interferon-γ+ [IFN-γ+]) and Th2 (CD4+ IL-4+ and CD4+ IL-5+); Tregs were labeled as CD4+CD25+CD62L+. The expression of each cell was determined by flow cytometry. Results: Our result described that CAE elicits CD11c+ IL-6+, CD4+ IFN-γ+, CD4+ IL-4+, and CD4+ IL-5+ and reduces CD4+CD25+CD62L+ significantly (p<0.05) in dose-dependent manner in mice after A. typica infection. Conclusion: The Th1/Th2 ratio after A. typica crude extract treatment exhibits a mixed pattern rather than the classical model allergy to food antigens. Our study is expected as a basic understanding of the changes in immune response after A. typica infection.

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Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism

Blood ◽

10.1182/blood-2007-09-113654 ◽

2008 ◽

Vol 111 (10) ◽

pp. 5163-5172 ◽

Cited By ~ 31

Author(s):

Jing Chen ◽

Mike Petrus ◽

Bonita R. Bryant ◽

Vinh Phuc Nguyen ◽

Mindy Stamer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Ex Vivo ◽

Proximal Promoter ◽

Type I ◽

Dependent Manner ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Spontaneous Proliferation

AbstractThe etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-κB motif in its proximal promoter, whereas IL-9 receptor-α (IL-9Rα) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Rα in ATL, a neutralizing monoclonal antibody directed toward IL-9Rα inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Rα on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Rα/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.

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Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

Cellular Physiology and Biochemistry ◽

10.1159/000374058 ◽

2015 ◽

Vol 36 (1) ◽

pp. 133-140 ◽

Cited By ~ 7

Author(s):

Jin-Chao Xu ◽

Yong-Bo Peng ◽

Ming-Yu Wei ◽

Yi-Fan Wu ◽

Donglin Guo ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Transient Receptor Potential ◽

Imaging System ◽

Receptor Potential ◽

Dependent Manner ◽

Ip3 Receptor ◽

Trpc3 Channel

Background/Aims: Bitter-tasting chloroquine can suppress T cell activation by inhibiting Ca2+ signaling. However, the mechanism of inhibition remains largely unclear. Methods: In this study, CD4+ T cells were isolated from the thymus, and the calcium content of CD4+ thymocytes was measured using fura-2 AM and a TILL imaging system. Pyrazole-3 (Pyr3), thapsigargin (TG), and caffeine were used to assess the effects of chloroquine on the intracellular Ca2+ content of CD4+ T cells. Results: In murine CD4+ thymocytes, chloroquine decreased the TG-triggered intracellular Ca2+ increase in a dose-dependent manner. In the absence of chloroquine under Ca2+-free conditions (0 mM Ca2+ and 0.5 mM EGTA), TG induced a transient Ca2+ increase. After restoration of the extracellular Ca2+ concentration to 2 mM, a dramatic Ca2+ increase occurred. This elevation was completely blocked by chloroquine and was markedly inhibited by Pyr3, a selective antagonist of transient receptor potential C3 (TRPC3) channel and stromal interaction molecule (STIM)/Orai channel. Furthermore, the TG-induced transient Ca2+ increase under Ca2+-free conditions was eliminated in the presence of chloroquine. Chloroquine also blocked the dialyzed inositol-1,4,5-trisphosphate (IP3)-induced intracellular Ca2+ increase. However, chloroquine was not able to decrease the caffeine-induced Ca2+ increase. Conclusion: These data indicate that chloroquine inhibits the elevation of intracellular Ca2+ in thymic CD4+ T cells by inhibiting IP3 receptor-mediated Ca2+ release from intracellular stores and TRPC3 channel-mediated and/or STIM/Orai channel-mediated Ca2+ influx.

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Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2108157118 ◽

2021 ◽

Vol 118 (46) ◽

pp. e2108157118

Author(s):

Kerstin Narr ◽

Yusuf I. Ertuna ◽

Benedict Fallet ◽

Karen Cornille ◽

Mirela Dimitrova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cd4 T Cells ◽

Memory B Cells ◽

Type I ◽

Clonal Deletion ◽

Cell Immunity ◽

B Cell Immunity

Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)–driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called “decimation,” of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I–driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell–intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell–mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell–based vaccination against persistent viral diseases.

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The activation of bystander CD8+ T cells and their roles in viral infection

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0316-1 ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Tae-Shin Kim ◽

Eui-Cheol Shin

Keyword(s):

T Cells ◽

Viral Infections ◽

Hepatitis A Virus ◽

Tissue Injury ◽

Strong Association ◽

Killer Cell ◽

Type I Interferons ◽

Type I ◽

Dependent Manner ◽

Bystander Activation

AbstractDuring viral infections, significant numbers of T cells are activated in a T cell receptor-independent and cytokine-dependent manner, a phenomenon referred to as “bystander activation.” Cytokines, including type I interferons, interleukin-18, and interleukin-15, are the most important factors that induce bystander activation of T cells, each of which plays a somewhat different role. Bystander T cells lack specificity for the pathogen, but can nevertheless impact the course of the immune response to the infection. For example, bystander-activated CD8+ T cells can participate in protective immunity by secreting cytokines, such as interferon-γ. They also mediate host injury by exerting cytotoxicity that is facilitated by natural killer cell-activating receptors, such as NKG2D, and cytolytic molecules, such as granzyme B. Interestingly, it has been recently reported that there is a strong association between the cytolytic function of bystander-activated CD8+ T cells and host tissue injury in patients with acute hepatitis A virus infection. The current review addresses the induction of bystander CD8+ T cells, their effector functions, and their potential roles in immunity to infection, immunopathology, and autoimmunity.

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