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1.
Curr Opin HIV AIDS ; 19(4): 179-186, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38747727

RESUMEN

PURPOSE OF REVIEW: HIV-1 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective prophylactic vaccine. Combination antiretroviral therapy (ART) suppresses HIV replication, but latent viral reservoirs allow the virus to persist and reignite active replication if ART is discontinued. Moreover, inflammation and immune disfunction persist despite ART-mediated suppression of HIV. Immune checkpoint molecules facilitate immune dysregulation and viral persistence. However, their therapeutic modulation may offer an avenue to enhance viral immune control for patients living with HIV-1 (PLWH). RECENT FINDINGS: The success of immune checkpoint inhibitor (ICI) therapy in oncology suggests that targeting these same immune pathways might be an effective therapeutic approach for treating PLWH. Several ICIs have been evaluated for their ability to reinvigorate exhausted T cells, and possibly reverse HIV latency, in both preclinical and clinical HIV-1 studies. SUMMARY: Although there are very encouraging findings showing enhanced CD8 + T-cell function with ICI therapy in HIV infection, it remains uncertain whether ICIs alone could demonstrably impact the HIV reservoir. Moreover, safety concerns and significant clinical adverse events present a hurdle to the development of ICI approaches. This review provides an update on the current knowledge regarding the development of ICIs for the remission of HIV-1 in PWH. We detail recent findings from simian immunodeficiency virus (SIV)-infected rhesus macaque models, clinical trials in PLWH, and the role of soluble immune checkpoint molecules in HIV pathogenesis.


Asunto(s)
Infecciones por VIH , Inhibidores de Puntos de Control Inmunológico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Animales , VIH-1/efectos de los fármacos , VIH-1/fisiología , VIH-1/inmunología
2.
Science ; 383(6687): 1104-1111, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38422185

RESUMEN

The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb-treated macaques. Viral control was correlated with the reprogramming of CD8+ T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.


Asunto(s)
Antirretrovirales , Proteínas Recombinantes de Fusión , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Humanos , Antirretrovirales/uso terapéutico , Antirretrovirales/farmacología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Linfocitos T CD8-positivos/virología , Inmunoterapia , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Carga Viral , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacología , Inducción de Remisión , Quimioterapia Combinada
3.
PLoS Comput Biol ; 16(10): e1008241, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33001979

RESUMEN

In order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate (95% credible interval: [18%, 62%]), and a 11% decrease of the viral growth rate (95% credible interval: [4%, 20%]). We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.


Asunto(s)
Antirretrovirales , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Activación Viral , Animales , Antirretrovirales/administración & dosificación , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Biomarcadores , Biología Computacional , Simulación por Computador , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Virus de la Inmunodeficiencia de los Simios/fisiología , Carga Viral/efectos de los fármacos , Activación Viral/efectos de los fármacos , Activación Viral/fisiología
4.
Front Immunol ; 11: 1935, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32983121

RESUMEN

Studies have shown that vaccine vectors and route of immunization can differentially activate different arms of the immune system. However, the effects of different HIV vaccine immunogens on mucosal inflammation have not yet been studied. Because mucosal sites are the primary route of HIV infection, we evaluated the cervico-vaginal inflammatory cytokine and chemokine levels of Mauritian cynomolgus macaques following immunization and boost using two different SIV vaccine immunogens. The PCS vaccine delivers 12 20-amino acid peptides overlapping the 12 protease cleavage sites, and the Gag/Env vaccine delivers the full Gag and full Env proteins of simian immunodeficiency virus. We showed that the PCS vaccine prime and boosts induced short-lived, lower level increases of a few pro-inflammatory/chemotactic cytokines. In the PCS-vaccine group only the levels of MCP-1 were significantly increased above the baseline (P = 0.0078, Week 6; P = 0.0078, Week 17; P = 0.0234; Week 51) following multiple boosts. In contrast, immunizations with the Gag/Env vaccine persistently increased the levels of multiple cytokines/chemokines. In the Gag/Env group, higher than baseline levels were consistently observed for IL-8 (P = 0.0078, Week 16; P = 0.0078, Week 17; P = 0.0156, Week 52), IL-1ß (P = 0.0234, Week 16; P = 0.0156, Week 17; P = 0.0156, Week 52), and MIP-1α (P = 0.0313, Week 16; P = 0.0156, Week 17; P = 0.0313, Week 52). Over time, repeated boosts altered the relative levels of these cytokines between the Gag/Env and PCS vaccine group. 18 weeks after final boost with a higher dosage, IP-10 levels (P = 0.0313) in the Gag/Env group remained higher than baseline. Thus, the influence of vaccine immunogens on mucosal inflammation needs to be considered when developing and evaluating candidate HIV vaccines.


Asunto(s)
Cuello del Útero/efectos de los fármacos , Citocinas/metabolismo , Productos del Gen env/administración & dosificación , Productos del Gen gag/administración & dosificación , Mediadores de Inflamación/metabolismo , Vacunas contra el SIDAS/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Vagina/efectos de los fármacos , Animales , Cuello del Útero/inmunología , Cuello del Útero/metabolismo , Femenino , Productos del Gen env/genética , Productos del Gen env/inmunología , Productos del Gen env/toxicidad , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Productos del Gen gag/toxicidad , Macaca fascicularis , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/inmunología , Membrana Mucosa/metabolismo , Vacunas contra el SIDAS/genética , Vacunas contra el SIDAS/inmunología , Vacunas contra el SIDAS/toxicidad , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Factores de Tiempo , Vacunación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/toxicidad , Vagina/inmunología , Vagina/metabolismo
5.
J Clin Invest ; 130(12): 6429-6442, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32853182

RESUMEN

After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates, for the first time to our knowledge, that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a potentially novel approach to developing an effective HIV vaccine.


Asunto(s)
Vacunas contra el SIDAS , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/inmunología , Administración Intravaginal , Animales , Femenino , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Macaca fascicularis , Vacunas contra el SIDAS/genética , Vacunas contra el SIDAS/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología
6.
Sci Transl Med ; 12(547)2020 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-32522808

RESUMEN

Zika virus infection in humans has been associated with serious reproductive and neurological complications. At present, no protective antiviral drug treatment is available. Here, we describe the testing and evaluation of the antiviral drug, galidesivir, against Zika virus infection in rhesus macaques. We conducted four preclinical studies in rhesus macaques to assess the safety, antiviral efficacy, and dosing strategies for galidesivir (BCX4430) against Zika virus infection. We treated 70 rhesus macaques infected by various routes with the Puerto Rico or Thai Zika virus isolates. We evaluated galidesivir administered as early as 90 min and as late as 72 hours after subcutaneous Zika virus infection and as late as 5 days after intravaginal infection. We evaluated the efficacy of a range of galidesivir doses with endpoints including Zika virus RNA in plasma, saliva, urine, and cerebrospinal fluid. Galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection. Galidesivir exhibited favorable pharmacokinetics with no observed teratogenic effects in rats or rabbits at any dose tested. The antiviral efficacy of galidesivir observed in the blood and central nervous system of infected animals warrants continued evaluation of this compound for the treatment of flaviviral infections.


Asunto(s)
Hepatitis C Crónica , Infección por el Virus Zika , Virus Zika , Animales , Antivirales/uso terapéutico , Macaca mulatta , Conejos , Ratas , Viremia/tratamiento farmacológico , Infección por el Virus Zika/tratamiento farmacológico
7.
Sci Rep ; 10(1): 6387, 2020 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-32286417

RESUMEN

Human immunodeficiency virus (HIV) infection is characterized by a massive loss of CD4 T cells in the gastrointestinal tract (GIT) that is accompanied by changes in the gut microbiome and microbial translocation that contribute to inflammation and chronic immune activation. Though highly active antiretroviral therapy (HAART) has led to better long-term outcomes in HIV infected patients, it has not been as effective at reverting pathogenesis in the GIT. Using the simian immunodeficiency virus (SIV) infection model, we show that combination antiretroviral therapy (c-ART) partially reverted microbial dysbiosis observed during SIV infection. Though the relative abundance of bacteria, their richness or diversity did not significantly differ between infected and treated animals, microbial dysbiosis was evident via multiple beta diversity metrics: Jaccard similarity coefficient, Bray-Curtis similarity coefficient, and Yue & Clayton theta similarity coefficient. Principal coordinates analysis (PCoA) clustered SIV-infected untreated animals away from healthy and treated animals that were clustered closely, indicating that c-ART partially reversed the gut dysbiosis associated with SIV infection. Metastats analysis identified specific operational taxonomic units (OTUs) falling within the Streptococcus, Prevotella, Acinetobacter, Treponema, and Lactobacillus genera that were differentially represented across the three groups. Our results suggest that complete viral suppression with c-ART could potentially revert microbial dysbiosis observed during SIV and HIV infections.


Asunto(s)
Antirretrovirales/uso terapéutico , Disbiosis/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/microbiología , Animales , Bacterias/clasificación , Bacterias/efectos de los fármacos , Macaca mulatta , Virus de la Inmunodeficiencia de los Simios , Carga Viral/efectos de los fármacos
8.
Nat Commun ; 9(1): 5429, 2018 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-30575753

RESUMEN

The precise time when the viral reservoir is seeded during acute HIV-1 infection remains unclear. We previously demonstrated that the viral reservoir was seeded by day 3 following SIVmac251 infection in rhesus monkeys. Here we report the impact of initiating ART on day 0 (6 h), 1, 2, or 3 following intrarectal SIVmac251 infection in 20 rhesus monkeys (N = 5/group). After 6 months of daily suppressive ART, antiretroviral drugs were discontinued, and viral rebound was monitored. 0% (0 of 5), 20% (1 of 5), 60% (3 of 5), and 100% (5 of 5) of animals that initiated ART on days 0 (6 h), 1, 2, or 3, respectively, showed viral rebound following ART discontinuation and correlated with integrated viral DNA in lymph node CD4+ T cells. These data demonstrate that the viral reservoir is seeded within the first few days of infection and that early ART initiation limits the viral reservoir.


Asunto(s)
Antirretrovirales/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Animales , Linfocitos T CD4-Positivos/inmunología , Quimioterapia Combinada , Macaca mulatta , Masculino , Modelos Biológicos , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología
9.
Nature ; 563(7733): E33, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30315222

RESUMEN

In this Brief Communications Arising Comment, the first three authors (Osuna, Lim and Kublin) should have been listed as equally contributing authors; this has been corrected online.

11.
PLoS One ; 13(8): e0202997, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30153293

RESUMEN

HIV mutates rapidly and infects CD4+ T cells, especially when they are activated. A vaccine targeting conserved, essential viral elements while limiting CD4+ T cell activation could be effective. Learning from natural immunity observed in a group of highly HIV-1 exposed seronegative Kenyan female sex workers, we are testing a novel candidate HIV vaccine targeting the 12 viral protease cleavage sites (PCSs) (the PCS vaccine), in comparison with a vaccine targeting full-length Gag and Env (the Gag/Env vaccine) in a Mauritian cynomolgus macaque/SIV model. In this study we evaluated these vaccines for induction of mucosal antibodies to SIV immunogens at the female genital tract. Bio-Plex and Western blot analyses of cervicovaginal lavage samples showed that both the PCS and Gag/Env vaccines can elicit mucosal IgG antibody responses to SIV immunogens. Significantly higher increase of anti-PCS antibodies was induced by the PCS vaccine than by the Gag/Env vaccine (p<0.0001). The effect of the mucosal antibody responses in protection from repeated low dose pathogenic SIVmac251 challenges is being evaluated.


Asunto(s)
Productos del Gen env/inmunología , Productos del Gen gag/inmunología , Péptido Hidrolasas/metabolismo , Proteolisis , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/enzimología , Virus de la Inmunodeficiencia de los Simios/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Antivirales/inmunología , Sitios de Unión , Reacciones Cruzadas , Femenino , Productos del Gen env/química , Productos del Gen env/metabolismo , Productos del Gen gag/química , Productos del Gen gag/metabolismo , Inmunización , Macaca fascicularis
12.
Immunology ; 155(4): 458-466, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30014618

RESUMEN

Antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection represents a major breakthrough in the treatment of HIV/acquired immune-deficiency syndrome. However, it remains unclear how ART influences virus-specific immune responses and understanding this is important for developing novel cure and eradication interventions for HIV-1. In the present study, we evaluate how ART impacts T-cell and antibody responses in simian immunodeficiency virus (SIV) -infected rhesus macaques. We evaluated CD4 and CD8 T-cell responses by multiparameter flow cytometry, viral loads by quantitative RT-PCR by a two-step process using SIV-specific primers and antibody neutralization function by luciferase-based TZM-bl assays. We demonstrate that macaques treated with ART exhibit phenotypic and qualitative effects on T-cell and antibody responses. Macaques on ART exhibited low numbers of virus-specific T-cell responses, and these responses appeared to be partially biased towards central memory subsets. More importantly, there were significantly reduced neutralizing antibody responses in macaques treated with ART. Collectively, these data improve the understanding of how virus-specific immune responses are generated during ART, and suggest the potential importance of therapeutic vaccines to maintain adaptive immunity during treated infection.


Asunto(s)
Antirretrovirales/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Diferenciación Celular/inmunología , Femenino , Activación de Linfocitos/inmunología , Macaca mulatta , Masculino , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios/inmunología , Subgrupos de Linfocitos T/citología , Carga Viral/inmunología
13.
Adv Exp Med Biol ; 1075: 241-263, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30030796

RESUMEN

Latently infected cells are very infrequent in CD4+ T cells from antiretroviral (ARV) treated individuals, with only approximately one in a million infected CD4+ T cells in blood. Given the low frequency of infected cells in vivo, multiple in vitro latency models have been developed to facilitate investigations into mechanisms of HIV latency, as well as to enable the evaluation of pharmacological and immunological interventions aimed at depleting latently infected cells. These in vitro models include clones of transformed cell lines with integrated HIV proviruses or primary CD4+ T cells from uninfected donors that have been infected with HIV in particular conditions. This chapter presents a description of these various in vitro models, along with an overview of their advantages and limitations.Preclinical animal models represent a critical bridge between in vitro studies and human clinical trials. Simian immunodeficiency virus (SIV) infection of Indian origin rhesus macaques has been well established as an informative model of HIV infection. Recent years have seen breakthroughs in ARVs that permit the potent suppression of SIV replication, enabling studies of latency and putative curative interventions in this model. Small animal models of HIV infection can be generated by engrafting immunodeficient mice with human immune cells. These "humanized mice" have provided valuable insights into HIV pathogenesis and are under development as models for studying HIV latency. We summarize both the promise of these models and outstanding challenges that remain to be overcome to realize their potential to inform efforts to cure HIV infection.


Asunto(s)
VIH-1/fisiología , Latencia del Virus , Animales , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD4-Positivos/virología , Línea Celular Transformada , Células Cultivadas , Células Clonales/virología , Técnicas de Cocultivo , Enfermedad Injerto contra Huésped , VIH-1/efectos de los fármacos , Xenoinjertos , Humanos , Técnicas In Vitro , Macaca mulatta , Ratones , Ratones Desnudos , Quimera por Radiación , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Virus de la Inmunodeficiencia de los Simios/fisiología , Latencia del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos
14.
Sci Transl Med ; 10(439)2018 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-29720451

RESUMEN

Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist-induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.


Asunto(s)
Antirretrovirales/uso terapéutico , Antivirales/efectos adversos , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Receptor Toll-Like 7/agonistas , Viremia/inducido químicamente , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Macaca mulatta , Masculino , Pteridinas/efectos adversos , Virus de la Inmunodeficiencia de los Simios/inmunología
15.
Blood Adv ; 2(2): 76-84, 2018 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-29365313

RESUMEN

Sequestering of latent HIV in follicular helper T cells within B-cell follicles that largely exclude cytotoxic T cells is a major barrier to cellular immune-based approaches to eradicate HIV. Here, we show that the clinical-grade human interleukin-15 (IL-15) superagonist ALT-803 activates and redirects simian immunodeficiency virus (SIV)-specific CD8+ T cells from the peripheral blood into B-cell follicles. In agreement with the increased trafficking of SIV-specific cytotoxic T cells to sites of cryptic viral replication, lymph nodes of elite controlling macaques contained fewer cells expressing SIV RNA or harboring SIV DNA post-ALT-803 treatment. These data establish ALT-803 as an immunotherapeutic for HIV and other chronic viral pathogens that evade host immunity by persisting in B-cell follicles.


Asunto(s)
Linfocitos B/virología , Linfocitos T CD8-positivos/inmunología , Proteínas/uso terapéutico , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , VIH/efectos de los fármacos , Humanos , Evasión Inmune/efectos de los fármacos , Interleucina-15/agonistas , Macaca/virología , Proteínas Recombinantes de Fusión , Linfocitos T Citotóxicos/inmunología
16.
Virus Res ; 254: 15-20, 2018 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-28811170

RESUMEN

The 2015 Brazilian Zika virus outbreak sparked a rapid response to control the spread of the virus. What was first understood to be a mild self-resolving infection is now linked to significant neurological defects in both neonates and adults. The WHO declared the 2016 Zika epidemic a public health emergency and issued an unprecedented recommendation to women in affected regions to delay pregnancy until the risks surrounding Zika virus could be understood, or the epidemic contained. Since that time, considerable effort has been dedicated to understanding Zika transmission and pathogenesis to aid the development of drugs and vaccines. Several models have emerged to study numerous facets of Zika biology; this review details the various model systems.


Asunto(s)
Modelos Animales de Enfermedad , Infección por el Virus Zika/virología , Animales , Antivirales/uso terapéutico , Técnicas de Cultivo de Célula , Interacciones Huésped-Patógeno , Ratones , Primates , Vacunas Virales , Virus Zika/fisiología , Infección por el Virus Zika/patología , Infección por el Virus Zika/prevención & control , Infección por el Virus Zika/terapia
17.
J Infect Dis ; 216(suppl_10): S928-S934, 2017 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-29267926

RESUMEN

Zika virus is a re-emerging flavivirus transmitted primarily by arthropod vectors. The recent devastating outbreak of Zika virus in Brazil was preceded by the slow global encroachment of this virus over many decades. To date, significant research efforts are underway to understand the spread and the unique pathogenesis of this virus; with the intent to rapidly develop vaccines and therapeutics. Several model systems have emerged to study Zika. This review will focus on the use of nonhuman primates to model Zika infection.


Asunto(s)
Vacunas Virales , Infección por el Virus Zika/prevención & control , Virus Zika/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Primates , Virus Zika/patogenicidad , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/terapia , Infección por el Virus Zika/virología
18.
PLoS One ; 12(10): e0186079, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28982126

RESUMEN

Cynomolgus macaques are an increasingly important nonhuman primate model for HIV vaccine research. SIV-free animals without pre-existing anti-SIV immune responses are generally needed to evaluate the effect of vaccine-induced immune responses against the vaccine epitopes. Here, in order to select such animals for vaccine studies, we screened 108 naïve female Mauritian cynomolgus macaques for natural (baseline) antibodies to SIV antigens using a Bio-Plex multiplex system. The antigens included twelve 20mer peptides overlapping the twelve SIV protease cleavage sites (-10/+10), respectively (PCS peptides), and three non-PCS Gag or Env peptides. Natural antibodies to SIV antigens were detected in subsets of monkeys. The antibody reactivity to SIV was further confirmed by Western blot using purified recombinant SIV Gag and Env proteins. As expected, the immunization of monkeys with PCS antigens elicited anti-PCS antibodies. However, unexpectedly, antibodies to non-PCS peptides were also induced, as shown by both Bio-Plex and Western blot analyses, while the non-PCS peptides do not share sequence homology with PCS peptides. The presence of natural and vaccine cross-inducible SIV antibodies in Mauritian cynomolgus macaques should be considered in animal selection, experimental design and result interpretation, for their best use in HIV vaccine research.


Asunto(s)
Anticuerpos Antivirales/inmunología , Reacciones Cruzadas , Vacunas contra el SIDAS/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Animales , Fármacos Anti-VIH/uso terapéutico , Antígenos Virales/inmunología , Western Blotting , Vectores Genéticos , Macaca fascicularis , Mauritania , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/fisiología , Replicación Viral
19.
Sci Transl Med ; 9(408)2017 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-28931655

RESUMEN

HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1-infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)-SF162P3-infected rhesus monkeys. We then show that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed challenge with SHIV-SF162P3 and SHIV-325c. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal that single bNAbs efficiently select resistant viruses from a diverse challenge swarm to establish infection, demonstrating the importance of bNAb cocktails for HIV-1 prevention.


Asunto(s)
Anticuerpos Neutralizantes/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/química , Secuencia de Bases , Epítopos/inmunología , Productos del Gen env/química , Productos del Gen env/genética , VIH-1/inmunología , Concentración 50 Inhibidora , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/virología
20.
Proc Natl Acad Sci U S A ; 114(33): 8847-8852, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28765371

RESUMEN

The recent outbreak of Zika virus (ZIKV) has been associated with fetal abnormalities and neurological complications, prompting global concern. Here we present a mathematical analysis of the within-host dynamics of plasma ZIKV burden in a nonhuman primate model, allowing for characterization of the growth and clearance of ZIKV within individual macaques. We estimate that the eclipse phase for ZIKV, the time between cell infection and viral production, is most likely short (∼4 h), the median within-host basic reproductive number R0 is 10.7, the rate of viral production is rapid (>25,000 virions d-1), and the lifetime of an infected cell while producing virus is ∼5 h. We also estimate that the minimum number of virions produced by an infected cell over its lifetime is ∼5,500. We assess the potential effect of an antiviral treatment that blocks viral replication, showing that the median time to undetectable plasma viral load (VL) can be reduced from ∼5 d to ∼3 d with a drug concentration ∼15 times the drug's EC50 when treatment is given prophylactically starting at the time of infection. In the case of favipiravir, a polymerase inhibitor with activity against ZIKV, we predict a dose of 150 mg/kg given twice a day initiated at the time of infection can reduce the peak median VL by ∼3 logs and shorten the time to undetectable median VL by ∼2 d, whereas treatment given 2 d postinfection is mostly ineffective in accelerating plasma VL loss in macaques.


Asunto(s)
Antivirales/farmacología , Modelos Biológicos , Carga Viral , Replicación Viral/efectos de los fármacos , Infección por el Virus Zika/sangre , Virus Zika/fisiología , Animales , Macaca mulatta
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