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1.
Nat Commun ; 10(1): 2753, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266936

RESUMO

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Sistemas CRISPR-Cas , Infecções por HIV/terapia , HIV-1/genética , Transferência Adotiva , Animais , Terapia Combinada , DNA Viral/genética , DNA Viral/imunologia , Edição de Genes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Camundongos , Resultado do Tratamento , Latência Viral
2.
Vet Microbiol ; 234: 1-7, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31213264

RESUMO

Hepatitis E virus is a zoonotic pathogen for which pigs have been identified as the main reservoir in industrialised countries. HEV infection dynamics in pig herds and pigs are influenced by several factors, including herd practices and possibly co-infection with immunomodulating viruses. This study therefore investigates the impact of porcine circovirus type 2 (PCV2) on HEV infection and transmission through experimental HEV/PCV2 co-infection of specific-pathogen-free pigs. No statistical difference between HEV-only and HEV/PCV2-infected animals was found for either the infectious period or the quantity of HEV shed in faeces. The HEV latency period was shorter for HEV/PCV2 co-infected pigs than for HEV-only infected pigs (11.6 versus 12.3 days). Its direct transmission rate was three times higher in cases of HEV/PCV2 co-infection than in cases of HEV-only infection (0.12 versus 0.04). On the other hand, the HEV transmission rate through environmental accumulation was lower in cases of HEV/PCV2 co-infection (4.3·10-6 versus 1.5·10-5 g/RNA copies/day for HEV-only infected pigs). The time prior to HEV seroconversion was 1.9 times longer in HEV/PCV2 co-infected pigs (49.4 versus 25.6 days for HEV-only infected pigs). In conclusion, our study shows that PCV2 affects HEV infection and transmission in pigs under experimental conditions.


Assuntos
Infecções por Circoviridae/veterinária , Coinfecção/veterinária , Hepatite E/veterinária , Doenças dos Suínos/transmissão , Animais , Circovirus/fisiologia , Coinfecção/virologia , Fezes/virologia , Hepatite E/transmissão , Vírus da Hepatite E , Distribuição Aleatória , Organismos Livres de Patógenos Específicos , Suínos , Doenças dos Suínos/virologia , Latência Viral , Eliminação de Partículas Virais
3.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(1): 89-101, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31102363

RESUMO

Herpes simplex virus (HSV), including HSV-1 and HSV-2, is an important pathogen that can cause many diseases. Usually these diseases are recurrent and incurable. After lytic infection on the surface of peripheral mucosa, HSV can enter sensory neurons and establish latent infection during which viral replication ceases. Moreover, latent virus can re-enter the replication cycle by reactivation and return to peripheral tissues to start recurrent infection. This ability to escape host immune surveillance during latent infection and to spread during reactivation is a viral survival strategy and the fundamental reason why no drug can completely eradicate the virus at present. Although there are many studies on latency and reactivation of HSV, and much progress has been made, many specific mechanisms of the process remain obscure or even controversial due to the complexity of this process and the limitations of research models. This paper reviews the major results of research on HSV latency and reactivation, and discusses future research directions in this field.


Assuntos
Herpes Simples , Herpesvirus Humano 1 , Ativação Viral , Latência Viral , Herpes Simples/virologia , Herpesvirus Humano 1/fisiologia , Humanos , Ativação Viral/fisiologia , Latência Viral/fisiologia , Replicação Viral
4.
Top Antivir Med ; 27(1): 2-6, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31136998

RESUMO

The annual Conference on Retroviruses and Opportunistic Infections remains the preeminent venue for the sharing and dissemination of research advances in the field of HIV and AIDS research. The 26th conference in Seattle featured highlights including news of additional individuals who experienced long-term virologic remission following a bone marrow transplant. The factors driving reservoir persistence gathered a lot of interest, as well as data presented on new factors involved in regulating HIV-1 latency. The effectiveness of the conference in disseminating new findings is further enhanced through themed discussions that focus the attention of participants on abstracts with a common theme. In addition, the Program Committee workshops provide an outstanding venue, directed to new investigators, fellows, and students, to receive updates on different aspects of HIV and AIDS research. These sessions add to the information-sharing environment provided by the conference.


Assuntos
Pesquisa Biomédica/tendências , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , Latência Viral , Humanos
5.
Cell Mol Life Sci ; 76(18): 3583-3600, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31129856

RESUMO

35 years since identification of HIV as the causative agent of AIDS, and 35 million deaths associated with this disease, significant effort is now directed towards the development of potential cures. Current anti-retroviral (ART) therapies for HIV/AIDS can suppress virus replication to undetectable levels, and infected individuals can live symptom free so long as treatment is maintained. However, removal of therapy allows rapid re-emergence of virus from a highly stable reservoir of latently infected cells that exist as a barrier to elimination of the infection with current ART. Prospects of a cure for HIV infection are significantly encouraged by two serendipitous cases where individuals have entered remission following stem cell transplantation from compatible HIV-resistant donors. However, development of a routine cure that could become available to millions of infected individuals will require a means of specifically purging cells harboring latent HIV, preventing replication of latent provirus, or destruction of provirus genomes by gene editing. Elimination of latently infected cells will require a means of exposing this population, which may involve identification of a natural specific biomarker or therapeutic intervention to force their exposure by reactivation of virus expression. Accordingly, the proposed "Shock and Kill" strategy involves treatment with latency-reversing agents (LRA) to induce HIV provirus expression thus exposing these cells to killing by cellular immunity or apoptosis. Current efforts to enable this strategy are directed at developing improved combinations of LRA to produce broad and robust induction of HIV provirus and enhancing the elimination of cells where replication has been reactivated by targeted immune modulation. Alternative strategies may involve preventing re-emergence virus from latently infected cells by "Lock and Block" intervention, where transcription of provirus is inhibited to prevent virus spread or disruption of the HIV provirus genome by genome editing.


Assuntos
Reservatórios de Doenças/virologia , Infecções por HIV/terapia , HIV-1/fisiologia , Antirretrovirais/uso terapêutico , Edição de Genes , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunidade Celular , Imunoterapia , Proteínas Recombinantes/uso terapêutico , Latência Viral
6.
BMC Res Notes ; 12(1): 242, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036079

RESUMO

OBJECTIVE: Resting CD4+ T cells are major reservoirs of latent HIV-1 infection, and may be formed during the early phase of the infection. Although CCR5-tropic (R5) HIV-1 is highly transmissible during the early phase, newly infected individuals have usually been exposed to a mixture of R5 and CXCR4-tropic (X4) viruses, and X4 viral DNA is also detectable in the host. Our aim was to identify which subsets of resting CD4+ T cells contribute to forming the latent reservoir in the presence of both X4 and R5 viruses. RESULTS: Primary resting CD4+ naïve T (TN) cells, CCR5- memory T (TM) cells, and CCR5+ TM cells isolated by flow cytometry were infected simultaneously with X4 and R5 HIV-1, which harbored different reporter genes, and were cultured in the resting condition. Flow cytometry at 3 days post-infection demonstrated that X4 HIV-1+ cells were present in all three subsets of cells, whereas R5 HIV-1+ cells were present preferentially in CCR5+ TM cells, but not in TN cells. Following CD3/CD28-mediated activation at 3 days post-infection, numbers of R5 HIV-1+ cells and X4 HIV-1+ cells increased significantly only in the CCR5+ TM subset, suggesting that it provides a major reservoir of replication-competent, latently infected viruses.


Assuntos
Linfócitos T CD4-Positivos/virologia , DNA Viral/genética , HIV-1/fisiologia , Receptores CCR5/genética , Receptores CXCR4/genética , Latência Viral , Adulto , Linfócitos T CD4-Positivos/imunologia , DNA Viral/metabolismo , Expressão Gênica , HIV-1/patogenicidade , Voluntários Saudáveis , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Cultura Primária de Células , Receptores CCR5/imunologia , Receptores CXCR4/imunologia , Tropismo Viral , Replicação Viral
9.
Virol Sin ; 34(2): 135-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31025296

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is etiologically linked to the development of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These malignancies often occur in immunosuppressed individuals, making KSHV infection-associated diseases an increasing global health concern with persistence of the AIDS epidemic. KSHV exhibits biphasic life cycles between latent and lytic infection and extensive transcriptional and posttranscriptional regulation of gene expression. As a member of the herpesvirus family, KSHV has evolved many strategies to evade the host immune response, which help the virus establish a successful lifelong infection. In this review, we summarize the current research status on the biology of latent and lytic viral infection, the regulation of viral life cycles and the related pathogenesis.


Assuntos
Herpesvirus Humano 8/fisiologia , Herpesvirus Humano 8/patogenicidade , Transcrição Genética , Replicação Viral , Animais , Hiperplasia do Linfonodo Gigante/virologia , Estudos Clínicos como Assunto , Expressão Gênica , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Evasão da Resposta Imune , Hospedeiro Imunocomprometido , Linfoma de Efusão Primária/virologia , Camundongos , Processamento Pós-Transcricional do RNA , Sarcoma de Kaposi/virologia , Proteínas Virais/genética , Latência Viral
10.
Virus Res ; 266: 15-24, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30951791

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman Disease (MCD). Recent mechanistic advances have discerned the importance of microRNAs in the virus-host relationship. KSHV has two modes of replication: lytic and latent phase. KSHV entry into permissive cells, establishment of infection, and maintenance of latency are contingent upon successful modulation of the host miRNA transcriptome. Apart from host cell miRNAs, KSHV also encodes viral miRNAs. Among various cellular and molecular targets, miRNAs are appearing to be key players in regulating viral pathogenesis. Therefore, the use of miRNAs as novel therapeutics has gained considerable attention as of late. This innovative approach relies on either mimicking miRNA species by identical oligonucleotides, or selective silencing of miRNA with specific oligonucleotide inhibitors. Here, we provide an overview of KSHV pathogenesis at the molecular level with special emphasis on the various roles miRNAs play during virus infection.


Assuntos
Herpesvirus Humano 8/genética , Herpesvirus Humano 8/patogenicidade , MicroRNAs/metabolismo , RNA Viral/metabolismo , Hiperplasia do Linfonodo Gigante/virologia , Regulação Viral da Expressão Gênica , Herpesvirus Humano 8/fisiologia , Humanos , Linfoma de Efusão Primária/virologia , MicroRNAs/genética , RNA Viral/genética , Sarcoma de Kaposi/virologia , Internalização do Vírus , Latência Viral , Replicação Viral
11.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936341

RESUMO

The use of immunosuppressing agents can act as a catalyst for viral reactivation, promoting systemic infection with organ involvement. Current literature remains sparse on this topic but does provide individual case reports involving single viruses. We present the case of an immunocompromised patient with skin lesions, pancreatitis, colitis and hepatitis. Work-up revealed varicella zoster virus, which likely put the patient at risk for multi-organ involvement, as well as clinical suspicion of other implicated viruses, specifically herpes simplex virus and cytomegalovirus. A high clinical index of suspicion along with biopsy guidance for viral involvement in immunocompromised patients is crucial for early diagnosis and treatment of these conditions.


Assuntos
Antivirais/uso terapêutico , Colite/virologia , Hepatite/virologia , Doenças da Boca/virologia , Pancreatite/virologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Dermatopatias Virais/patologia , Ativação Viral/imunologia , Infecções por Citomegalovirus/imunologia , Evolução Fatal , Feminino , Herpes Simples/imunologia , Herpes Zoster/imunologia , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Mucosa Bucal/virologia , Multimorbidade , Conforto do Paciente , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Simplexvirus/imunologia , Dermatopatias Virais/terapia , Latência Viral
12.
MBio ; 10(2)2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940699

RESUMO

After an adaptive immune response is mounted, gammaherpesviruses achieve persistence through the utilization of viral noncoding RNAs to craft a suitable host cell environment in an immunologically transparent manner. While gammaherpesvirus long noncoding RNAs (lncRNAs) and microRNAs have been recognized for some time and have been actively investigated, a recent spate of reports have now identified repertoires of the circular RNA (circRNA) class of noncoding RNAs in both the lymphocryptovirus and rhadinovirus genera of gammaherpesviruses. Despite the recent nature of these findings, the detection of circRNAs across viruses and viral gene expression programs, the conservation of some viral circRNAs, and their detection in the clinical setting already raises the spectrum of functional importance in gammaherpesvirus biology and associated malignancies. Here, we provide an overview of currently known gammaherpesvirus circular RNAs and discuss reported physical and contextual properties that may be germane to future functional studies. With the Epstein-Barr virus (EBV) circRNAome being the most extensively studied to date, our discussions will be weighted toward EBV circRNAs while also addressing circRNAs discovered in the rhesus macaque lymphocryptovirus (rLCV), the Kaposi's sarcoma herpesvirus (KSHV), and the murid gammaherpesvirus 68 (MHV68). We hope that this will help set the stage for future investigations into the functions and relevance of this new class of viral noncoding RNAs in infection and disease.


Assuntos
Gammaherpesvirinae/fisiologia , RNA Viral/genética , RNA/genética , Latência Viral , Animais , Infecções por Herpesviridae/virologia , Humanos , RNA não Traduzido/genética
13.
PLoS Comput Biol ; 15(4): e1006849, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30978183

RESUMO

Quantitative viral outgrowth assays (QVOA) use limiting dilutions of CD4+ T cells to measure the size of the latent HIV-1 reservoir, a major obstacle to curing HIV-1. Efforts to reduce the reservoir require assays that can reliably quantify its size in blood and tissues. Although QVOA is regarded as a "gold standard" for reservoir measurement, little is known about its accuracy and precision or about how cell storage conditions or laboratory-specific practices affect results. Owing to this lack of knowledge, confidence intervals around reservoir size estimates-as well as judgments of the ability of therapeutic interventions to alter the size of the replication-competent but transcriptionally inactive latent reservoir-rely on theoretical statistical assumptions about dilution assays. To address this gap, we have carried out a Bayesian statistical analysis of QVOA reliability on 75 split samples of peripheral blood mononuclear cells (PBMC) from 5 antiretroviral therapy (ART)-suppressed participants, measured using four different QVOAs at separate labs, estimating assay precision and the effect of frozen cell storage on estimated reservoir size. We found that typical assay results are expected to differ from the true value by a factor of 1.6 to 1.9 up or down. Systematic assay differences comprised a 24-fold range between the assays with highest and lowest scales, likely reflecting differences in viral outgrowth readout and input cell stimulation protocols. We also found that controlled-rate freezing and storage of samples did not cause substantial differences in QVOA compared to use of fresh cells (95% probability of < 2-fold change), supporting continued use of frozen storage to allow transport and batched analysis of samples. Finally, we simulated an early-phase clinical trial to demonstrate that batched analysis of pre- and post-therapy samples may increase power to detect a three-fold reservoir reduction by 15 to 24 percentage points.


Assuntos
Infecções por HIV/virologia , HIV-1 , Carga Viral/métodos , Latência Viral , Fármacos Anti-HIV/uso terapêutico , Teorema de Bayes , Linfócitos T CD4-Positivos/virologia , Biologia Computacional , Simulação por Computador , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Funções Verossimilhança , Cadeias de Markov , Método de Monte Carlo , Reprodutibilidade dos Testes , Carga Viral/estatística & dados numéricos , Replicação Viral
14.
Retrovirology ; 16(1): 8, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940165

RESUMO

BACKGROUND: Persistence of latent, replication-competent provirus is the main impediment towards the cure of HIV infection. One of the critical questions concerning HIV latency is the role of integration site selection in HIV expression. Inhibition of the interaction between HIV integrase and its chromatin tethering cofactor LEDGF/p75 is known to reduce integration and to retarget residual provirus to regions resistant to reactivation. LEDGINs, small molecule inhibitors of the interaction between HIV integrase and LEDGF/p75, provide an interesting tool to study the underlying mechanisms. During early infection, LEDGINs block the interaction with LEDGF/p75 and allosterically inhibit the catalytic activity of IN (i.e. the early effect). When present during virus production, LEDGINs interfere with proper maturation due to enhanced IN oligomerization in the progeny virions (i.e. the late effect). RESULTS: We studied the effect of LEDGINs present during virus production on the transcriptional state of the residual virus. Infection of cells with viruses produced in the presence of LEDGINs resulted in a residual reservoir that was refractory to activation. Integration of residual provirus was less favored near epigenetic markers associated with active transcription. However, integration near H3K36me3 and active genes, both targeted by LEDGF/p75, was not affected. Also in primary cells, LEDGIN treatment induced a reservoir resistant to activation due to a combined early and late effect. CONCLUSION: LEDGINs present a research tool to study the link between integration and transcription, an essential question in retrovirology. LEDGIN treatment during virus production altered integration of residual provirus in a LEDGF/p75-independent manner, resulting in a reservoir that is refractory to activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , HIV-1/fisiologia , Fatores de Transcrição/genética , Integração Viral , Latência Viral , Replicação Viral , Linhagem Celular , Células Cultivadas , Integrase de HIV/genética , HIV-1/genética , Humanos , Leucócitos Mononucleares/virologia , Ligação Proteica , Provírus/fisiologia , Ativação Viral
15.
Virol Sin ; 34(3): 278-286, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30953292

RESUMO

MicroRNAs (miRNAs) encoded by latency-associated transcript are associated with both latent and acute stages of herpes simplex virus 2 (HSV-2) infection. In this study, miRNA-H4-5p and miRNA-H4-3p were ectopically expressed in HeLa cells to explore potential cellular targets of viral miRNAs and demonstrate their potential biological functions. The results showed that miRNA-H4-5p could reverse apoptosis induced by actinomycin D (Act-D) and promote cell cycle progression, but miRNA-H4-3p had no such obvious functions. Bioinformatics analysis, luciferase report assay, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blotting demonstrated that miRNA-H4-5p could bind to the 3'-untranslated region (UTR) of cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase-like 2 (CDKL2) to negatively regulate their expression. We verified that these two targeted genes were associated with cell apoptosis and cell cycle. Furthermore, in HeLa cells infected with HSV-2, we detected significantly reduced expression of CDKN2A and CDKL2 and demonstrated the negative regulation effect of miRNA-H4-5p on these two target genes. Our findings show that viral miRNAs play a vital role in regulating the expression of the host's cellular genes that participate in cell apoptosis and progression to reshape the cellular environment in response to HSV-2 infection, providing further information on the roles of encoded herpesvirus miRNAs in pathogen-host interaction.


Assuntos
Apoptose , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Dactinomicina/farmacologia , Herpesvirus Humano 2/genética , MicroRNAs/genética , Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo , Ciclo Celular , Biologia Computacional , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células HeLa , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Virais/genética , Latência Viral
16.
Crit Rev Oncol Hematol ; 135: 30-38, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819444

RESUMO

Epstein-Barr virus (EBV) is believed to be a pathogen causing a number of human cancers, but the pathogenic mechanisms remain unclear. An increasing number of studies have indicated that EBV-encoded microRNAs (EBV miRNAs) are expressed in a latency type- and tumor type-dependent manner, playing important roles in the development and progression of EBV-associated tumors. By targeting one or more genes of the virus and the host, EBV miRNAs are responsible for the deregulation of a variety of viral and host cell biological processes, including viral replication, latency maintenance, immune evasion, cell apoptosis and metabolism, and tumor proliferation and metastasis. In addition, some EBV miRNAs can be used as excellent diagnostic, prognostic and treatment efficacy predictive biomarkers for EBV-associated tumors. More importantly, EBV miRNA-targeting therapeutics have emerged and have been developing rapidly, which may open a new era in the treatment of EBV-associated tumors in the near future.


Assuntos
Infecções por Vírus Epstein-Barr/genética , MicroRNAs/genética , Neoplasias/patologia , Neoplasias/virologia , Infecções Tumorais por Vírus/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Humanos , RNA Viral/genética , Evasão Tumoral/genética , Infecções Tumorais por Vírus/complicações , Latência Viral/genética , Replicação Viral/genética
17.
Math Biosci Eng ; 16(2): 619-635, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30861659

RESUMO

Although a number of cost-e ective strategies have been proposed for the chemotherapy of HIV infection, the termination level of viral load and latent reservoir is barely considered. However, the viral load at the termination time is an important biomarker because suppressing viral load to below the detection limit is a major objective of current antiretroviral therapy. The pool size of latently infected cells at the termination time may also play a critical role in predicting a rapid viral rebound to the pretreatment level or post-treatment control. In this work, we formulate an optimal control problem by incorporating the termination level in terms of viral load, latently and productively infected T cells into an existing HIV model. The necessary condition for this optimal system is derived using the Pontryagin's maximum principle. Numerical analysis is carried out using Runge-Kutta 4 method for the forward-backward sweep. Our results suggest that introducing the termination viral load into the control provides a better strategy in HIV chemotherapy.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Carga Viral , Latência Viral , Algoritmos , Controle de Doenças Transmissíveis , Simulação por Computador , Farmacorresistência Viral , Infecções por HIV/virologia , Humanos , Modelos Biológicos , Software , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Replicação Viral
18.
Viruses ; 11(2)2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30813403

RESUMO

Bats harbor a myriad of viruses and some of these viruses may have spilled over to other species including humans. Spillover events are rare and several factors must align to create the "perfect storm" that would ultimately lead to a spillover. One of these factors is the increased shedding of virus by bats. Several studies have indicated that bats have unique defense mechanisms that allow them to be persistently or latently infected with viruses. Factors leading to an increase in the viral load of persistently infected bats would facilitate shedding of virus. This article reviews the unique nature of bat immune defenses that regulate virus replication and the various molecular mechanisms that play a role in altering the balanced bat⁻virus relationship.


Assuntos
Quirópteros/imunologia , Quirópteros/virologia , Reservatórios de Doenças/virologia , Latência Viral/imunologia , Vírus/imunologia , Animais , Tolerância Imunológica , Carga Viral , Replicação Viral , Eliminação de Partículas Virais , Vírus/patogenicidade
19.
EBioMedicine ; 42: 97-108, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30824386

RESUMO

BACKGROUND: The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. METHODS: Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs) and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. FINDINGS: Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with DCs triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR + DC-stimulation reversed latency more frequently. Such a "one-two punch" strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. INTERPRETATION: This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Latência Viral , Adulto , Idoso , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , NF-kappa B/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-fos/química , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/química , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais , Latência Viral/imunologia
20.
Virus Res ; 265: 115-121, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30905686

RESUMO

HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review we will discuss general cell contact-dependent mechanisms that HIV-1 utilizes for its spread and the evidence pointing to cell-to-cell transmission as a mechanism for the establishment and maintenance of latent infection.


Assuntos
Linfócitos T CD4-Positivos/virologia , Reservatórios de Doenças/virologia , Infecções por HIV/transmissão , HIV-1/fisiologia , Latência Viral , Animais , HIV-1/patogenicidade , Humanos , Camundongos , Fenômenos Fisiológicos Virais
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