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2.
Viruses ; 12(6)2020 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-32517260

RESUMO

The Australasian Virology Society (AVS) aims to promote, support and advocate for the discipline of virology in the Australasian region. The society was incorporated in 2011 after 10 years operating as the Australian Virology Group (AVG) founded in 2001, coinciding with the inaugural biennial scientific meeting. AVS conferences aim to provide a forum for the dissemination of all aspects of virology, foster collaboration, and encourage participation by students and post-doctoral researchers. The tenth Australasian Virology Society (AVS10) scientific meeting was held on 2-5 December 2019 in Queenstown, New Zealand. This report highlights the latest research presented at the meeting, which included cutting-edge virology presented by our international plenary speakers Ana Fernandez-Sesma and Benjamin tenOever, and keynote Richard Kuhn. AVS10 honoured female pioneers in Australian virology, Lorena Brown and Barbara Coulson. We report outcomes from the AVS10 career development session on "Successfully transitioning from post-doc to lab head", winners of best presentation awards, and the AVS gender equity policy, initiated in 2013. Plans for the 2021 meeting are underway which will celebrate the 20th anniversary of AVS where it all began, in Fraser Island, Queensland, Australia.

3.
Proc Natl Acad Sci U S A ; 117(17): 9529-9536, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32284399

RESUMO

Bats are reservoirs of emerging viruses that are highly pathogenic to other mammals, including humans. Despite the diversity and abundance of bat viruses, to date they have not been shown to harbor exogenous retroviruses. Here we report the discovery and characterization of a group of koala retrovirus-related (KoRV-related) gammaretroviruses in Australian and Asian bats. These include the Hervey pteropid gammaretrovirus (HPG), identified in the scat of the Australian black flying fox (Pteropus alecto), which is the first reproduction-competent retrovirus found in bats. HPG is a close relative of KoRV and the gibbon ape leukemia virus (GALV), with virion morphology and Mn2+-dependent virion-associated reverse transcriptase activity typical of a gammaretrovirus. In vitro, HPG is capable of infecting bat and human cells, but not mouse cells, and displays a similar pattern of cell tropism as KoRV-A and GALV. Population studies reveal the presence of HPG and KoRV-related sequences in several locations across northeast Australia, as well as serologic evidence for HPG in multiple pteropid bat species, while phylogenetic analysis places these bat viruses as the basal group within the KoRV-related retroviruses. Taken together, these results reveal bats to be important reservoirs of exogenous KoRV-related gammaretroviruses.

4.
Open Forum Infect Dis ; 6(10): ofz376, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31660341

RESUMO

Background: HIV and bacterial sexually transmissible infection (STI) notifications among men who have sex with men (MSM) have increased in Australia and many other countries. The relationship between HIV infection and other STIs has been demonstrated previously. However, the relationship between the cumulative history of STIs and subsequent HIV infection remains largely unexplored and limits our understanding of the mechanisms underpinning the elevated HIV risk. Methods: Data from HIV-negative MSM who attended high-HIV caseload primary care clinics in Melbourne, Australia, from 2007 to 2014 with 2 or more HIV and STI tests were included. Controlling for sexual behaviors self-reported at clinic visits, discrete time survival analyses using generalized linear modeling estimated the effect of an STI at the prior test event and the cumulative history of STIs (none, 1, 2, or more [repeated]) on risk of HIV infection. Results: A total of 8941 MSM met the study criteria; 227 (2.5%) were diagnosed with HIV over the follow-up period. Adjusting for sexual behaviors, a cumulative history of repeated rectal gonorrhea infections (adjusted hazard ratio [aHR], 6.27; 95% confidence interval [CI], 2.68-14.50) and a single rectal gonorrhea infection (aHR, 2.09; 95% CI, 1.15-3.79) were associated with increased HIV infection risk. Conclusions: Repeated and single rectal gonorrhea infections were independently associated with increased HIV infection risk. These findings suggest that MSM with any history of rectal gonorrhea, particularly repeat rectal gonorrhea, represent a group for whom preventive interventions for HIV should be emphasized.

5.
AIDS Res Hum Retroviruses ; 35(6): 553-556, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31037950

RESUMO

Most HIV-1 transmissions occur at mucosae and involve exposure to semen. Semen contains immunomodulatory factors, which inhibit anti-HIV-1 natural killer cell and T cell responses. We demonstrate high concentrations (1:2 dilution) of seminal plasma (SP) inhibit monocyte phagocytosis and anti-HIV-1 Fc-dependent functions of both neutrophils and monocytes. In addition, slightly lower SP concentrations (1:2-1:10 dilutions) inhibit granulocyte phagocytosis and oxidative burst of both monocytes and granulocytes. These observations may have implications for HIV-1 infectivity after mucosal exposure.

6.
J Virol ; 93(12)2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30918071

RESUMO

HIV-1 replication requires direct interaction between HIV-1 reverse transcriptase (RT) and cellular eukaryotic translation elongation factor 1A (eEF1A). Our previous work showed that disrupting this interaction inhibited HIV-1 uncoating, reverse transcription, and replication, indicating its potential as an anti-HIV-1 target. In this study, we developed a sensitive, live-cell split-luciferase complementation assay (NanoBiT) to quantitatively measure inhibition of HIV-1 RT interaction with eEF1A. We used this to screen a small molecule library and discovered small-molecule oxazole-benzenesulfonamides (C7, C8, and C9), which dose dependently and specifically inhibited the HIV-1 RT interaction with eEF1A. These compounds directly bound to HIV-1 RT in a dose-dependent manner, as assessed by a biolayer interferometry (BLI) assay, but did not bind to eEF1A. These oxazole-benzenesulfonamides did not inhibit enzymatic activity of recombinant HIV-1 RT in a homopolymer assay but did inhibit reverse transcription and infection of both wild-type (WT) and nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1 in a dose-dependent manner in HEK293T cells. Infection of HeLa cells was significantly inhibited by the oxazole-benzenesulfonamides, and the antiviral activity was most potent against replication stages before 8 h postinfection. In human primary activated CD4+ T cells, C7 inhibited HIV-1 infectivity and replication up to 6 days postinfection. The data suggest a novel mechanism of HIV-1 inhibition and further elucidate how the RT-eEF1A interaction is important for HIV-1 replication. These compounds provide potential to develop a new class of anti-HIV-1 drugs to treat WT and NNRTI-resistant strains in people infected with HIV.IMPORTANCE Antiretroviral drugs protect many HIV-positive people, but their success can be compromised by drug-resistant strains. To combat these strains, the development of new classes of HIV-1 inhibitors is essential and a priority in the field. In this study, we identified small molecules that bind directly to HIV-1 reverse transcriptase (RT) and inhibit its interaction with cellular eEF1A, an interaction which we have previously identified as crucial for HIV-1 replication. These compounds inhibit intracellular HIV-1 reverse transcription and replication of WT HIV-1, as well as HIV-1 mutants that are resistant to current RT inhibitors. A novel mechanism of action involving inhibition of the HIV-1 RT-eEF1A interaction is an important finding and a potential new way to combat drug-resistant HIV-1 strains in infected people.

7.
Sci Rep ; 9(1): 3555, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837554

RESUMO

We conducted a pilot open-label randomised controlled trial of combined (oestrogen-progesterone) oral contraceptive pill (COCP)-exposure aimed to examine its effect on BV-recurrence following first-line antibiotics compared to antibiotics alone. Ninety-five women with symptomatic BV were prescribed antibiotic therapy, randomised to COCP-exposure (intervention) or current non-hormonal contraceptive practices (control) and followed monthly for six-months or until BV-recurrence. Modified intention-to-treat methods requiring either ≥1 clinical (primary/Amsel-outcome) or ≥1 microbiological (secondary/Nugent-outcome) BV-recurrence assessment were applied to determine cumulative recurrence rates. Secondary Cox regression analyses assessed factors associated with recurrence in all women. 92/95 women randomised provided baseline requirements. BV-recurrence rates were similar in women randomised to the COCP (primary/Amsel-outcome: 10/100PY, 95%CI: 6,19/100PY) compared to controls (14/100PY, 95%CI: 9, 21/100PY, p = 0.471). In secondary analyses sex with the same pre-treatment regular sexual partner (RSP; Amsel: Adjusted Hazard Ratio [AHR] = 3.13, 95%CI: 1.41, 6.94, p = 0.005; Nugent: AHR = 2.97, 95%CI: 1.49, 5.83, p = 0.002) and BV-history (Amsel: AHR = 3.03, 95%CI: 1.14, 6.28; Nugent: AHR = 2.78, 95%CI: 1.22, 6.33) were associated with increased BV-recurrence. This pilot RCT of COCP-exposure did not improve BV cure but found sex with an RSP and BV-history were associated with recurrence, although impacted by sample size and attrition. These data indicate reinfection from an untreated RSP and persistence of BV-associated bacteria are integral to the pathogenesis of recurrence and may overwhelm potential beneficial effects of hormonal contraception on the vaginal microbiota.

8.
Eur J Pharm Biopharm ; 137: 218-226, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30851352

RESUMO

HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two- and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.


Assuntos
Enfuvirtida/administração & dosagem , Inibidores da Fusão de HIV/administração & dosagem , HIV/efeitos dos fármacos , Polietilenoglicóis/química , Animais , Linhagem Celular , Enfuvirtida/farmacocinética , Enfuvirtida/farmacologia , Ensaio de Imunoadsorção Enzimática , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Humanos , Linfa/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
9.
AIDS Res Hum Retroviruses ; 35(3): 219-228, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30638028

RESUMO

Bacterial vaginosis (BV) is a common yet poorly understood vaginal condition that has become a major focus of HIV transmission and immunology research. Varied terminologies are used by clinicians and researchers to describe microbial communities that reside in the female reproductive tract (FRT), which is driven, in part, by microbial genetic and metabolic complexity, evolving diagnostic and molecular techniques, and multidisciplinary perspectives of clinicians, epidemiologists, microbiologists, and immunologists who all appreciate the scientific importance of understanding mechanisms that underlie BV. This Perspectives article aims to clarify the varied terms used to describe the cervicovaginal microbiota and its "nonoptimal" state, under the overarching term of BV. The ultimate goal is to move toward language standardization in future literature that facilitates a better understanding of the impact of BV on FRT immunology and risk of sexually transmitted infections, including HIV.


Assuntos
Suscetibilidade a Doenças/microbiologia , Transmissão de Doença Infecciosa , Infecções por HIV/transmissão , Vaginose Bacteriana/imunologia , Adulto , Citocinas/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Inflamação/imunologia , Lactobacillus/imunologia , Microbiota/genética , Microbiota/imunologia , RNA Ribossômico 16S/genética , Risco , Terminologia como Assunto , Vagina/imunologia , Vagina/microbiologia
10.
Viruses ; 11(1)2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609802

RESUMO

The filoviruses Ebolavirus and Marburgvirus are among the deadliest viral pathogens known to infect humans, causing emerging diseases with fatality rates of up to 90% during some outbreaks. The replication cycles of these viruses are comprised of numerous complex molecular processes and interactions with their human host, with one key feature being the means by which nascent virions exit host cells to spread to new cells and ultimately to a new host. This review focuses on our current knowledge of filovirus egress and the viral and host factors and processes that are involved. Within the virus, these factors consist of the major matrix protein, viral protein 40 (VP40), which is necessary and sufficient for viral particle release, and nucleocapsid and glycoprotein that interact with VP40 to promote egress. In the host cell, some proteins are hijacked by filoviruses in order to enhance virion budding capacity that include members of the family of E3 ubiquitin ligase and the endosomal sorting complexes required for transport (ESCRT) pathway, while others such as tetherin inhibit viral egress. An understanding of these molecular interactions that modulate viral particle egress provides an important opportunity to identify new targets for the development of antivirals to prevent and treat filovirus infections.


Assuntos
Ebolavirus/fisiologia , Interações entre Hospedeiro e Microrganismos , Marburgvirus/fisiologia , Liberação de Vírus , Animais , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Camundongos , Nucleocapsídeo/genética , Nucleocapsídeo/metabolismo , Proteínas do Nucleocapsídeo/genética , Proteínas do Nucleocapsídeo/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo
11.
Cell Microbiol ; 21(1): e12953, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30216959

RESUMO

Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti-IN compound, budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, budesonide or its analogue flunisolide, were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2-LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. The work presented here represents a platform for further development of these specific inhibitors of HIV replication with therapeutic and prophylactic potential.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Budesonida/farmacologia , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV/efeitos dos fármacos , HIV/enzimologia , Integração Viral/efeitos dos fármacos , Animais , Budesonida/química , Linhagem Celular , Fluocinolona Acetonida/análogos & derivados , Fluocinolona Acetonida/química , Fluocinolona Acetonida/farmacologia , Inibidores de Integrase de HIV/química , Humanos , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
12.
Artigo em Inglês | MEDLINE | ID: mdl-31998660

RESUMO

Non-optimal vaginal microbiota, as observed in bacterial vaginosis (BV), is typically characterized by a depletion of beneficial lactobacilli and an abundance of numerous anaerobes. These non-optimal conditions are associated with subclinical cervicovaginal inflammation and an increased risk of HIV infection compared to women colonized with optimal vaginal microbiota dominated by lactobacilli. Lactic acid (LA) is a major organic acid metabolite produced by vaginal lactobacilli that elicits anti-inflammatory effects from cervicovaginal epithelial cells and is dramatically depleted during BV. However, it is unclear if LA retains its anti-inflammatory activity in the presence of vaginal microbiota metabolites comprising short chain fatty acids (SCFAs) and succinic acid, which are also produced by an optimal vaginal microbiota. Furthermore, the immunomodulatory effect of SCFAs and succinic acid on cervicovaginal epithelial cells at higher concentrations present during BV is unknown. Here we report that in the presence of physiologically relevant concentrations of SCFAs and succinic acid at pH 3.9 (as found in women with lactobacillus-dominated microbiota) LA induced an anti-inflammatory state in cervicovaginal epithelial cells and inhibited inflammation elicited by the toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid and Pam3CSK4. When cervicovaginal epithelial cells were treated with a vaginal microbiota metabolite mixture representative of BV, containing a lower concentration of LA but higher concentrations of SCFA/succinic acid at pH 7, no anti-inflammatory was observed. Rather, the vaginal microbiota metabolite mixture representative of BV dysregulated the immune response of cervicovaginal epithelial cells during prolonged and sustained treatments. This was evidenced by increased basal and TLR-induced production of pro-inflammatory cytokines including tumor necrosis factor-α, but decreased basal production of chemokines including RANTES and IP-10. Further characterization of individual components of the BV vaginal microbiota mixture suggested that acetic acid is an important vaginal microbiota metabolite capable of eliciting diverse immunomodulatory effects on a range of cervicovaginal epithelial cell targets. These findings indicate that elevated levels of SCFAs are a potential source of cervicovaginal inflammation in women experiencing BV, and support the unique anti-inflammatory properties of LA on cervicovaginal epithelial cells as well as a role for LA or LA-producing lactobacilli to reverse genital inflammation associated with increased HIV risk.

13.
mSphere ; 3(4)2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976641

RESUMO

Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. While lactic acid has potent HIV virucidal activity in vitro, whether lactic acid present in the vaginal lumen inactivates HIV has not been investigated. Here we evaluated the anti-HIV-1 activity of native, minimally diluted cervicovaginal fluid obtained from women of reproductive age (n = 20) with vaginal microbiota dominated by Lactobacillus spp. Inhibition of HIVBa-L was significantly associated with the protonated form of lactic acid in cervicovaginal fluid. The HIVBa-L inhibitory activity observed in the <3-kDa acidic filtrate was similar to that of the corresponding untreated native cervicovaginal fluid as well as that of clarified neat cervicovaginal fluid subjected to protease digestion. These ex vivo studies indicate that protonated lactic acid is a major anti-HIV-1 metabolite present in acidic cervicovaginal fluid, suggesting a potential role in reducing HIV transmission by inactivating virus introduced or shed into the cervicovaginal lumen.IMPORTANCE The Lactobacillus-dominated vaginal microbiota is associated with a reduced risk of acquiring and transmitting HIV and other sexually transmitted infections (STIs). Lactic acid is a major organic acid metabolite produced by lactobacilli that acidifies the vagina and has been reported to have inhibitory activity in vitro against bacterial, protozoan, and viral STIs, including HIV infections. However, the anti-HIV properties of lactic acid in native vaginal lumen fluids of women colonized with Lactobacillus spp. have not yet been established. Our study, using native cervicovaginal fluid from women, found that potent and irreversible anti-HIV-1 activity is significantly associated with the concentration of the protonated (acidic, uncharged) form of lactic acid. This work advances our understanding of the mechanisms by which vaginal microbiota modulate HIV susceptibility and could lead to novel strategies to prevent women from acquiring HIV or transmitting the virus during vaginal intercourse and vaginal birth.


Assuntos
Líquidos Corporais/química , Líquidos Corporais/virologia , HIV-1/efeitos dos fármacos , Ácido Láctico/metabolismo , Vagina/química , Vagina/virologia , Adulto , Feminino , HIV-1/fisiologia , Humanos , Viabilidade Microbiana/efeitos dos fármacos , Adulto Jovem
14.
Mol Biol Evol ; 35(7): 1626-1637, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617834

RESUMO

Bats have attracted attention in recent years as important reservoirs of viruses deadly to humans and other mammals. These infections are typically nonpathogenic in bats raising questions about innate immune differences that might exist between bats and other mammals. The APOBEC3 gene family encodes antiviral DNA cytosine deaminases with important roles in the suppression of diverse viruses and genomic parasites. Here, we characterize pteropid APOBEC3 genes and show that species within the genus Pteropus possess the largest and most diverse array of APOBEC3 genes identified in any mammal reported to date. Several bat APOBEC3 proteins are antiviral as demonstrated by restriction of retroviral infectivity using HIV-1 as a model, and recombinant A3Z1 subtypes possess strong DNA deaminase activity. These genes represent the first group of antiviral restriction factors identified in bats with extensive diversification relative to homologues in other mammals.


Assuntos
Quirópteros/genética , Citosina Desaminase/genética , Evolução Molecular , Interações Hospedeiro-Patógeno , Animais , Quirópteros/metabolismo , Quirópteros/virologia , HIV-1
15.
Microbiome ; 6(1): 29, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409534

RESUMO

In the cervicovaginal environment, the production of hydrogen peroxide (H2O2) by vaginal Lactobacillus spp. is often mentioned as a critical factor to the in vivo vaginal microbiota antimicrobial properties. We present several lines of evidence that support the implausibility of H2O2 as an "in vivo" contributor to the cervicovaginal milieu antimicrobial properties. An alternative explanation is proposed, supported by previous reports ascribing protective and antimicrobial properties to other factors produced by Lactobacillus spp. capable of generating H2O2. Under this proposal, lactic acid rather than H2O2 plays an important role in the antimicrobial properties of protective vaginal Lactobacillus spp. We hope this commentary will help future research focus on more plausible mechanisms by which vaginal Lactobacillus spp. exert their antimicrobial and beneficial properties, and which have in vivo and translational relevance.


Assuntos
Anti-Infecciosos/farmacologia , Peróxido de Hidrogênio/química , Ácido Láctico/farmacologia , Lactobacillus/química , Vagina/microbiologia , Anti-Infecciosos/química , Hipóxia Celular , Feminino , Genoma Bacteriano , Humanos , Peróxido de Hidrogênio/farmacologia , Ácido Láctico/química , Microbiota
16.
Res Microbiol ; 168(9-10): 782-792, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28435139

RESUMO

Vaginal eubiosis is characterised by beneficial lactobacillus-dominated microbiota. In contrast, vaginal dysbiosis (e.g. bacterial vaginosis, BV), characterised by an overgrowth of multiple anaerobes, is associated with an increased risk of adverse urogenital and reproductive health outcomes. A major distinguishing feature between the vaginal environment in states of eubiosis and dysbiosis is a high concentration of lactic acid, produced by lactobacilli, that acidifies the vagina in eubiosis versus a sharp drop in lactic acid and an increase in pH in dysbiosis. Here we review the antimicrobial, antiviral and immunomodulatory properties of lactic acid and the use of lactic acid and lactobacilli probiotics in preventing or treating BV.


Assuntos
Disbiose/prevenção & controle , Ácido Láctico/metabolismo , Lactobacillus/metabolismo , Probióticos/uso terapêutico , Vagina/microbiologia , Vaginose Bacteriana/prevenção & controle , Disbiose/microbiologia , Feminino , Humanos , Microbiota , Vaginose Bacteriana/tratamento farmacológico
17.
Artigo em Inglês | MEDLINE | ID: mdl-27993846

RESUMO

Therapeutic strategies that target the latent HIV-1 reservoir in resting CD4+ T cells of infected individuals are always administered in the presence of combination antiretroviral therapy. Using a primary cell of HIV-1 latency, we evaluated whether different antiviral drug classes affected latency reversal (as assessed by extracellular virus production) by anti-CD3/CD28 monoclonal antibodies or bryostatin 1. We found that the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine significantly decreased HIV-1 production, by ≥1 log.


Assuntos
Fármacos Anti-HIV/farmacologia , Benzoxazinas/farmacologia , Briostatinas/farmacologia , HIV-1/efeitos dos fármacos , Rilpivirina/farmacologia , Replicação Viral/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais/farmacologia , Antígenos CD28/antagonistas & inibidores , Antígenos CD28/genética , Antígenos CD28/imunologia , Complexo CD3/genética , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Expressão Gênica , HIV-1/genética , HIV-1/crescimento & desenvolvimento , Humanos , Interleucina-2/farmacologia , Cultura Primária de Células , Latência Viral/efeitos dos fármacos
18.
AIDS ; 30(18): 2787-2793, 2016 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-27677159

RESUMO

OBJECTIVE: Synonymous substitutions K65K/K66K in HIV-1 reverse transcriptase alleviate fitness and fidelity defects in HIV-1 molecular clones harboring thymidine analogue mutations (TAMs); however, their potential for transmission and persistence is unknown. Here, we investigated the temporal appearance of K65K/K66K relative to TAMs in a HIV-1 cohort, their prevalence over time, and their impact on viral fitness in the context of patient-derived reverse transcriptase sequences. METHODS: Retrospective analyses of the temporal appearance and longitudinal prevalence of synonymous substitutions and drug resistance mutations were performed using the British Columbia Centre for Excellence in HIV/AIDS Drug Treatment Program (DTP) database. Plasma-derived HIV-1 from the DTP was used to generate infectious molecular clones. Growth competition assays were performed to determine viral fitness. RESULTS: The prevalence of K65K/K66K in drug-naïve individuals tripled from 11% in 1997 to 37% in 2014 (P < 0.0001, n = 5221), with K66K mainly accounting for the increase. These mutations emerged in drug-treated individuals without TAMs in 14% of the cohort and conferred a fitness advantage in the context of patient-derived multidrug-resistant (MDR) virus in the absence of drug. CONCLUSION: The appearance of K65K/K66K in drug-treated individuals was largely independent of TAMs, suggesting alternative factors are likely associated with their emergence. The increasing K65K/K66K prevalence to over a third of treatment-naïve individuals in the mostly subtype B DTP cohort and their ability to confer a fitness advantage to multidrug-resistant virus might explain the transmission and persistence of virus harbouring K65K/K66K in untreated individuals, and highlights their role in adaptive HIV-1 evolution.


Assuntos
Substituição de Aminoácidos , Infecções por HIV/virologia , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , Proteínas Mutantes/genética , Mutação de Sentido Incorreto , Adaptação Biológica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colúmbia Britânica/epidemiologia , Evolução Molecular , Feminino , Genótipo , Infecções por HIV/epidemiologia , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Adulto Jovem
19.
Virology ; 492: 1-10, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26896929

RESUMO

The low fidelity of HIV replication facilitates immune and drug escape. Some reverse transcriptase (RT) inhibitor drug-resistance mutations increase RT fidelity in biochemical assays but their effect during viral replication is unclear. We investigated the effect of RT mutations K65R, Q151N and V148I on SIV replication and fidelity in vitro, along with SIV replication in pigtailed macaques. SIVmac239-K65R and SIVmac239-V148I viruses had reduced replication capacity compared to wild-type SIVmac239. Direct virus competition assays demonstrated a rank order of wild-type>K65R>V148I mutants in terms of viral fitness. In single round in vitro-replication assays, SIVmac239-K65R demonstrated significantly higher fidelity than wild-type, and rapidly reverted to wild-type following infection of macaques. In contrast, SIVmac239-Q151N was replication incompetent in vitro and in pigtailed macaques. Thus, we showed that RT mutants, and specifically the common K65R drug-resistance mutation, had impaired replication capacity and higher fidelity. These results have implications for the pathogenesis of drug-resistant HIV.


Assuntos
Farmacorresistência Viral/genética , DNA Polimerase Dirigida por RNA/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Proteínas Virais/genética , Replicação Viral/genética , Animais , Sequência de Bases , Linhagem Celular , Células HEK293 , Humanos , Macaca nemestrina , Masculino , Dados de Sequência Molecular , Mutação , Plasmídeos/química , Plasmídeos/imunologia , DNA Polimerase Dirigida por RNA/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T/imunologia , Linfócitos T/virologia , Carga Viral , Proteínas Virais/imunologia
20.
Proc Natl Acad Sci U S A ; 113(10): 2696-701, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26903655

RESUMO

Bats harbor many emerging and reemerging viruses, several of which are highly pathogenic in other mammals but cause no clinical signs of disease in bats. To determine the role of interferons (IFNs) in the ability of bats to coexist with viruses, we sequenced the type I IFN locus of the Australian black flying fox, Pteropus alecto, providing what is, to our knowledge, the first gene map of the IFN region of any bat species. Our results reveal a highly contracted type I IFN family consisting of only 10 IFNs, including three functional IFN-α loci. Furthermore, the three IFN-α genes are constitutively expressed in unstimulated bat tissues and cells and their expression is unaffected by viral infection. Constitutively expressed IFN-α results in the induction of a subset of IFN-stimulated genes associated with antiviral activity and resistance to DNA damage, providing evidence for a unique IFN system that may be linked to the ability of bats to coexist with viruses.


Assuntos
Quirópteros/genética , Perfilação da Expressão Gênica , Interferon Tipo I/genética , Interferon-alfa/genética , Animais , Sequência de Bases , Linhagem Celular , Quirópteros/metabolismo , Quirópteros/virologia , Mapeamento Cromossômico , Evolução Molecular , Células HEK293 , Vírus Hendra/fisiologia , Interações Hospedeiro-Patógeno , Humanos , Immunoblotting , Interferon Tipo I/metabolismo , Interferon-alfa/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico
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