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1.
Front Immunol ; 15: 1338218, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742109

RESUMO

Cytotoxic T lymphocyte (CTL) motility is an important feature of effective CTL responses and is impaired when CTLs become exhausted, e.g. during chronic retroviral infections. A prominent T cell exhaustion marker is programmed cell death protein 1 (PD-1) and antibodies against the interaction of PD-1 and PD-ligand 1 (PD-L1) are known to improve CTL functions. However, antibody blockade affects all PD-1/PD-L1-expressing cell types, thus, the observed effects cannot be attributed selectively to CTLs. To overcome this problem, we performed CRISPR/Cas9 based knockout of the PD-1 coding gene PDCD1 in naïve Friend Retrovirus (FV)-specific CTLs. We transferred 1,000 of these cells into mice where they proliferated upon FV-infection. Using intravital two-photon microscopy we visualized CTL motility in the bone marrow and evaluated cytotoxic molecule expression by flow cytometry. Knockout of PDCD1 improved the CTL motility at 14 days post infection and enhanced the expression of cytotoxicity markers. Our data show the potential of genetic tuning of naive antiviral CTLs and might be relevant for future designs of improved T cell-mediated therapies.


Assuntos
Movimento Celular , Camundongos Knockout , Receptor de Morte Celular Programada 1 , Infecções por Retroviridae , Linfócitos T Citotóxicos , Animais , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Movimento Celular/genética , Infecções por Retroviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Camundongos Endogâmicos C57BL , Vírus da Leucemia Murina de Friend/imunologia , Técnicas de Inativação de Genes , Linfócitos T CD8-Positivos/imunologia , Sistemas CRISPR-Cas , Citotoxicidade Imunológica
2.
New Microbiol ; 47(1): 38-46, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38700882

RESUMO

The shortage of organs for human transplantation is a topic of extreme interest, and xenotransplantation with porcine organs has been recognized as a promising solution. However, the potential spillover linked to infectious agents present in pigs remains a concern. Among these, Pig Endogenous Retroviruses (PERVs), whose proviral DNAs are integrated in the genome of all pig breeds, represent an extremely important biological risk. This study aims to evaluate PERVs distribution in several swine cell lines and samples of domestic and feral pigs. Moreover, the capacity of PERVs to infect human and non-human primate cells and to integrate in the cellular genome was tested by Real-Time PCR and by Reverse Transcriptase assay. Results indicated a widespread diffusion of PERVs both in cell lines and samples analysed: the viral genome was found in all the established cell lines, in 40% of the primary cell lines and in 60% of the tissue samples tested. The assays indicated that the virus can be transmitted from porcine to human cells: in the specific case, infected NSK and NPTr cells allow passage to human 293 and MRC-5 cells with active production of the virus demonstrable via PCR and RT assay. In light of these aspects and also the lack of studies on PERVs, it appears clear that there are still many questions to be clarified, also by means of future studies, before xenotransplantation can be considered microbiologically safe.


Assuntos
Retrovirus Endógenos , Animais , Retrovirus Endógenos/genética , Retrovirus Endógenos/isolamento & purificação , Suínos , Humanos , Linhagem Celular , Infecções por Retroviridae/veterinária , Infecções por Retroviridae/virologia , Infecções por Retroviridae/transmissão
3.
Microbiol Spectr ; 12(6): e0432323, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38687078

RESUMO

An investigation into retrovirus was conducted in six species of bats (Myotis aurascens, Myotis petax, Myotis macrodactylus, Miniopterus fuliginosus, Rhinolophus ferrumequinum, and Pipistrellus abramus) inhabiting South Korea. Exogenous retroviruses (XRVs) were detected in the tissue samples of R. ferrumequinum individuals by PCR assay. Proviruses were identified in all tissue samples through viral quantification using a digital PCR assay per organ (lung, intestine, heart, brain, wing, kidney, and liver), with viral loads varying greatly between each organ. In phylogenetic analysis based on the whole genome, the Korean bat retroviruses and the R. ferrumequinum retrovirus (RfRV) strain formed a new clade distinct from the Gammaretrovirus clade. The phylogenetic results determined these viruses to be RfRV-like viruses. In the Simplot comparison, Korean RfRV-like viruses exhibited relatively strong fluctuated patterns in the latter part of the envelope gene area compared to other gene areas. Several point mutations within this region (6,878-7,774 bp) of these viruses were observed compared to the RfRV sequence. One Korean RfRV-like virus (named Y4b strain) was successfully recovered in the Raw 264.7 cell line, and virus particles replicated in the cells were confirmed by transmission electron microscopy. RfRVs (or RfRV-like viruses) have been spreading since their first discovery in 2012, and the Korean RfRV-like viruses were assumed to be XRVs that evolved from RfRV.IMPORTANCER. ferrumequinum retrovirus (RfRV)-like viruses were identified in greater horseshoe bats in South Korea. These RfRV-like viruses were considered exogenous retroviruses (XRVs) that emerged from RfRV. Varying amounts of provirus detected in different organs suggest ongoing viral activity, replication, and de novo integration in certain organs. Additionally, the successful recovery of the virus in the Raw 264.7 cell line provides strong evidence supporting their status as XRVs. These viruses have now been identified in South Korea and, more recently, in Kenya since RfRV was discovered in China in 2012, indicating that RfRVs (or RfRV-like viruses) have spread worldwide.


Assuntos
Quirópteros , Filogenia , Animais , Quirópteros/virologia , República da Coreia , Camundongos , Provírus/genética , Provírus/isolamento & purificação , Infecções por Retroviridae/virologia , Infecções por Retroviridae/veterinária , Retroviridae/isolamento & purificação , Retroviridae/classificação , Retroviridae/genética , Genoma Viral , Carga Viral
4.
Viruses ; 16(4)2024 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-38675836

RESUMO

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity.


Assuntos
HIV-1 , Vírus da Leucemia Murina , Fosfoproteínas , Animais , Camundongos , Humanos , HIV-1/imunologia , HIV-1/genética , Vírus da Leucemia Murina/genética , Vírus da Leucemia Murina/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/imunologia , Replicação Viral , Linhagem Celular , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/virologia
5.
Front Cell Infect Microbiol ; 14: 1379962, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38655281

RESUMO

The notion that viruses played a crucial role in the evolution of life is not a new concept. However, more recent insights suggest that this perception might be even more expansive, highlighting the ongoing impact of viruses on host evolution. Endogenous retroviruses (ERVs) are considered genomic remnants of ancient viral infections acquired throughout vertebrate evolution. Their exogenous counterparts once infected the host's germline cells, eventually leading to the permanent endogenization of their respective proviruses. The success of ERV colonization is evident so that it constitutes 8% of the human genome. Emerging genomic studies indicate that endogenous retroviruses are not merely remnants of past infections but rather play a corollary role, despite not fully understood, in host genetic regulation. This review presents some evidence supporting the crucial role of endogenous retroviruses in regulating host genetics. We explore the involvement of human ERVs (HERVs) in key physiological processes, from their precise and orchestrated activities during cellular differentiation and pluripotency to their contributions to aging and cellular senescence. Additionally, we discuss the costs associated with hosting a substantial amount of preserved viral genetic material.


Assuntos
Retrovirus Endógenos , Retrovirus Endógenos/genética , Retrovirus Endógenos/fisiologia , Humanos , Animais , Diferenciação Celular , Interações Hospedeiro-Patógeno/genética , Interações entre Hospedeiro e Microrganismos/genética , Infecções por Retroviridae/virologia , Senescência Celular/genética , Provírus/genética , Provírus/fisiologia , Evolução Molecular
6.
Viruses ; 16(3)2024 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-38543763

RESUMO

The interest in endogenous retroviruses (ERVs) has been fueled by their impact on the evolution of the host genome. In this study, we used multiple pipelines to conduct a de novo exploration and annotation of ERVs in 13 species of the Caprinae subfamily. Through analyses of sequence identity, structural organization, and phylogeny, we defined 28 ERV groups within Caprinae, including 19 gamma retrovirus groups and 9 beta retrovirus groups. Notably, we identified four recent and potentially active groups prevalent in the Caprinae genomes. Additionally, our investigation revealed that most long noncoding genes (lncRNA) and protein-coding genes (PC) contain ERV-derived sequences. Specifically, we observed that ERV-derived sequences were present in approximately 75% of protein-coding genes and 81% of lncRNA genes in sheep. Similarly, in goats, ERV-derived sequences were found in approximately 74% of protein-coding genes and 75% of lncRNA genes. Our findings lead to the conclusion that the majority of ERVs in the Caprinae genomes can be categorized as fossils, representing remnants of past retroviral infections that have become permanently integrated into the genomes. Nevertheless, the identification of the Cap_ERV_20, Cap_ERV_21, Cap_ERV_24, and Cap_ERV_25 groups indicates the presence of relatively recent and potentially active ERVs in these genomes. These particular groups may contribute to the ongoing evolution of the Caprinae genome. The identification of putatively active ERVs in the Caprinae genomes raises the possibility of harnessing them for future genetic marker development.


Assuntos
Retrovirus Endógenos , RNA Longo não Codificante , Infecções por Retroviridae , Animais , Ovinos , Retrovirus Endógenos/genética , RNA Longo não Codificante/genética , Evolução Molecular , Filogenia
7.
Commun Biol ; 7(1): 350, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514810

RESUMO

Koalas (Phascolarctos cinereus) have experienced a history of retroviral epidemics leaving their trace as heritable endogenous retroviruses (ERVs) in their genomes. A recently identified ERV lineage, named phaCin-ß, shows a pattern of recent, possibly current, activity with high insertional polymorphism in the population. Here, we investigate geographic patterns of three focal ERV lineages of increasing estimated ages, from the koala retrovirus (KoRV) to phaCin-ß and to phaCin-ß-like, using the whole-genome sequencing of 430 koalas from the Koala Genome Survey. Thousands of ERV loci were found across the population, with contrasting patterns of polymorphism. Northern individuals had thousands of KoRV integrations and hundreds of phaCin-ß ERVs. In contrast, southern individuals had higher phaCin-ß frequencies, possibly reflecting more recent activity and a founder effect. Overall, our findings suggest high ERV burden in koalas, reflecting historic retrovirus-host interactions. Importantly, the ERV catalogue supplies improved markers for conservation genetics in this endangered species.


Assuntos
Retrovirus Endógenos , Gammaretrovirus , Phascolarctidae , Infecções por Retroviridae , Humanos , Animais , Retrovirus Endógenos/genética , Phascolarctidae/genética , Infecções por Retroviridae/genética , Gammaretrovirus/genética , Sequenciamento Completo do Genoma
8.
J Virol ; 98(4): e0177123, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38440982

RESUMO

Endogenous retroviruses (ERVs) are remnants of ancestral viral infections. Feline leukemia virus (FeLV) is an exogenous and endogenous retrovirus in domestic cats. It is classified into several subgroups (A, B, C, D, E, and T) based on viral receptor interference properties or receptor usage. ERV-derived molecules benefit animals, conferring resistance to infectious diseases. However, the soluble protein encoded by the defective envelope (env) gene of endogenous FeLV (enFeLV) functions as a co-factor in FeLV subgroup T infections. Therefore, whether the gene emerged to facilitate viral infection is unclear. Based on the properties of ERV-derived molecules, we hypothesized that the defective env genes possess antiviral activity that would be advantageous to the host because FeLV subgroup B (FeLV-B), a recombinant virus derived from enFeLV env, is restricted to viral transmission among domestic cats. When soluble truncated Env proteins from enFeLV were tested for their inhibitory effects against enFeLV and FeLV-B, they inhibited viral infection. Notably, this antiviral machinery was extended to infection with the Gibbon ape leukemia virus, Koala retrovirus A, and Hervey pteropid gammaretrovirus. Although these viruses used feline phosphate transporter 1 (fePit1) and phosphate transporter 2 as receptors, the inhibitory mechanism involved competitive receptor binding in a fePit1-dependent manner. The shift in receptor usage might have occurred to avoid the inhibitory effect. Overall, these findings highlight the possible emergence of soluble truncated Env proteins from enFeLV as a restriction factor against retroviral infection and will help in developing host immunity and antiviral defense by controlling retroviral spread.IMPORTANCERetroviruses are unique in using reverse transcriptase to convert RNA genomes into DNA, infecting germ cells, and transmitting to offspring. Numerous ancient retroviral sequences are known as endogenous retroviruses (ERVs). The soluble Env protein derived from ERVs functions as a co-factor that assists in FeLV-T infection. However, herein, we show that the soluble Env protein exhibits antiviral activity and provides resistance to mammalian retrovirus infection through competitive receptor binding. In particular, this finding may explain why FeLV-B transmission is not observed among domestic cats. ERV-derived molecules can benefit animals in an evolutionary arms race, highlighting the double-edged-sword nature of ERVs.


Assuntos
Produtos do Gene env , Vírus da Leucemia Felina , Leucemia Felina , Animais , Gatos , Retrovirus Endógenos/genética , Retrovirus Endógenos/metabolismo , Produtos do Gene env/genética , Produtos do Gene env/metabolismo , Vírus da Leucemia Felina/classificação , Vírus da Leucemia Felina/genética , Vírus da Leucemia Felina/metabolismo , Vírus da Leucemia do Macaco Gibão/genética , Vírus da Leucemia do Macaco Gibão/metabolismo , Leucemia Felina/genética , Leucemia Felina/metabolismo , Leucemia Felina/virologia , Proteínas de Transporte de Fosfato/genética , Proteínas de Transporte de Fosfato/metabolismo , Receptores Virais/metabolismo , Infecções por Retroviridae/metabolismo , Infecções por Retroviridae/virologia , Solubilidade , Feminino
9.
Nat Commun ; 15(1): 2154, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461177

RESUMO

Five to ten percent of mammalian genomes is occupied by multiple clades of endogenous retroviruses (ERVs), that may count thousands of members. New ERV clades arise by retroviral infection of the germline followed by expansion by reinfection and/or retrotransposition. ERV mobilization is a source of deleterious variation, driving the emergence of ERV silencing mechanisms, leaving "DNA fossils". Here we show that the ERVK[2-1-LTR] clade is still active in the bovine and a source of disease-causing alleles. We develop a method to measure the rate of ERVK[2-1-LTR] mobilization, finding an average of 1 per ~150 sperm cells, with >10-fold difference between animals. We perform a genome-wide association study and identify eight loci affecting ERVK[2-1-LTR] mobilization. We provide evidence that polymorphic ERVK[2-1-LTR] elements in four of these loci cause the association. We generate a catalogue of full length ERVK[2-1-LTR] elements, and show that it comprises 15% of C-type autonomous elements, and 85% of D-type non-autonomous elements lacking functional genes. We show that >25% of the variance of mobilization rate is determined by the number of C-type elements, yet that de novo insertions are dominated by D-type elements. We propose that D-type elements act as parasite-of-parasite gene drives that may contribute to the observed demise of ERV elements.


Assuntos
Retrovirus Endógenos , Infecções por Retroviridae , Animais , Bovinos , Masculino , Retrovirus Endógenos/genética , Estudo de Associação Genômica Ampla , Sêmen , Espermatozoides , Infecções por Retroviridae/genética , Mamíferos/genética
10.
Front Immunol ; 14: 1296355, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38094304

RESUMO

Natural killer (NK) cells are cytotoxic innate immune cells, able to recognize and eliminate virus-infected as well as cancer cells. Metabolic reprogramming is crucial for their activity as they have enhanced energy and nutritional demands for their functions during an infection. Fatty acids (FAs) represent an important source of cellular energy and are essential for proliferation of immune cells. However, the precise role of FAs for NK cells activity in retrovirus infection was unknown. Here we show that activated NK cells increase the expression of the FA uptake receptor CD36 and subsequently the uptake of FAs upon acute virus infection. We found an enhanced flexibility of NK cells to utilize FAs as source of energy compare to naïve NK cells. NK cells that were able to generate energy from FAs showed an augmented target cell killing and increased expression of cytotoxic parameters. However, NK cells that were unable to generate energy from FAs exhibited a severely decreased migratory capacity. Our results demonstrate that NK cells require FAs in order to fight acute virus infection. Susceptibility to severe virus infections as it is shown for people with malnutrition may be augmented by defects in the FA processing machinery, which might be a target to therapeutically boost NK cell functions in the future.


Assuntos
Infecções por Retroviridae , Retroviridae , Humanos , Ácidos Graxos , Células Matadoras Naturais
11.
Arch Virol ; 168(12): 298, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-38010495

RESUMO

This study focused on the involvement of koala retrovirus (KoRV) in pneumonia in koalas. Three deceased pneumonic koalas from a Japanese zoo were examined in this study. Hematological and histopathological findings were assessed, and KoRV proviral DNA loads in the blood and tissues were compared with those of eight other KoRV-infected koalas from different zoos. Demographic data and routine blood profiles were collected, and blood and tissue samples were analyzed to rule out concurrent infections in pneumonic koalas. KoRV subtyping and measurement of the KoRV proviral DNA load were performed by polymerase chain reaction (PCR) using specific primers targeting the pol and env genes. The results showed that the koalas had histopathologically suppurative and fibrinous pneumonia. Chlamydiosis was not detected in any of the animals. PCR analysis revealed KoRV-A, -B, and -C infections in all koalas, except for animals K10-11, which lacked KoRV-B. Significant variations in the proviral DNA loads of these KoRV subtypes were observed in all tissues and disease groups. Most tissues showed reduced KoRV loads in koalas with pneumonia, except in the spleen, which had significantly higher loads of total KoRV (2.54 × 107/µg DNA) and KoRV-A (4.74 × 107/µg DNA), suggesting potential immunosuppression. This study revealed the intricate dynamics of KoRV in various tissues, indicating its potential role in koala pneumonia via immunosuppression and opportunistic infections. Analysis of the levels of KoRV proviral DNA in different tissues will shed light on viral replication and the resulting pathogenesis in future studies.


Assuntos
Gammaretrovirus , Phascolarctidae , Pneumonia , Infecções por Retroviridae , Animais , Infecções por Retroviridae/veterinária , Gammaretrovirus/genética , Retroviridae/genética , Provírus/genética , Pneumonia/veterinária , DNA
12.
Top Antivir Med ; 31(4): 523-528, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37704198

RESUMO

The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) represented the first fully in-person conference since the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic began. CROI continues as the premier conference in which delegates can appraise themselves of almost every facet of HIV/AIDS research as well as emerging and re-emerging pathogens such as SARS-CoV-2 and mpox. The return to an in-person format is particularly important for early-stage investigators, who were faced with challenges of advancing their independent research careers during the SARS-CoV-2 pandemic. The personnel interactions and face-to-face meetings between junior investigators and their peers enable collaboration that is important in the academic development process. A very packed program showcased research advances in basic research, clinical, and epidemiology/public health endeavors around HIV and other pandemic viruses. Session presentation summaries, themed discussion sessions, and scientific workshops condense and assimilate specific areas of research that are particularly useful for delegates who want to see the state of research in areas that may be outside their specific areas of interest. The conference organizers drew on more than 1000 accepted abstracts to assemble a dynamic and engaging program that was appealing to infectious disease researchers worldwide.


Assuntos
Síndrome da Imunodeficiência Adquirida , COVID-19 , Infecções por Retroviridae , Humanos , SARS-CoV-2 , Pesquisa , Pesquisadores
13.
Top Antivir Med ; 31(4): 538-542, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37704199

RESUMO

Comorbid conditions have major impacts on the health, quality of life, and survival of people with HIV, particularly as they age. The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) featured excellent science related to specific comorbidities, such as cardiovascular disease (CVD), cancer, and obesity. Studies investigating factors that may contribute to CVD, such as mental health disorders, antiretroviral therapies, and activation of hormonal pathways, were featured prominently. Other studies sought to understand the epidemiology of non-AIDS-defining cancers in people with HIV. As at previous CROI conferences, weight gain attributable to antiretroviral therapies was a major theme, and several abstracts focused on the important question of whether weight decreases after discontinuation of antiretroviral therapy (ART) regimens associated with weight gain. This review focuses on abstracts presented at CROI 2023 in these areas, highlighting those with the most clinical impact.


Assuntos
Doenças Cardiovasculares , Infecções por HIV , Infecções por Retroviridae , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Qualidade de Vida , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Aumento de Peso
14.
Top Antivir Med ; 31(4): 543-555, 2023 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-37704201

RESUMO

The 2023 Conference on Retroviruses and Opportunistic Infections (CROI) featured new and impactful findings about neuropsychiatric complications in people with HIV and other infections. Reports included new evidence of (a) the importance of myeloid cells in the pathogenesis of HIV disease in the central nervous system, including as an HIV reservoir; (b) eukaryotic and prokaryotic viruses in cerebrospinal fluid during suppressive antiretroviral therapy; (c) the influence of sex on pathogenesis, including in novel neuropsychiatric biotypes identified by machine learning and other methods;(d) premature aging in people with HIV, including the brain-age gap observed on magnetic resonance imaging; (e) cellular and soluble biomarkers of neuropsychiatric complications in people with HIV; and (f) the neurotoxicity of certain antiretroviral drugs. This review summarizes these and other new findings and highlights new research directions for the neuro-HIV field.


Assuntos
Senilidade Prematura , Infecções por HIV , Infecções por Retroviridae , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Antirretrovirais/efeitos adversos , Encéfalo/diagnóstico por imagem
15.
J Virol ; 97(8): e0068523, 2023 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-37578238

RESUMO

Differential responses to viral infections are influenced by the genetic makeup of the host. Studies of resistance to retroviruses in human populations are complicated due to the inability to conduct proof-of-principle studies. Inbred mouse lines, which have a range of susceptible phenotypes to retroviruses, are an ideal tool to identify and characterize mechanisms of resistance and define their genetic underpinnings. YBR/Ei mice become infected with Mouse Mammary Tumor Virus, a mucosally transmitted murine retrovirus, but eliminate the virus from their pedigrees. Virus elimination correlates with a lack of virus-specific neonatal oral tolerance, which is a major mechanism for blocking the anti-virus response in susceptible mice. Virus control is unrelated to virus-neutralizing antibodies, cytotoxic CD8+ T cells, NK cells, and NK T cells, which are the best characterized mechanisms of resistance to retroviruses. We identified a single, dominant locus that controls the resistance mechanism, which we provisionally named attenuation of virus titers (Avt) and mapped to the distal region of chromosome 18. IMPORTANCE Elucidation of the mechanism that mediates resistance to retroviruses is of fundamental importance to human health, as it will ultimately lead to knowledge of the genetic differences among individuals in susceptibility to microbial infections.


Assuntos
Infecções por Retroviridae , Retroviridae , Camundongos , Animais , Humanos , Linfócitos T CD8-Positivos , Camundongos Endogâmicos , Linfócitos T Citotóxicos , Suscetibilidade a Doenças
16.
JCI Insight ; 8(13)2023 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-37427590

RESUMO

Antiviral immunity often requires CD8+ cytotoxic T lymphocytes (CTLs) that actively migrate and search for virus-infected targets. Regulatory T cells (Tregs) have been shown to suppress CTL responses, but it is not known whether this is also mediated by effects on CTL motility. Here, we used intravital 2-photon microscopy in the Friend retrovirus (FV) mouse model to define the impact of Tregs on CTL motility throughout the course of acute infection. Virus-specific CTLs were very motile and had frequent short contacts with target cells at their peak cytotoxic activity. However, when Tregs were activated and expanded in late-acute FV infection, CTLs became significantly less motile and contacts with target cells were prolonged. This phenotype was associated with development of functional CTL exhaustion. Tregs had direct contacts with CTLs in vivo and, importantly, their experimental depletion restored CTL motility. Our findings identify an effect of Tregs on CTL motility as part of their mechanism of functional impairment in chronic viral infections. Future studies must address the underlying molecular mechanisms.


Assuntos
Infecções por Retroviridae , Linfócitos T Citotóxicos , Camundongos , Animais , Linfócitos T Reguladores , Retroviridae , Linfócitos T CD8-Positivos
17.
Viruses ; 15(7)2023 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-37515223

RESUMO

Simian retrovirus subtype 8 (SRV-8) infections have been reported in cynomolgus monkeys (Macaca fascicularis) in China and America, but its pathogenicity and immunogenicity are rarely reported. In this work, the SRV-8-infected monkeys were identified from the monkeys with anemia, weight loss, and diarrhea. To clarify the impact of SRV-8 infection on cynomolgus monkeys, infected monkeys were divided into five groups according to disease progression. Hematoxylin (HE) staining and viral loads analysis showed that SRV-8 mainly persisted in the intestine and spleen, causing tissue damage. Additionally, the dynamic variations of blood routine indexes, innate and adaptive immunity, and the transcriptomic changes in peripheral blood cells were analyzed during SRV-8 infection. Compared to uninfected animals, red blood cells, hemoglobin, and white blood cells were reduced in SRV-8-infected monkeys. The percentage of immune cell populations was changed after SRV-8 infection. Furthermore, the number of hematopoietic stem cells decreased significantly during the early stages of SRV-8 infection, and returned to normal levels after antibody-mediated viral clearance. Finally, global transcriptomic analysis in PBMCs from SRV-8-infected monkeys revealed distinct gene expression profiles across different disease stages. In summary, SRV-8 infection can cause severe pathogenicity and immune disturbance in cynomolgus monkeys, and it might be responsible for fatal virus-associated immunosuppressive syndrome.


Assuntos
Betaretrovirus , Infecções por Retroviridae , Retrovirus dos Símios , Animais , Macaca fascicularis , Infecções por Retroviridae/veterinária , Virulência , Betaretrovirus/genética
18.
Top Antivir Med ; 31(3): 445-467, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37315511

RESUMO

Several innovative methods were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI) targeting different aspects of the HIV care continuum to improve testing, linkage to care, and viral suppression. Some of these approaches were directed at more vulnerable groups, such as pregnant women, adolescents, and individuals who inject drugs. In contrast was the devastating impact of the COVID-19 pandemic, with negative outcomes on HIV viral load suppression and retention in care. Data were presented on hepatitis B virus (HBV) suppression showing that tenofovir alafenamide (TAF)/emtricitabine (FTC)/bictegravir (BIC) may be superior to tenofovir disoproxil fumarate/FTC plus dolutegravir in suppressing HBV in HIV/HBV-coinfected individuals. A pilot study examining a 4-week trial of direct-acting antiviral therapy to treat hepatitis C in recently infected individuals showed lower rates of sustained virologic response at 12 weeks than longer courses. Additional data were presented on the use of long-acting cabotegravir/rilpivirine, comparing this regimen with oral TAF/FTC/BIC and the use of long-acting cabotegravir/rilpivirine in those with viremia. Data were presented on a novel strategy of lenacapavir with 2 broadly neutralizing antibodies given every 6 months as maintenance antiretroviral therapy (ART). Data were presented on improving HIV care outcomes in adolescents, interventions to prevent mother-to-child transmission, and HIV reservoirs in children and adolescents. Data were also presented on interactions between ART and hormonal contraception, as well as ART-related weight gain and impact on pregnancy. A study examining BIC pharmacokinetics in pregnancy was presented, as well as retrospective data on outcomes of adolescents receiving TAF/FTC/BIC.


Assuntos
Fármacos Anti-HIV , COVID-19 , Hepatite C Crônica , Infecções por Retroviridae , Adolescente , Feminino , Humanos , Gravidez , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Emtricitabina/uso terapêutico , Transmissão Vertical de Doenças Infecciosas , Pandemias , Projetos Piloto , Estudos Retrospectivos , Rilpivirina
19.
Top Antivir Med ; 31(3): 468-492, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37315512

RESUMO

At the 2023 Conference on Retroviruses and Opportunistic Infections (CROI), several investigators used tests of recent HIV infection to track which populations are currently most heavily impacted by HIV and to estimate HIV infection rates in those populations. Assisted partner notification for HIV was successfully applied for spouses of persons with HIV and sexual and injection partners of people who inject drugs; however, delays in linkage to care were seen for non-spousal partners in one study. Lack of awareness of HIV positive status remains an issue in various populations; several presentations focused on novel strategies for improving HIV testing uptake in these populations. Doxycycline administered as 200 mg post sexual exposure significantly reduced the risk of syphilis, chlamydia, and gonorrhea infection in men who have sex with men but did not prevent bacterial sexually transmitted infections (STIs) in cis-gender women; reasons for this discrepancy are currently being explored. Although oral HIV preexposure prophylaxis (PrEP) is increasingly being used in populations in greatest need of prevention tools, PrEP uptake and persistence remain low in a number of key populations, including people who inject drugs. Several innovative delivery models show early promise in addressing gaps along the PrEP continuum. The successful use of injectable cabotegravir PrEP in several populations was presented at this conference, although uptake remains low globally. The pipeline of novel long-acting and rapid-onset PrEP agents appears to be robust, including implants, vaginal rings, and topical inserts, with several presentations focusing on preclinical and early clinical trials.


Assuntos
Infecções por HIV , Infecções por Retroviridae , Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Masculino , Feminino , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Infecções Sexualmente Transmissíveis/tratamento farmacológico , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle
20.
Top Antivir Med ; 31(3): 493-509, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37315513

RESUMO

Studies of acute and post-acute COVID-19 were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI). Early treatment with ensitrelvir, a novel protease inhibitor, hastened viral clearance and symptom resolution during coronavirus disease 2019 (COVID-19) and appeared to reduce the prevalence of long COVID symptoms. The development of novel agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including those with broader sarbecovirus activity such as anti-angiotensin-converting enzyme 2 monoclonal antibodies, is underway. A growing understanding of the pathophysiology of long COVID has provided several potential therapeutic targets for individuals experiencing this condition. Efforts to understand COVID-19 in people with HIV have led to novel insights into the biology and natural history of SARS-CoV-2 coinfection in this vulnerable subpopulation. These and other studies are summarized herein.


Assuntos
COVID-19 , Infecções por Retroviridae , Humanos , SARS-CoV-2 , Síndrome de COVID-19 Pós-Aguda , Antivirais/uso terapêutico
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