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An improved understanding of the underlying physicochemical properties of respiratory aerosol that influence viral infectivity may open new avenues to mitigate the transmission of respiratory diseases such as COVID-19. Previous studies have shown that an increase in the pH of respiratory aerosols following generation due to changes in the gas-particle partitioning of pH buffering bicarbonate ions and carbon dioxide is a significant factor in reducing SARS-CoV-2 infectivity. We show here that a significant increase in SARS-CoV-2 aerostability results from a moderate increase in the atmospheric carbon dioxide concentration (e.g. 800 ppm), an effect that is more marked than that observed for changes in relative humidity. We model the likelihood of COVID-19 transmission on the ambient concentration of CO2, concluding that even this moderate increase in CO2 concentration results in a significant increase in overall risk. These observations confirm the critical importance of ventilation and maintaining low CO2 concentrations in indoor environments for mitigating disease transmission. Moreover, the correlation of increased CO2 concentration with viral aerostability need to be better understood when considering the consequences of increases in ambient CO2 levels in our atmosphere.
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COVID-19 , Dióxido de Carbono , SARS-CoV-2 , Dióxido de Carbono/metabolismo , Dióxido de Carbono/análisis , COVID-19/transmisión , COVID-19/virología , Humanos , Concentración de Iones de Hidrógeno , Aerosoles , Humedad , Ventilación , Aerosoles y Gotitas Respiratorias/metabolismo , Aerosoles y Gotitas Respiratorias/virología , Atmósfera/químicaRESUMEN
To date, an affordable, effective treatment for an HIV-1 cure remains only a concept with most "latency reversal" agents (LRAs) lacking specificity for the latent HIV-1 reservoir and failing in early clinical trials. We assessed HIV-1 latency reversal using a multivalent HIV-1-derived virus-like particle (HLP) to treat samples from 32 people living with HIV-1 (PLWH) in Uganda, US and Canada who initiated combined antiretroviral therapy (cART) during chronic infection. Even after 5-20 years on stable cART, HLP could target CD4+ T cells harbouring latent HIV-1 reservoir resulting in 100-fold more HIV-1 release into culture supernatant than by common recall antigens, and 1000-fold more than by chemotherapeutic LRAs. HLP induced release of a divergent and replication-competent HIV-1 population from PLWH on cART. These findings suggest HLP provides a targeted approach to reactivate the majority of latent HIV-1 proviruses among individuals infected with HIV-1.
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Infecciones por VIH , VIH-1 , Humanos , Latencia del Virus , Linfocitos T CD4-Positivos , CanadáRESUMEN
Background: Due to COVID-19, pandemic preparedness emerges as a key imperative, necessitating new approaches to accelerate development of reagents against infectious pathogens. Methods: Here, we developed an integrated approach combining synthetic, computational and structural methods with in vitro antibody selection and in vivo immunization to design, produce and validate nature-inspired nanoparticle-based reagents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: Our approach resulted in two innovations: (i) a thermostable nasal vaccine called ADDoCoV, displaying multiple copies of a SARS-CoV-2 receptor binding motif derived epitope and (ii) a multivalent nanoparticle superbinder, called Gigabody, against SARS-CoV-2 including immune-evasive variants of concern (VOCs). In vitro generated neutralizing nanobodies and electron cryo-microscopy established authenticity and accessibility of epitopes displayed by ADDoCoV. Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Vaccinating mice resulted in antibodies cross-reacting with VOCs including Delta and Omicron. Conclusion: Our study elucidates Adenovirus-derived dodecamer (ADDomer)-based nanoparticles for use in active and passive immunization and provides a blueprint for crafting reagents to combat respiratory viral infections.
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The mechanistic factors hypothesized to be key drivers for the loss of infectivity of viruses in the aerosol phase often remain speculative. Using a next-generation bioaerosol technology, we report measurements of the aero-stability of several SARS-CoV-2 variants of concern in aerosol droplets of well-defined size and composition at high (90%) and low (40%) relative humidity (RH) upwards of 40 min. When compared with the ancestral virus, the infectivity of the Delta variant displayed different decay profiles. At low RH, a loss of viral infectivity of approximately 55% was observed over the initial 5 s for both variants. Regardless of RH and variant, greater than 95% of the viral infectivity was lost after 40 min of being aerosolized. Aero-stability of the variants correlate with their sensitivities to alkaline pH. Removal of all acidic vapours dramatically increased the rate of infectivity decay, with 90% loss after 2 min, while the addition of nitric acid vapour improved aero-stability. Similar aero-stability in droplets of artificial saliva and growth medium was observed. A model to predict loss of viral infectivity is proposed: at high RH, the high pH of exhaled aerosol drives viral infectivity loss; at low RH, high salt content limits the loss of viral infectivity.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiología , Aerosoles y Gotitas RespiratoriasRESUMEN
Vesicular stomatitis virus (VSV) remains an attractive platform for a potential HIV-1 vaccine but hurdles remain, such as selection of a highly immunogenic HIV-1 Envelope (Env) with a maximal surface expression on recombinant rVSV particles. An HIV-1 Env chimera with the transmembrane domain (TM) and cytoplasmic tail (CT) of SIVMac239 results in high expression on the approved Ebola vaccine, rVSV-ZEBOV, also harboring the Ebola Virus (EBOV) glycoprotein (GP). Codon-optimized (CO) Env chimeras derived from a subtype A primary isolate (A74) are capable of entering a CD4+/CCR5+ cell line, inhibited by HIV-1 neutralizing antibodies PGT121, VRC01, and the drug, Maraviroc. The immunization of mice with the rVSV-ZEBOV carrying the CO A74 Env chimeras results in anti-Env antibody levels as well as neutralizing antibodies 200-fold higher than with the NL4-3 Env-based construct. The novel, functional, and immunogenic chimeras of CO A74 Env with the SIV_Env-TMCT within the rVSV-ZEBOV vaccine are now being tested in non-human primates.
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Respiratory pathogens can be spread though the transmission of aerosolised expiratory secretions in the form of droplets or particulates. Understanding the fundamental aerosol parameters that govern how such pathogens survive whilst airborne is essential to understanding and developing methods of restricting their dissemination. Pathogen viability measurements made using Controlled Electrodynamic Levitation and Extraction of Bioaerosol onto Substrate (CELEBS) in tandem with a comparative kinetics electrodynamic balance (CKEDB) measurements allow for a direct comparison between viral viability and evaporation kinetics of the aerosol with a time resolution of seconds. Here, we report the airborne survival of mouse hepatitis virus (MHV) and determine a comparable loss of infectivity in the aerosol phase to our previous observations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the addition of clinically relevant concentrations of mucin to the bioaerosol, there is a transient mitigation of the loss of viral infectivity at 40% RH. Increased concentrations of mucin promoted heterogenous phase change during aerosol evaporation, characterised as the formation of inclusions within the host droplet. This research demonstrates the role of mucus in the aerosol phase and its influence on short-term airborne viral stability.
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COVID-19 , SARS-CoV-2 , Animales , Ratones , Viabilidad Microbiana , Mucinas , Aerosoles y Gotitas RespiratoriasAsunto(s)
Microbiología del Aire , Aerosoles y Gotitas Respiratorias , Infecciones del Sistema Respiratorio , Virosis , Tos , Humanos , Concentración de Iones de Hidrógeno , Aerosoles y Gotitas Respiratorias/virología , Infecciones del Sistema Respiratorio/transmisión , Infecciones del Sistema Respiratorio/virología , Virosis/transmisiónRESUMEN
A rare but natural polymorphism in the HIV-1 envelope (Env) glycoprotein, lysine at position 425 was selected as a mutation conferring resistance to maraviroc (MVC) in vitro. N425K has not been identified in HIV-infected individuals failing an MVC-based treatment. This study reports that the rare K425 polymorphism in an HIV-1 subtype A Env has increased affinity for CD4, resulting in faster host cell entry kinetics and the ability to scavenge for low cell surface expression of CD4 to mediate entry. Whereas the subtype A wild-type isolate-74 Env (N425) is inhibited by soluble (s) CD4, HIV-1 with K425 A74 Env shows enhanced infection and the ability to infect CCR5+ cells when pretreated with sCD4. Upon adding K425 or N425 HIV-1 to CD4+/CCR5+ cells along with RANTES/CCL3, only K425 HIV-1 was able to infect cells when CCR5 recycled/returned to the cell surface at 12 h post-treatment. These findings suggest that upon binding to CD4, K425 Env may maintain a stable State 2 "open" conformation capable of engaging CCR5 for entry. Only K425 was significantly more sensitivity than wild-type N425 A74 to inhibition by the CD4 binding site (bs) compound, BMS-806, the CD4bs antibody, VRC01 and N6, and the single-chain CD4i antibody, SCm9. K425 A74 was also capable of activating B cells expressing the VRC01 surface immunoglobulin. In summary, despite increased replicative fitness, we propose that K425 HIV-1 may be counterselected within infected individuals if K425 HIV-1 is rapidly eliminated by CD4bs-neutralizing antibodies. IMPORTANCE Typically, a natural amino acid polymorphism is found as the wild-type sequence in the HIV-1 population if it provides a selective advantage to the virus. The natural K425 polymorphism in HIV-1 Env results in higher host cell entry efficiency and greater replicative fitness by virtue of its high binding affinity to CD4. The studies presented herein suggest that the rare K425 HIV-1, compared to the common N425 HIV-1, may be more sensitive to inhibition by CD4bs-neutralizing antibodies (i.e., antibodies that bind to the CD4 binding pocket on the HIV-1 envelope glycoprotein). If CD4bs antibodies did emerge in an infected individual, the K425 HIV-1 may be hypersensitive to inhibition, and thus this K425 virus variant may be removed from the HIV-1 swarm despite its higher replication fitness. Studies are now underway to determine whether addition of the K425 polymorphism into the Envelope-based HIV-1 vaccines could enhance protective immunity.
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Proteína gp120 de Envoltorio del VIH , VIH-1 , Internalización del Virus , Anticuerpos Neutralizantes/metabolismo , Sitios de Unión , Antígenos CD4/metabolismo , Farmacorresistencia Viral/genética , Anticuerpos Anti-VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Maraviroc/farmacología , Polimorfismo Genético , Unión ProteicaRESUMEN
Understanding the factors that influence the airborne survival of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in aerosols is important for identifying routes of transmission and the value of various mitigation strategies for preventing transmission. We present measurements of the stability of SARS-CoV-2 in aerosol droplets (â¼5 to 10 µm equilibrated radius) over timescales spanning 5 s to 20 min using an instrument to probe survival in a small population of droplets (typically 5 to 10) containing â¼1 virus/droplet. Measurements of airborne infectivity change are coupled with a detailed physicochemical analysis of the airborne droplets containing the virus. A decrease in infectivity to â¼10% of the starting value was observable for SARS-CoV-2 over 20 min, with a large proportion of the loss occurring within the first 5 min after aerosolization. The initial rate of infectivity loss was found to correlate with physical transformation of the equilibrating droplet; salts within the droplets crystallize at relative humidities (RHs) below 50%, leading to a near-instant loss of infectivity in 50 to 60% of the virus. However, at 90% RH, the droplet remains homogenous and aqueous, and the viral stability is sustained for the first 2 min, beyond which it decays to only 10% remaining infectious after 10 min. The loss of infectivity at high RH is consistent with an elevation in the pH of the droplets, caused by volatilization of CO2 from bicarbonate buffer within the droplet. Four different variants of SARS-CoV-2 were compared and found to have a similar degree of airborne stability at both high and low RH.
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Partículas y Gotitas de Aerosol , COVID-19 , SARS-CoV-2 , Partículas y Gotitas de Aerosol/química , Partículas y Gotitas de Aerosol/aislamiento & purificación , COVID-19/transmisión , Humanos , Humedad , Concentración de Iones de Hidrógeno , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/patogenicidadRESUMEN
PURPOSE: The purpose of this study was to examine speech-language pathologists' (SLPs) opinions on their scope of practice related to reading, self-reported background training, current caseloads, and confidence in their abilities to define, assess, and provide effective treatment for reading-related difficulties. METHOD: SLPs (N = 271) from across the United States completed an online survey assessing their opinions on scope of practice, education and training in reading, and confidence in defining, assessing, and treating reading-related difficulties. RESULTS: A majority of respondents agreed that the identification, assessment, prevention, and intervention of reading disabilities are all within the scope of practice of SLPs. However, a majority also reported that literacy instruction is more heavily the responsibility of teachers than SLPs, and approximately half felt similarly regarding prevention, assessment, identification, and intervention of reading disabilities. Many respondents did not feel that their training in reading was adequate and felt that more graduate coursework should be dedicated to literacy. There was a lot of variability in responses when asked how often respondents focus on reading skills with clients, ranging from almost daily to never; however, results indicate that SLPs rarely administer reading assessments. Overall, respondents were more confident in their ability to define versus assess or provide therapy for various reading subskills. CONCLUSION: Despite SLPs agreeing that reading is within their scope of practice and feeling confident in some aspects of reading, graduate programs for speech-language pathology may need to provide greater training in literacy, especially related to reading assessment and diagnosis.
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Trastornos de la Comunicación , Sordera , Humanos , Patólogos , Lectura , Alcance de la Práctica , Habla , Estados UnidosRESUMEN
Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.
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Clorhidrato de Fingolimod , Vacunas de ADN , Clorhidrato de Fingolimod/farmacología , Factores Inmunológicos , Inmunosupresores , Glicoles de Propileno , Esfingosina , Linfocitos T , Vacunas de ADN/genéticaRESUMEN
Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection.
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Anticuerpos ampliamente neutralizantes/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , Infecciones por VIH/terapia , VIH-1/inmunología , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/inmunología , Animales , Especificidad de Anticuerpos , Anticuerpos ampliamente neutralizantes/clasificación , Anticuerpos ampliamente neutralizantes/inmunología , Técnicas de Transferencia de Gen , Genes env , Terapia Genética , Variación Genética , Anticuerpos Anti-VIH/clasificación , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Inmunidad Humoral , Inmunización Pasiva , Modelos Inmunológicos , Desarrollo de Vacunas , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
HIV-1 persists in infected individuals despite years of antiretroviral therapy (ART), due to the formation of a stable and long-lived latent viral reservoir. Early ART can reduce the latent reservoir and is associated with post-treatment control in people living with HIV (PLWH). However, even in post-treatment controllers, ART cessation after a period of time inevitably results in rebound of plasma viraemia, thus lifelong treatment for viral suppression is indicated. Due to the difficulties of sustained life-long treatment in the millions of PLWH worldwide, a cure is undeniably necessary. This requires an in-depth understanding of reservoir formation and dynamics. Differences exist in treatment guidelines and accessibility to treatment as well as social stigma between low- and-middle income countries (LMICs) and high-income countries. In addition, demographic differences exist in PLWH from different geographical regions such as infecting viral subtype and host genetics, which can contribute to differences in the viral reservoir between different populations. Here, we review topics relevant to HIV-1 cure research in LMICs, with a focus on sub-Saharan Africa, the region of the world bearing the greatest burden of HIV-1. We present a summary of ART in LMICs, highlighting challenges that may be experienced in implementing a HIV-1 cure therapeutic. Furthermore, we discuss current research on the HIV-1 latent reservoir in different populations, highlighting research in LMIC and gaps in the research that may facilitate a global cure. Finally, we discuss current experimental cure strategies in the context of their potential application in LMICs.
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Terapia Antirretroviral Altamente Activa/normas , Países en Desarrollo/estadística & datos numéricos , Reservorios de Enfermedades/virología , Infecciones por VIH/tratamiento farmacológico , Latencia del Virus/efectos de los fármacos , África del Sur del Sahara/epidemiología , Terapia Antirretroviral Altamente Activa/métodos , Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Costo de Enfermedad , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , VIH-1/genética , VIH-1/patogenicidad , HumanosRESUMEN
Exposure of the genital mucosa to a genetically diverse viral swarm from the donor HIV-1 can result in breakthrough and systemic infection by a single transmitted/founder (TF) virus in the recipient. The highly diverse HIV-1 envelope (Env) in this inoculating viral swarm may have a critical role in transmission and subsequent immune response. Thus, chronic (Envchronic) and acute (Envacute) Env chimeric HIV-1 were tested using multivirus competition assays in human mucosal penile and cervical tissues. Viral competition analysis revealed that Envchronic viruses resided and replicated mainly in the tissue, while Envacute viruses penetrated the human tissue and established infection of CD4+ T cells more efficiently. Analysis of the replication fitness, as tested in peripheral blood mononuclear cells (PBMCs), showed similar replication fitness of Envacute and Envchronic viruses, which did not correlate with transmission fitness in penile tissue. Further, we observed that chimeric Env viruses with higher replication in genital mucosal tissue (chronic Env viruses) had higher binding affinity to C-type lectins. Data presented herein suggest that the inoculating HIV-1 may be sequestered in the genital mucosal tissue (represented by chronic Env HIV-1) but that a single HIV-1 clone (e.g., acute Env HIV-1) can escape this trapped replication for systemic infection.IMPORTANCE During heterosexual HIV-1 transmission, a genetic bottleneck occurs in the newly infected individual as the virus passes from the mucosa, leading to systemic infection with a single transmitted HIV-1 clone in the recipient. This bottleneck in the recipient has just been described (K. Klein et al., PLoS Pathog 14:e1006754, https://doi.org/10.1371/journal.ppat.1006754), and the mechanisms involved in this selection process have not been elucidated. However, understanding mucosal restriction is of the utmost importance for understanding dynamics of infections and for designing focused vaccines. Using our human penile and cervical mucosal tissue models for mixed HIV infections, we provide evidence that HIV-1 from acute/early infection, compared to that from chronic infection, can more efficiently traverse the mucosal epithelium and be transmitted to T cells, suggesting higher transmission fitness. This study focused on the role of the HIV-1 envelope in transmission and provides strong evidence that HIV transmission may involve breaking the mucosal lectin trap.
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Cuello del Útero/virología , Infecciones por VIH/transmisión , VIH-1/genética , Leucocitos Mononucleares/virología , Membrana Mucosa/virología , Pene/virología , Proteínas Virales/genética , Femenino , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/aislamiento & purificación , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , ARN Viral/análisis , ARN Viral/genéticaRESUMEN
BACKGROUND: During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this viral reservoir. Previously investigated LRAs have largely failed to achieve a robust latency reversal sufficient for reduction of latent HIV pool or the potential of virus-free remission in the absence of treatment. METHODS: We utilize a polyvalent virus-like particle (VLP) formulation called Activator Vector (ACT-VEC) to 'shock' provirus into transcriptional activity. Ex vivo co-culture experiments were used to evaluate the efficacy of ACT-VEC in relation to other LRAs in individuals diagnosed and treated during the acute stage of infection. IFN-γ ELISpot, qRT-PCR and Illumina MiSeq were used to evaluate antigenicity, latency reversal, and diversity of induced virus respectively. FINDINGS: Using samples from HIV+ patients diagnosed and treated at acute/early infection, we demonstrate that ACT-VEC can reverse latency in HIV infected CD4 T cells to a greater extent than other major recall antigens as stimuli or even mitogens such as PMA/Iono. Furthermore, ACT-VEC activates more latent HIV-1 than clinically tested HDAC inhibitors or protein kinase C agonists. INTERPRETATION: Taken together, these results show that ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments. FUNDING: NIH and CIHR.
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Vectores Genéticos , Infecciones por VIH/virología , VIH-1/fisiología , Activación Viral , Latencia del Virus , Adulto , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Femenino , Regulación Viral de la Expresión Génica/efectos de los fármacos , Orden Génico , Vectores Genéticos/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/virología , ARN Viral , Carga Viral , Replicación Viral/genética , Adulto JovenRESUMEN
An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV-1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection against HIV-1 acquisition. This review will outline the history of HIV vaccine development, novel technologies being applied to HIV vaccinology and immunogen design, as well as the studies that are ongoing to advance our understanding of vaccine-induced immune correlates of protection.
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Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/terapia , VIH-1/inmunología , Vacunas contra el SIDA/administración & dosificación , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunogenicidad Vacunal , Evaluación de Resultado en la Atención de Salud , Relación Estructura-Actividad , Vacunación , Proteínas Virales/química , Proteínas Virales/genética , Proteínas Virales/inmunologíaRESUMEN
It is acknowledged that vaccines remain the best hope for eliminating the HIV-1 epidemic. However, the failure to produce effective vaccine immunogens and the inability of conventional delivery strategies to elicit the desired immune responses remains a central theme and has ultimately led to a significant roadblock in HIV vaccine development. Consequently, significant efforts have been applied to generate novel vaccine antigens and delivery agents, which mimic viral structures for optimal immune induction. Here, we review the latest developments that have occurred in the nanoparticle vaccine field, with special emphasis on strategies that are being utilized to attain highly immunogenic, systemic, and mucosal anti-HIV humoral and cellular immune responses. This includes the design of novel immunogens, the central role of antigen-presenting cells, delivery routes, and biodistribution of nanoparticles to lymph nodes. In particular, we will focus on virus-like-particle formulations and their preclinical uses within the HIV prophylactic vaccine setting.
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Vacunas contra el SIDA , Síndrome de Inmunodeficiencia Adquirida , VIH-1/inmunología , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Nanopartículas/uso terapéutico , Vacunas de Partículas Similares a Virus/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/patología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Animales , Humanos , LiposomasRESUMEN
First identified as the etiological agent behind Acquired Immunodeficiency Syndrome (AIDS) in the early 1980s, HIV-1 has continued to spread into a global pandemic and major public health concern. Despite the success of antiretroviral therapy at reducing HIV-1 viremia and preventing the dramatic CD4+ T-cell collapse, infected individuals remain HIV positive for life. Unfortunately, it is increasingly clear that natural immunity is not, and may never be, protective against this pathogen. Therefore, efficacious vaccine interventions, which can either prevent infection or eradicate the latent viral reservoir and effect cure, are a major medical priority. Here we describe the development of a safe vaccine platform, currently being utilized in on-going prophylactic and therapeutic preclinical studies and consisting of highly heterogeneous virus-like particle formulations that represent the virus diversity within infected individuals. These VLPs contain no 5'LTR, no functional integrase, and have a severely mutated stem loop 1-thereby preventing any potential reverse transcription, integration, and RNA packaging. Furthermore, we demonstrate that these VLPs are morphologically identical to wild-type virus with polyvalent Env in a functional form. Finally, we show that the VLPs are antigenic and capable of generating strong immune recall responses.
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Despite the significant success of combination anti-retroviral therapy to reduce HIV viremia and save lives, HIV-1 infection remains a lifelong infection that must be appropriately managed. Advances in the understanding of the HIV infection process and insights from vaccine development in other biomedical fields such as cancer, imaging, and genetic engineering have fueled rapid advancements in HIV cure research. In the last few years, several studies have focused on the development of "Kick and Kill" therapies to reverse HIV latency and kick start viral translational activity. This has been done with the aim that concomitant anti-retroviral treatment and the elicited immune responses will prevent de novo infections while eradicating productively infected cells. In this review, we describe our perspective on HIV cure and the new approaches we are undertaking to eradicate the established pro-viral reservoir.