scholarly journals Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics

2010 ◽  
Vol 12 ◽  
Author(s):  
John S. Albin ◽  
Reuben S. Harris
Keyword(s):  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Virion Infectivity Factor ◽  
Viral Particles ◽  
Viral Cdna ◽  
Basic Biology ◽  
Apobec3 Proteins ◽  
In Vivo Effects ◽  
Hiv 1

Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarise, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins, and survey strategies and progress towards developing therapeutics aimed at the APOBEC3–Vif axis.

scholarly journals Structural Insights into APOBEC3-Mediated Lentiviral Restriction

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 587 ◽  
Author(s):  
Krista A. Delviks-Frankenberry ◽  
Belete A. Desimmie ◽  
Vinay K. Pathak
Keyword(s):  
Defense Mechanisms ◽  
Cytidine Deaminase ◽  
Immune Defense ◽  
Restriction Factors ◽  
Intrinsic Immunity ◽  
Viral Pathogens ◽  
Cytidine Deaminases ◽  
Virion Infectivity Factor ◽  
Coordinated Expression ◽  
Hiv 1

Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.

scholarly journals G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission

2021 ◽  
Vol 22 (16) ◽  
pp. 8366
Author(s):  
Ignacio Relaño-Rodríguez ◽  
María de la Sierra Espinar-Buitrago ◽  
Vanessa Martín-Cañadilla ◽  
Rafael Gómez-Ramírez ◽  
María Ángeles Muñoz-Fernández
Keyword(s):  
T Cells ◽  
Developed Countries ◽  
Main Role ◽  
Viral Particles ◽  
Carbosilane Dendrimer ◽  
Science Community ◽  
New Compounds ◽  
Hiv 1

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but is also re-emerging in several developed countries, thus the development of new compounds able to inhibit the virus, either for prophylaxis or treatment, is still needed. Nanotechnology has provided the science community with several new tools for biomedical applications. G2-S16 is a polyanionic carbosilane dendrimer capable of inhibiting HIV-1 in vitro and in vivo by interacting directly with viral particles. One of the main barriers for HIV-1 eradication is the reservoirs created in primoinfection. These reservoirs, mainly in T cells, are untargetable by actual drugs or immune system. Thus, one approach is inhibiting HIV-1 from reaching these reservoir cells. In this context, macrophages play a main role as they can deliver viral particles to T cells establishing reservoirs. We showed that G2-S16 dendrimer is capable of inhibiting the infection from infected macrophages to healthy T CD4/CD8 lymphocytes by eliminating HIV-1 infectivity inside macrophages, so they are not able to carry infectious particles to other body locations, thus preventing the reservoirs from forming.

scholarly journals High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

2010 ◽  
Vol 84 (23) ◽  
pp. 12300-12314 ◽  
Author(s):  
Hanna-Mari Tervo ◽  
Oliver T. Keppler
Keyword(s):  
T Cells ◽  
Late Phase ◽  
Small Animal ◽  
Receptor Complex ◽  
Restriction Factors ◽  
Cyclin T1 ◽  
Primary Rabbit ◽  
Species Specific ◽  
Hiv 1

ABSTRACT An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

scholarly journals In vivo Effects of Romidepsin on T-Cell Activation, Apoptosis and Function in the BCN02 HIV-1 Kick&Kill Clinical Trial

2020 ◽  
Vol 11 ◽  
Author(s):  
Miriam Rosás-Umbert ◽  
Marta Ruiz-Riol ◽  
Marco A. Fernández ◽  
Marta Marszalek ◽  
Pep Coll ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
And Function ◽  
In Vivo Effects ◽  
Hiv 1

scholarly journals Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and cofactor required for A3 degradation

2020 ◽  
pp. jbc.RA120.015828
Author(s):  
Kirsten M. Knecht ◽  
Yingxia Hu ◽  
Diana Rubene ◽  
Matthew Cook ◽  
Samantha J Ziegler ◽  
...  
Keyword(s):  
Viral Infections ◽  
Zinc Ion ◽  
Binding Motif ◽  
Cytidine Deaminases ◽  
Visna Virus ◽  
Primate Lentiviruses ◽  
Maedi Visna Virus ◽  
Hiv 1

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called Vif, which recruits A3 proteins to Cullin-RING E3 ubiquitin ligases such as Cul5 for ubiquitylation and subsequent proteasomal degradation. While Vif proteins from primate lentiviruses like HIV-1 utilize the transcription factor CBFβ as a non-canonical cofactor to stabilize the complex, maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Since CBFβ and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that while some common motifs between HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.

scholarly journals Human APOBEC3G Prevents Emergence of Infectious Endogenous Retrovirus in Mice

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Rebecca S. Treger ◽  
Maria Tokuyama ◽  
Huiping Dong ◽  
Karen Salas-Briceno ◽  
Susan R. Ross ◽  
...  
Keyword(s):  
Ectopic Expression ◽  
Endogenous Retrovirus ◽  
Endogenous Retroviruses ◽  
Toll Like Receptor ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Endogenous Loci ◽  
Human Apobec3g

ABSTRACT Endogenous retroviruses (ERV) are found throughout vertebrate genomes, and failure to silence their activation can have deleterious consequences on the host. Mutation and subsequent disruption of ERV loci is therefore an indispensable component of the cell-intrinsic defenses that maintain the integrity of the host genome. Abundant in vitro and in silico evidence have revealed that APOBEC3 cytidine-deaminases, including human APOBEC3G (hA3G), can potently restrict retrotransposition; yet, in vivo data demonstrating such activity is lacking, since no replication-competent human ERV have been identified. In mice deficient for Toll-like receptor 7 (TLR7), transcribed ERV loci can recombine and generate infectious ERV. In this study, we show that ectopic expression of hA3G can prevent the emergence of replication-competent, infectious ERV in Tlr7−/− mice. Mice encode one copy of Apobec3 in their genome. ERV reactivation in Tlr7−/− mice was comparable in the presence or absence of Apobec3. In contrast, expression of a human APOBEC3G transgene abrogated emergence of infectious ERV in the Tlr7−/− background. No ERV RNA was detected in the plasma of hA3G+ Apobec3−/− Tlr7−/− mice, and infectious ERV virions could not be amplified through coculture with permissive cells. These data reveal that hA3G can potently restrict active ERV in vivo and suggest that expansion of the APOBEC3 locus in primates may have helped to provide for the continued restraint of ERV in the human genome. IMPORTANCE Although APOBEC3 proteins are known to be important antiviral restriction factors in both mice and humans, their roles in the restriction of endogenous retroviruses (ERV) have been limited to in vitro studies. Here, we report that human APOBEC3G expressed as a transgene in mice prevents the emergence of infectious ERV from endogenous loci. This study reveals that APOBEC3G can powerfully restrict active retrotransposons in vivo and demonstrates how transgenic mice can be used to investigate host mechanisms that inhibit retrotransposons and reinforce genomic integrity.

In vivo effects of methamphetamine on HIV-1 replication: A population-based study

2016 ◽  
Vol 159 ◽  
pp. 246-254 ◽  
Author(s):  
Junjun Jiang ◽  
Minlian Wang ◽  
Bingyu Liang ◽  
Yi Shi ◽  
Qijian Su ◽  
...  
Keyword(s):  
Population Based ◽  
Population Based Study ◽  
In Vivo Effects ◽  
Hiv 1

scholarly journals APOBEC proteins and intrinsic resistance to HIV-1 infection

2008 ◽  
Vol 364 (1517) ◽  
pp. 675-687 ◽  
Author(s):  
Michael H Malim
Keyword(s):  
Critical Role ◽  
Intrinsic Resistance ◽  
Cytidine Deaminases ◽  
Virus Particles ◽  
History Of ◽  
Infected Cells ◽  
Apobec Family ◽  
Negative Sense ◽  
Hiv 1

Members of the APOBEC family of cellular polynucleotide cytidine deaminases, most notably APOBEC3G and APOBEC3F, are potent inhibitors of HIV-1 infection. Wild type HIV-1 infections are largely spared from APOBEC3G/F function through the action of the essential viral protein, Vif. In the absence of Vif, APOBEC3G/F are encapsidated by budding virus particles leading to excessive cytidine (C) to uridine (U) editing of negative sense reverse transcripts in newly infected cells. This registers as guanosine (G) to adenosine (A) hypermutations in plus-stranded cDNA. In addition to this profoundly debilitating effect on genetic integrity, APOBEC3G/F also appear to inhibit viral DNA synthesis by impeding the translocation of reverse transcriptase along template RNA. Because the functions of Vif and APOBEC3G/F proteins oppose each other, it is likely that fluctuations in the Vif–APOBEC balance may influence the natural history of HIV-1 infection, as well as viral sequence diversification and evolution. Given Vif's critical role in suppressing APOBEC3G/F function, it can be argued that pharmacologic strategies aimed at restoring the activity of these intrinsic anti-viral factors in the context of infected cells in vivo have clear therapeutic merit, and therefore deserve aggressive pursuit.

scholarly journals Identification of a Novel Human Immunodeficiency Virus Type 1 Integrase Interactor, Gemin2, That Facilitates Efficient Viral cDNA Synthesis In Vivo

2006 ◽  
Vol 80 (12) ◽  
pp. 5670-5677 ◽  
Author(s):  
Seiji Hamamoto ◽  
Hironori Nishitsuji ◽  
Teruo Amagasa ◽  
Mari Kannagi ◽  
Takao Masuda
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Host Protein ◽  
Cdna Synthesis ◽  
Immunodeficiency Virus ◽  
Viral Cdna ◽  
Hiv 1

ABSTRACT Retroviral integrase (IN) catalyzes the integration of viral cDNA into a host chromosome. Additional roles have been suggested for IN, including uncoating, reverse transcription, and nuclear import of the human immunodeficiency virus type 1 (HIV-1) genome. However, the underlying mechanism is largely unknown. Here, using a yeast two-hybrid system, we identified a survival motor neuron (SMN)-interacting protein 1 (Gemin2) that binds to HIV-1 IN. Reduction of Gemin2 with small interfering RNA duplexes (siGemin2) dramatically reduced HIV-1 infection in human primary monocyte-derived macrophages and also reduced viral cDNA synthesis. In contrast, siGemin2 did not affect HIV-1 expression from the integrated proviral DNA. Although Gemin2 was undetectable in cell-free viral particles, coimmunoprecipitation experiments using FLAG-tagged Gemin2 strongly suggested that Gemin2 interacts with the incoming viral genome through IN. Further experiments reducing SMN or other SMN-interacting proteins suggested that Gemin2 might act on HIV-1 either alone or with unknown proteins to facilitate efficient viral cDNA synthesis soon after infection. Thus, we provide the evidence for a novel host protein that binds to HIV-1 IN and facilitates viral cDNA synthesis and subsequent steps that precede integration in vivo.

Sign in / Sign up

Export Citation Format

Share Document