latently infected
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2022 ◽  
Author(s):  
Tung Truong ◽  
Manuel Hayn ◽  
Camilla Kaas Frich ◽  
Lucy Kate Ladefoged ◽  
Morten Jarlstad Olesen ◽  
...  

Eliminating latently infected cells is a highly challenging, indispensable step towards the overall cure for HIV/AIDS. We recognized that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent toxin, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. We hypothesized that this presents opportunities to design prodrugs that are specifically activated by the HIV protease. To investigate this, a series of MMAF derivatives was synthesized and evaluated in cell culture using latently HIV-infected cells. Cytotoxicity of compounds was enhanced upon latency reversal by up to 11-fold. In a mixed cell population, nanomolar concentrations of the lead compound depleted predominantly the HIV-infected cells and in doing so markedly enriched the pool with the uninfected cells. Despite expectation, mechanism of action of the synthesized toxins was not as HIV protease-specific prodrugs, but likely through the synergy of toxicities between the toxin and the reactivated virus.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jocelyn T. Kim ◽  
Tian-Hao Zhang ◽  
Camille Carmona ◽  
Bryanna Lee ◽  
Christopher S. Seet ◽  
...  

AbstractHIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.


2022 ◽  
Vol 12 ◽  
Author(s):  
Marisierra Espinar-Buitrago ◽  
Ma Angeles Muñoz-Fernández

Due to the success of combined antiretroviral therapy (cART) in recent years, the pathological outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved substantially, achieving undetectable viral loads in most cases. Nevertheless, the presence of a viral reservoir formed by latently infected cells results in patients having to maintain treatment for life. In the absence of effective eradication strategies against HIV-1, research efforts are focused on obtaining a cure. One of these approaches is the creation of therapeutic vaccines. In this sense, the most promising one up to now is based on the establishing of the immunological synapse between dendritic cells (DCs) and T lymphocytes (TL). DCs are one of the first cells of the immune system to encounter HIV-1 by acting as antigen presenting cells, bringing about the interaction between innate and adaptive immune responses mediated by TL. Furthermore, TL are the end effector, and their response capacity is essential in the adaptive elimination of cells infected by pathogens. In this review, we summarize the knowledge of the interaction between DCs with TL, as well as the characterization of the specific T-cell response against HIV-1 infection. The use of nanotechnology in the design and improvement of vaccines based on DCs has been researched and presented here with a special emphasis.


2022 ◽  
Vol 12 ◽  
Author(s):  
Maria A. Navarrete-Muñoz ◽  
Carlos Llorens ◽  
José M. Benito ◽  
Norma Rallón

Combination antiretroviral therapy (cART) effectively blocks HIV replication but cannot completely eliminate HIV from the body mainly due to establishment of a viral reservoir. To date, clinical strategies designed to replace cART for life and alternatively to eliminate the HIV reservoir have failed. The reduced expression of viral antigens in the latently infected cells is one of the main reasons behind the failure of the strategies to purge the HIV reservoir. This situation has forced the scientific community to search alternative therapeutic strategies to control HIV infection. In this regard, recent findings have pointed out extracellular vesicles as therapeutic agents with enormous potential to control HIV infection. This review focuses on their role as pro-viral and anti-viral factors, as well as their potential therapeutic applications.


mBio ◽  
2022 ◽  
Author(s):  
Justin T. Landis ◽  
Ryan Tuck ◽  
Yue Pan ◽  
Carson N. Mosso ◽  
Anthony B. Eason ◽  
...  

Latency is the defining characteristic of the Herpesviridae and central to the tumorigenesis phenotype of Kaposi’s sarcoma-associated herpesvirus (KSHV). KSHV-driven primary effusion lymphomas (PEL) rapidly develop resistance to therapy, suggesting tumor instability and plasticity.


2021 ◽  
Vol 25 (9) ◽  
pp. 1661-1670
Author(s):  
A.A. Danhausa ◽  
E.E. Daniel ◽  
C.J. Shawulu ◽  
A.M. Nuhu ◽  
L. Philemon

Regardless of many decades of research, the widespread availability of a vaccine and more recently highly visible WHO efforts to promote a unified global control strategy, Tuberculosis remains a leading cause of infectious mortality. In this paper, a Mathematical Model for Tuberculosis Epidemic with Passive Immunity and Drug-Sensitivity is presented. We carried out analytical studies of the model where the population comprises of eight compartments: passively immune infants, susceptible, latently infected with DS-TB. The Disease Free Equilibrium (DFE) and the Endemic Equilibrium (EE) points were established. The next generation matrix method was used to obtain the reproduction number for drug sensitive (𝑅𝑜𝑠) Tuberculosis. We obtained the disease-free equilibrium for drug sensitive TB which is locally asymptotically stable when 𝑅𝑜𝑠 < 1 indicating that tuberculosis eradication is possible within the population. We also obtained the global stability of the disease-free equilibrium and results showed that the disease-free equilibrium point is globally asymptotically stable when 𝑅𝑜𝑠 ≤ 1 which indicates that tuberculosis naturally dies out.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 77
Author(s):  
Gabriel Siracusano ◽  
Lucia Lopalco

Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved the sustained control of HIV-1 replication, however, the life-long treatment does not eradicate long-lived latently infected reservoirs and can result in multiple side effects including the development of multidrug-resistant escape mutants. Antibody-based treatments have emerged as alternative approaches for a HIV-1 cure. Here, we will review clinical advances in coreceptor-targeting antibodies, with respect to anti-CCR5 antibodies in particular, which are currently being generated to target the early stages of infection. Among the Env-specific antibodies widely accepted as relevant in cure strategies, the potential role of those targeting CD4-induced (CD4i) epitopes of the CD4-binding site (CD4bs) in eliminating HIV-1 infected cells has gained increasing interest and will be presented. Together, with approaches targeting the HIV-1 replication cycle, we will discuss the strategies aimed at boosting and modulating specific HIV-1 immune responses, highlighting the harnessing of TLR agonists for their dual role as latency reverting agents (LRAs) and immune-modulatory compounds. The synergistic combinations of different approaches have shown promising results to ultimately enable a HIV-1 cure.


2021 ◽  
Vol 12 ◽  
Author(s):  
Paulo Ranaivomanana ◽  
Rila Ratovoson ◽  
Crisca Razafimahatratra ◽  
Arimanitra Razafimahefa ◽  
Jonathan Hoffmann ◽  
...  

IntroductionPregnancy triggers an alteration of the immune functions and increases the risk of developing the active tuberculosis (TB) symptoms in exposed women. The effect of pregnancy on the Mycobacterium tuberculosis-specific immune responses used for most of the TB immunodiagnostic assays is not well documented. Here we investigated the changes in the M. tuberculosis-specific IFN-γ production in age-matched pregnant and non-pregnant women according to their TB exposition status.MethodsWe conducted a prospective cohort study on HIV-seronegative pregnant and non-pregnant women with compatible pulmonary TB symptoms addressed to TB healthcare facilities in Antananarivo, Madagascar. Active pulmonary TB was bacteriologically assessed with culture from sputum samples. Clinical data and blood samples were collected at inclusion and after 6 months of follow-up for each individual included. Whole blood samples were stimulated with QuantiFERON TB-Gold Plus (QFT-P) assay antigens. Plasma IFN-γ concentrations were then assessed by ELISA.ResultsA total of 284 women were investigated for the study including 209 pregnant women without confirmed TB (pNTB), 24 pregnant women with bacteriologically confirmed active TB (pATB), 16 non-pregnant women with active TB (ATB), and 35 non-pregnant healthy donors (HC). At inclusion, IFN-γ responses are lower in the pregnant women compared to their age-matched non-pregnant counterparts and independently of their TB status. Among the pregnant women, higher concentrations of M. tuberculosis-specific IFN-γ were observed in those exposed to TB, but with a lower magnitude in the active TB compared to the latently infected pregnant women (p &lt; 0.05 with TB1 and p &lt; 0.01 with TB2). After 6 months of follow-up, the M. tuberculosis-specific IFN-γ responses return to their baseline concentrations except for the pregnant women treated for TB for which none of the QFT-P positive reversed to negative (0%, 0/10) at the end of their TB treatment.ConclusionThese results support the concept of specific immune priorities characterized by a concomitant reduction in inflammatory immunity during pregnancy and corroborate the important role of activating the M. tuberculosis-specific immune responses to control the infection when the pregnant women are exposed to the pathogen.


2021 ◽  
Author(s):  
Corentin Mallet ◽  
Jade Cochard ◽  
Sébastien Leclercq ◽  
Laetitia Trapp-Fragnet ◽  
Philippe Chouteau ◽  
...  

Latency is a hallmark of herpesviruses, allowing them to persist into their host without virions production. Acute exposure to hypoxia (below 3% O 2 ) was identified as a trigger of latent-to-lytic switch (reactivation) for human oncogenic gamma-herpesviruses (KSHV and EBV). Therefore, we hypothesized that hypoxia could also induce reactivation of Marek’s disease virus (MDV), sharing biological properties with EBV and KSHV (notably oncogenic properties), into lymphocytes. Acute exposure to hypoxia (1% O 2 ) of two MDV-latently infected cell lines derived from MD tumors (3867K and MSB-1) induced MDV reactivation. A bioinformatic analysis of the RB-1B MDV genome revealed 214 putative hypoxia-response element consensus sequences on 119 open reading frames. RT-qPCR analysis showed five MDV genes strongly upregulated early after hypoxia. In 3867K cells under normoxia, pharmacological agents mimicking hypoxia (MLN4924 and CoCl 2 ) increased MDV reactivation, but to a lower level than real hypoxia. Overexpression of wild-type or stabilized human hypoxia inducible factor-1α (HIF-1α) in MSB-1 cells in normoxia also promoted MDV reactivation. In such conditions, lytic cycle was detected in cells with a sustainable HIF-1α expression, but also in HIF-1α negative cells, indicating that MDV reactivation is mediated by HIF-1, in a direct and/or indirect manner. Lastly, we demonstrated by a reporter assay that HIF-1α overexpression induced the transactivation of two viral promoters, shown upregulated in hypoxia. These results suggest that hypoxia may play a crucial role in the late lytic replication phase observed in vivo in MDV-infected chickens exhibiting tumors, since a hypoxic microenvironment is a hallmark of most solid tumors. IMPORTANCE Latent-to-lytic switch of herpesviruses (aka reactivation) is responsible for pathology recurrences and/or viral shedding. Studying physiological triggers of reactivation is therefore important for health to limit lesions and viral transmission. Marek's disease virus (MDV) is a potent oncogenic alpha-herpesvirus establishing latency in T-lymphocytes and causing lethal T-lymphomas in chickens. In vivo , a second lytic phase is observed during tumoral stage. Hypoxia being a hallmark of tumors, we wondered whether hypoxia induces MDV reactivation in latently-infected T-lymphocytes, like previously shown for EBV and KSHV in B-lymphocytes. In this study, we demonstrated that acute hypoxia (1% O2) triggers MDV reactivation in two MDV transformed T-cell lines. We provide some molecular basis of this reactivation by showing that hypoxia inducible factor (HIF-1) overexpression induces MDV reactivation to a similar extend than hypoxia after 24 hours. Hypoxia is therefore a reactivation stimulus shared by mammalian and avian oncogenic herpesviruses of different genus.


Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2512
Author(s):  
Chuen-Yen Lau ◽  
Matthew A. Adan ◽  
Frank Maldarelli

Antiretroviral therapy (ART) effectively reduces cycles of viral replication but does not target proviral populations in cells that persist for prolonged periods and that can undergo clonal expansion. Consequently, chronic human immunodeficiency virus (HIV) infection is sustained during ART by a reservoir of long-lived latently infected cells and their progeny. This proviral landscape undergoes change over time on ART. One of the forces driving change in the landscape is the clonal expansion of infected CD4 T cells, which presents a key obstacle to HIV eradication. Potential mechanisms of clonal expansion include general immune activation, antigenic stimulation, homeostatic proliferation, and provirus-driven clonal expansion, each of which likely contributes in varying, and largely unmeasured, amounts to maintaining the reservoir. The role of clinical events, such as infections or neoplasms, in driving these mechanisms remains uncertain, but characterizing these forces may shed light on approaches to effectively eradicate HIV. A limited number of individuals have been cured of HIV infection in the setting of bone marrow transplant; information from these and other studies may identify the means to eradicate or control the virus without ART. In this review, we describe the mechanisms of HIV-1 persistence and clonal expansion, along with the attempts to modify these factors as part of reservoir reduction and cure strategies.


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