scholarly journals APOBEC3 versus Retroviruses, Immunity versus Invasion: Clash of the Titans

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ann M. Sheehy ◽  
Julie Erthal
Keyword(s):  
Clinical Intervention ◽  
Immune Defense ◽  
Restriction Factors ◽  
Defense Proteins ◽  
Tremendous Amount ◽  
Unexpected Findings ◽  
And Function ◽  
Vif Protein ◽  
Hiv 1

Since the identification of APOBEC3G (A3G) as a potent restriction factor of HIV-1, a tremendous amount of effort has led to a broadened understanding of both A3G and the APOBEC3 (A3) family to which it belongs. In spite of the fine-tuned viral counterattack to A3 activity, in the form of the HIV-1 Vif protein, enthusiasm for leveraging the Vif : A3G axis as a point of clinical intervention remains high. In an impressive explosion of information over the last decade, additional A3 family members have been identified as antiviral proteins, mechanistic details of the restrictive capacity of these proteins have been elucidated, structure-function studies have revealed important molecular details of the Vif : A3G interaction, and clinical cohorts have been scrutinized for correlations between A3 expression and function and viral pathogenesis. In the last year, novel and unexpected findings regarding the role of A3G in immunity have refocused efforts on exploring the potential of harnessing the natural power of this immune defense. These most recent reports allude to functions of the A3 proteins that extend beyond their well-characterized designation as restriction factors. The emerging story implicates the A3 family as not only defense proteins, but also as participants in the broader innate immune response.

scholarly journals Structure, Function, and Interactions of the HIV-1 Capsid Protein

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 100
Author(s):  
Eric Rossi ◽  
Megan E. Meuser ◽  
Camille J. Cunanan ◽  
Simon Cocklin
Keyword(s):  
Life Cycle ◽  
Capsid Protein ◽  
Adaptor Proteins ◽  
Restriction Factors ◽  
Gag Polyprotein ◽  
Immunodeficiency Virus ◽  
Host Cell Factors ◽  
Hiv 1

The capsid (CA) protein of the human immunodeficiency virus type 1 (HIV-1) is an essential structural component of a virion and facilitates many crucial life cycle steps through interactions with host cell factors. Capsid shields the reverse transcription complex from restriction factors while it enables trafficking to the nucleus by hijacking various adaptor proteins, such as FEZ1 and BICD2. In addition, the capsid facilitates the import and localization of the viral complex in the nucleus through interaction with NUP153, NUP358, TNPO3, and CPSF-6. In the later stages of the HIV-1 life cycle, CA plays an essential role in the maturation step as a constituent of the Gag polyprotein. In the final phase of maturation, Gag is cleaved, and CA is released, allowing for the assembly of CA into a fullerene cone, known as the capsid core. The fullerene cone consists of ~250 CA hexamers and 12 CA pentamers and encloses the viral genome and other essential viral proteins for the next round of infection. As research continues to elucidate the role of CA in the HIV-1 life cycle and the importance of the capsid protein becomes more apparent, CA displays potential as a therapeutic target for the development of HIV-1 inhibitors.

scholarly journals Neutralizing Antibodies Targeting HIV-1 gp41

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1210
Author(s):  
Christophe Caillat ◽  
Delphine Guilligay ◽  
Guidenn Sulbaran ◽  
Winfried Weissenhorn
Keyword(s):  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Somatic Mutations ◽  
Heptad Repeat ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Research ◽  
Membrane Components ◽  
And Function ◽  
Hiv 1

HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.

scholarly journals Chemokines: understanding their role in T-lymphocyte biology

1998 ◽  
Vol 333 (3) ◽  
pp. 457-470 ◽  
Author(s):  
Stephen G. WARD ◽  
John WESTWICK
Keyword(s):  
T Lymphocytes ◽  
Chemokine Receptors ◽  
Protein Tyrosine Kinase ◽  
Cell Function ◽  
Signalling Pathways ◽  
Cc Chemokine ◽  
Intracellular Signalling Pathways ◽  
And Function ◽  
Hiv 1

The chemokines are a complex superfamily of small, secreted proteins that were initially characterized through their chemotactic effects on a variety of leucocytes. The superfamily is divided into families based on structural and genetic considerations and have been termed the CXC, CC, C and CX3C families. Chemokines from these families have a key role in the recruitment and function of T lymphocytes. Moreover, T lymphocytes have also been identified as a source of a number of chemokines. T lymphocytes also express most of the known CXC and CC chemokine receptors to an extent that depends on their state of activation/differentiation and/or the activating stimuli. The expression of two chemokine receptors, namely CXCR4 and CCR5, together with the regulated production of their respective ligands, appears to be extremely important in determining sensitivity of T cells to HIV-1 infection. The intracellular events which mediate the effects of chemokines, particularly those elicited by the CC chemokine RANTES, include activation of both G-protein- and protein tyrosine kinase-coupled signalling pathways. The present review describes our current understanding of the structure and expression of chemokines and their receptors, the effects of chemokines on T-cell function(s), the intracellular signalling pathways activated by chemokines and the role of certain chemokines and chemokine receptors in determining sensitivity to HIV-1 infection.

scholarly journals Divergence in dimerization and activity of primate APOBEC3C

2021 ◽  
Author(s):  
Amit Gaba ◽  
Mark A Hix ◽  
Sana Suhail ◽  
Ben Flath ◽  
Brock Boysan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
World Monkey ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Host Restriction ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Vif Protein ◽  
Hiv 1

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Multiple integrated analyses determined why rhA3C was not active against HIV-1 and how to increase this activity. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity also promoted dimerization. Although rhA3C shares a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C, establish the amino acid network for dimerization and increased activity, and track the loss and gain of A3C antiviral activity in primates. The coevolutionary analysis of the A3C dimerization interface provides a basis from which to analyze dimerization interfaces of other A3 family members.

scholarly journals The SAM domain of mouse SAMHD1 is critical for its activation and regulation

2017 ◽  
Author(s):  
Olga Buzovetsky ◽  
Chenxiang Tang ◽  
Kirsten Knecht ◽  
Jenna M. Antonucci ◽  
Li Wu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Bound States ◽  
Restriction Factor ◽  
Activation Process ◽  
Catalytic Core ◽  
Sam Domain ◽  
And Function ◽  
Hiv 1 ◽  
Viral Reverse Transcription

ABSTRACTHuman SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. SAMHD1 is allosterically activated by nucleotides that induce assembly of the active tetramer. Although the catalytic core of hSAMHD1 has been studied extensively, previous structures have not captured the regulatory SAM domain. In this study, we determined the first crystal structure of full-length SAMHD1 by capturing mouse SAMHD1 (mSAMHD1) structures in three different nucleotide bound states. Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we found that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide new insights into the regulation of SAMHD1 activity, thereby will facilitate the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.

scholarly journals Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx

2021 ◽  
Vol 17 (10) ◽  
pp. e1009609
Author(s):  
Michaël M. Martin ◽  
Roy Matkovic ◽  
Pauline Larrous ◽  
Marina Morel ◽  
Angélique Lasserre ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Restriction Factors ◽  
Viral Dna ◽  
Host Restriction ◽  
Viral Expression ◽  
Host Restriction Factors ◽  
Human Immunodeficiency Viruses ◽  
Hiv 1

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.

scholarly journals Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx

2021 ◽  
Author(s):  
Michaël M Martin ◽  
Roy Matkovic ◽  
Pauline Larrous ◽  
Marina Morel ◽  
Angélique Lasserre ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Restriction Factors ◽  
Viral Dna ◽  
Host Restriction ◽  
Viral Expression ◽  
Host Restriction Factors ◽  
Human Immunodeficiency Viruses ◽  
Hiv 1

Human Immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) succeed to evade host immune defenses by using their viral auxiliary proteins to antagonize host restriction factors. HIV-2/SIVsmm Vpx is known for degrading SAMHD1, a factor impeding the reverse transcription. More recently, Vpx was also shown to counteract HUSH, a complex constituted of TASOR, MPP8 and periphilin, which blocks viral expression from the integrated viral DNA. In a classical ubiquitin ligase hijacking model, Vpx bridges the DCAF1 ubiquitin ligase substrate adaptor to SAMHD1, for subsequent ubiquitination and degradation. Here, we investigated whether the same mechanism is at stake for Vpx-mediated HUSH degradation. While we confirm that Vpx bridges SAMHD1 to DCAF1, we show that TASOR can interact with DCAF1 in the absence of Vpx. Nonetheless, this association was stabilized in the presence of Vpx, suggesting the existence of a ternary complex. The N-terminal PARP-like domain of TASOR is involved in DCAF1 binding, but not in Vpx binding. We also characterized a series of HIV-2 Vpx point mutants impaired in TASOR degradation, while still degrading SAMHD1. Vpx mutants ability to degrade TASOR correlated with their capacity to enhance HIV-1 minigenome expression as expected. Strikingly, several Vpx mutants impaired for TASOR degradation, but not for SAMHD1 degradation, had a reduced binding affinity for DCAF1, but not for TASOR. In macrophages, Vpx R34A-R42A and Vpx R42A-Q47A-V48A, strongly impaired in DCAF1, but not in TASOR binding, could not degrade TASOR, while being efficient in degrading SAMHD1. Altogether, our results highlight the central role of a robust Vpx-DCAF1 association to trigger TASOR degradation. We then propose a model in which Vpx interacts with both TASOR and DCAF1 to stabilize a TASOR-DCAF1 complex. Furthermore, our work identifies Vpx mutants enabling the study of HUSH restriction independently from SAMHD1 restriction in primary myeloid cells.

scholarly journals Cellular and Biochemical Mechanisms of the Retroviral Restriction Factor SAMHD1

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Li Wu
Keyword(s):  
Host Protein ◽  
Nucleic Acid Metabolism ◽  
Target Cells ◽  
Restriction Factors ◽  
Host Proteins ◽  
Retroviral Infection ◽  
Deoxynucleoside Triphosphate ◽  
Biochemical Mechanisms ◽  
Hiv 1

Replication of HIV-1 and other retroviruses is dependent on numerous host proteins in the cells. Some of the host proteins, however, function as restriction factors to block retroviral infection of target cells. The host protein SAMHD1 has been identified as the first mammalian deoxynucleoside triphosphate triphosphohydrolase (dNTPase), which blocks the infection of HIV-1 and other retroviruses in non-cycling immune cells. SAMHD1 protein is highly expressed in human myeloid-lineage cells and CD4+ T-lymphocytes, but its retroviral restriction function is only observed in noncycling cells. Recent studies have revealed biochemical mechanisms of SAMHD1-mediated retroviral restriction. In this review, the latest progress on SAMHD1 research is summarized and the mechanisms by which SAMHD1 mediates retroviral restriction are analyzed. Although the physiological function of SAMHD1 is largely unknown, this review provides perspectives about the role of endogenous SAMHD1 protein in maintaining normal cellular function, such as nucleic acid metabolism and the proliferation of cells.

scholarly journals Vif of Feline Immunodeficiency Virus from Domestic Cats Protects against APOBEC3 Restriction Factors from Many Felids

2010 ◽  
Vol 84 (14) ◽  
pp. 7312-7324 ◽  
Author(s):  
Jörg Zielonka ◽  
Daniela Marino ◽  
Henning Hofmann ◽  
Naoya Yuhki ◽  
Martin Löchelt ◽  
...  
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Domestic Cat ◽  
Moderate Degree ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Immunodeficiency Virus ◽  
Specific Restriction ◽  
Species Specific ◽  
Vif Protein ◽  
Hiv 1

ABSTRACT To get more insight into the role of APOBEC3 (A3) cytidine deaminases in the species-specific restriction of feline immunodeficiency virus (FIV) of the domestic cat, we tested the A3 proteins present in big cats (puma, lion, tiger, and lynx). These A3 proteins were analyzed for expression and sensitivity to the Vif protein of FIV. While A3Z3s and A3Z2-Z3s inhibited Δvif FIV, felid A3Z2s did not show any antiviral activity against Δvif FIV or wild-type (wt) FIV. All felid A3Z3s and A3Z2-Z3s were sensitive to Vif of the domestic cat FIV. Vif also induced depletion of felid A3Z2s. Tiger A3s showed a moderate degree of resistance against the Vif-mediated counter defense. These findings may imply that the A3 restriction system does not play a major role to prevent domestic cat FIV transmission to other Felidae. In contrast to the sensitive felid A3s, many nonfelid A3s actively restricted wt FIV replication. To test whether VifFIV can protect also the distantly related human immunodeficiency virus type 1 (HIV-1), a chimeric HIV-1.VifFIV was constructed. This HIV-1.VifFIV was replication competent in nonpermissive feline cells expressing human CD4/CCR5 that did not support the replication of wt HIV-1. We conclude that the replication of HIV-1 in some feline cells is inhibited only by feline A3 restriction factors and the absence of the appropriate receptor or coreceptor.

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