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Advances in Experimental Medicine and... 2022The discovery of the G-protein coupled-receptor (GPCR) CXCR4 as a major coreceptor of HIV-1 entry about three decades ago explained why the chemokine SDF-1/CXCL12...
The discovery of the G-protein coupled-receptor (GPCR) CXCR4 as a major coreceptor of HIV-1 entry about three decades ago explained why the chemokine SDF-1/CXCL12 inhibits specific viral strains. The knowledge that RANTES, MlP-1α, and MlP-1β specifically inhibit other primary HIV-1 strains allowed the rapid discovery of CCR5 as second major viral coreceptor and explained why individuals with deletions in CCR5 are protected against sexual HIV-1 transmission. Here, we provide an update on endogenous ligands of GPCRs that act as endogenous inhibitors of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) entry. In addition, we summarize the development of optimized derivatives of endogenous GPCR ligands and their perspectives as antiviral agents and beyond. Finally, we provide examples for other endogenous peptides that may contribute to our innate immune defense against HIV-1 and other viral pathogens and offer prospects for preventive or therapeutic development.
Topics: Animals; HIV Fusion Inhibitors; HIV Infections; HIV-1; HIV-2; Humans; Ligands; Peptides; Receptors, CCR5; Receptors, G-Protein-Coupled; Signal Transduction; Simian Immunodeficiency Virus
PubMed: 35412135
DOI: 10.1007/978-981-16-8702-0_5 -
Viruses Mar 2021I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab...
I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab made groundbreaking discoveries on retroviral proteins during that time, including many features that could not have been inferred or anticipated from straightforward sequence information. Building on the Oroszlan lab results, my colleagues and I demonstrated that the zinc fingers in nucleocapsid proteins play a crucial role in genomic RNA encapsidation; that the N-terminal myristylation of the Gag proteins of many retroviruses is important for their association with the plasma membrane before particle assembly is completed; and that gammaretroviruses initially synthesize their Env protein as an inactive precursor and then truncate the cytoplasmic tail of the transmembrane protein, activating Env fusogenicity, during virus maturation. We also elucidated several aspects of the mechanism of translational suppression in gene expression in gammaretroviruses; amazingly, this is a fundamentally different mechanism of suppression from that in most other retroviral genera.
Topics: Cell Membrane; History, 21st Century; Retroviridae; Viral Proteins
PubMed: 33809689
DOI: 10.3390/v13030491 -
Frontiers in Cellular and Infection... 2021Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer's... (Review)
Review
Mouse mammary tumor virus (MMTV) is a virus that induces breast cancer in mice. During lactation, MMTV can transmit from mother to offspring through milk, and Peyer's patches (PPs) in mouse intestine are the first and specific target organ. MMTV can be transported into PPs by microfold cells and then activate antigen-presenting cells (APCs) by directly binding with Toll-like receptors (TLRs) whereas infect them through mouse transferrin receptor 1 (mTfR1). After being endocytosed, MMTV is reversely transcribed and the cDNA inserts into the host genome. Superantigen (SAg) expressed by provirus is presented by APCs to cognate CD4 T cells MHCII molecules to induce SAg response, which leads to substantial proliferation and recruitment of related immune cells. Both APCs and T cells can be infected by MMTV and these extensively proliferated lymphocytes and recruited dendritic cells act as hotbeds for viral replication and amplification. In this case, intestinal lymphatic tissues can actually become the source of infection for the transmission of MMTV , which results in mammary gland infection by MMTV and eventually lead to the occurrence of breast cancer.
Topics: Animals; Female; Intestines; Mammary Tumor Virus, Mouse; Mice; Mice, Inbred BALB C; Retroviridae Infections; Superantigens; T-Lymphocytes; Tumor Virus Infections
PubMed: 35096654
DOI: 10.3389/fcimb.2021.807462 -
PLoS Pathogens Feb 2023The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), primarily infects CD4+ T-cells in vivo. Infectious spread within this cell population requires...
The complex retrovirus, human T-cell leukemia virus type 1 (HTLV-1), primarily infects CD4+ T-cells in vivo. Infectious spread within this cell population requires direct contact between virally-infected and target cells. The HTLV-1 accessory protein, HBZ, was recently shown to enhance HTLV-1 infection by activating intracellular adhesion molecule 1 (ICAM-1) expression, which promotes binding of infected cells to target cells and facilitates formation of a virological synapse. In this study we show that HBZ additionally enhances HTLV-1 infection by activating expression of myoferlin (MyoF), which functions in membrane fusion and repair and vesicle transport. Results from ChIP assays and quantitative reverse transcriptase PCR indicate that HBZ forms a complex with c-Jun or JunB at two enhancer sites within the MYOF gene and activates transcription through recruitment of the coactivator p300/CBP. In HTLV-1-infected T-cells, specific inhibition of MyoF using the drug, WJ460, or shRNA-mediated knockdown of MyoF reduced infection efficiency. This effect was associated with a decrease in cell adhesion and an intracellular reduction in the abundance of HTLV-1 envelope (Env) surface unit (SU) and transmembrane domain (TM). Lysosomal protease inhibitors partially restored SU levels in WJ460-treated cells, and SU localization to LAMP-2 sites was increased by MyoF knockdown, suggesting that MyoF restricts SU trafficking to lysosomes for degradation. Consistent with these effects, less SU was associated with cell-free virus particles. Together, these data suggest that MyoF contributes to HTLV-1 infection through modulation of Env trafficking and cell adhesion.
Topics: Humans; Basic-Leucine Zipper Transcription Factors; CD4-Positive T-Lymphocytes; Human T-lymphotropic virus 1; Retroviridae Proteins
PubMed: 36827461
DOI: 10.1371/journal.ppat.1011202 -
Progress in Biophysics and Molecular... Mar 2021Electron cryotomography is a rapidly evolving method for imaging macromolecules directly within the native environment of cells and tissues. Combined with sub-tomogram... (Review)
Review
Electron cryotomography is a rapidly evolving method for imaging macromolecules directly within the native environment of cells and tissues. Combined with sub-tomogram averaging, it allows structural and cell biologists to obtain sub-nanometre resolution structures in situ. However, low throughput in cryo-ET sample preparation and data acquisition, as well as difficulties in target localisation and sub-tomogram averaging image processing, limit its widespread usability. In this review, we discuss new advances in the field that address these throughput and technical problems. We focus on recent efforts made to resolve issues in sample thinning, improvement in data collection speed at the microscope, strategies for localisation of macromolecules using correlated light and electron microscopy and advancements made to improve resolution in sub-tomogram averaging. These advances will considerably decrease the amount of time and effort required for cryo-ET and sub-tomogram averaging, ushering in a new era of structural biology where in situ macromolecular structure determination will be routine.
Topics: Capsid Proteins; Cells; Cryoelectron Microscopy; High-Throughput Screening Assays; Humans; Image Processing, Computer-Assisted; Macromolecular Substances; Molecular Conformation; Optical Imaging; Retroviridae; Viral Proteins
PubMed: 32579969
DOI: 10.1016/j.pbiomolbio.2020.05.010 -
Viruses Apr 2021My memories of Steve go back over 50 years. While precise dates are no longer in my memory bank, circumstances and emotions remain alive and easy to recall. These...
My memories of Steve go back over 50 years. While precise dates are no longer in my memory bank, circumstances and emotions remain alive and easy to recall. These memories tell the story of a remarkable human being, a true practitioner of his craft always, faithful to the basic principles of scientific pursuit, with integrity, honesty, and enthusiasm well beyond the norm. We had a professional symbiotic relationship that lasted over 20 years, resulting in over 50 publications in scientific journals and meeting abstracts. During that time, our fortunes rose in tandem, and when it was time to go our separate ways, he was more than ready to flourish on his own. Our personal friendship remained constant, and we enjoyed sharing meals and stories with family and friends over the years. In retrospect, I take pride in having played a role in a portion of his remarkable scientific journey. A few key anecdotes will illustrate some aspects of this summary. By way of a disclaimer, this is not a comprehensive review of the vast field of viral oncology and the selection of references is intentionally narrow. No slight is intended to the many outstanding investigators that were our contemporaries and at times collaborators during the period from the early 70s to the mid-80s.
Topics: HIV; History, 20th Century; History, 21st Century; Humans; Male; Narration; Research; Retroviridae
PubMed: 33916360
DOI: 10.3390/v13040622 -
Postepy Biochemii Dec 2020Oncogenic viruses (oncoviruses) are implicated in approximately 12% of all human cancers. Currently, the viruses known to cause human cancer are: Hepatitis B and C...
Oncogenic viruses (oncoviruses) are implicated in approximately 12% of all human cancers. Currently, the viruses known to cause human cancer are: Hepatitis B and C viruses (HBV and HCV), Human Papillomaviruses (HPV), Merkel Cell Polyomavirus (MCV), Human Herpesvirus-8 (HHV-8), Epstein-Barr Virus (EBV) and Human T-cell lymphotropic virus-1 (HTLV-1). However, oncoviruses are not complete carcinogens, need additional factors andisplay different roles in transformation. Oncoviruses can directly disrupt important regulatory cell genes by inserting virus genom into the DNA of the host cell. They also contain their own genes that damage the regulation of the cell. Some viruses have v-onc that cause disregulation of cellular processes and can lead to cancerous growth.
Topics: Hepacivirus; Humans; Neoplasms; Oncogenic Viruses; Retroviridae
PubMed: 33470075
DOI: 10.18388/pb.2020_360 -
Retrovirology Sep 2022
Topics: Awards and Prizes; Retroviridae
PubMed: 36068604
DOI: 10.1186/s12977-022-00606-3 -
Voprosy Virusologii Dec 2023The review article conducts an in-depth analysis of information gleaned from a comprehensive literature search across Scopus, Web of Science, and MedLine databases. The... (Review)
Review
The review article conducts an in-depth analysis of information gleaned from a comprehensive literature search across Scopus, Web of Science, and MedLine databases. The focal point of this search revolves around the identification and exploration of the mechanisms orchestrated by host cell factors in the replication cycle of the human immunodeficiency virus (HIV-1, Retroviridae: ). The article delves into two primary categories of proteins, namely HIV dependence factors (such as CypA, LEDGF, TSG101) and restriction factors (including SERINС5, TRIM5α, APOBEC3G), providing illustrative examples. The current understanding of the functioning mechanisms of these proteins is elucidated, and an evaluation is presented on the potential development of drugs for treating HIV infection. These drugs aim to either inhibit or stimulate the activity of host factors, offering insights into promising avenues for future research and therapeutic advancements.
Topics: Humans; HIV Infections; Ubiquitin-Protein Ligases; Cell Line; HIV-1; Virus Replication
PubMed: 38156565
DOI: 10.36233/0507-4088-207 -
Viruses Jan 2021The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses.... (Review)
Review
The APOBEC3 family of proteins in mammals consists of cellular cytosine deaminases and well-known restriction factors against retroviruses, including lentiviruses. genes are highly amplified and diversified in mammals, suggesting that their evolution and diversification have been driven by conflicts with ancient viruses. At present, lentiviruses, including HIV, the causative agent of AIDS, are known to encode a viral protein called Vif to overcome the antiviral effects of the APOBEC3 proteins of their hosts. Recent studies have revealed that the acquisition of an anti-APOBEC3 ability by lentiviruses is a key step in achieving successful cross-species transmission. Here, we summarize the current knowledge of the interplay between mammalian APOBEC3 proteins and viral infections and introduce a scenario of the coevolution of mammalian genes and viruses.
Topics: APOBEC Deaminases; Animals; Disease Resistance; Evolution, Molecular; Genetic Variation; Genome, Viral; Host-Pathogen Interactions; Humans; Lentivirus; Phylogeny; Retroviridae; Retroviridae Infections; Species Specificity; vif Gene Products, Human Immunodeficiency Virus
PubMed: 33477360
DOI: 10.3390/v13010124