Trial, Error, and Breakthrough: A Review of HIV Vaccine Development

Barry, Sheila M.; Lora, Alfredo J Mena; Novak, Richard M.

doi:10.4172/2155-6113.1000359

Cited by 7 publications

(4 citation statements)

References 142 publications

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“…Over 36.9 million people are living with HIV/AIDS [1]. In the absence of a vaccine against HIV-1, cARTs are needed to control the spread and progression of the virus [2,3]. These ARTs target HIV-1 envelope (Env) interactions with its co-receptor (CR) or fusion with the cell membrane, reverse transcriptase (RT), integrase (IN), and protease (PR) [3,4].…”

Section: Introductionmentioning

confidence: 99%

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

et al. 2020

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The ability of HIV-1 to evolve resistance to combined antiretroviral therapies (cARTs) has stimulated research into alternative means of controlling this infection. We assayed >60 modulators of RNA alternative splicing (AS) to identify new inhibitors of HIV-1 RNA processing-a segment of the viral lifecycle not targeted by current drugs-and discovered compound N-[4-chloro-3-(trifluoromethyl)phenyl]-7-nitro-2,1,3-benzoxadiazol-4-amine (5342191) as a potent inhibitor of both wild-type (Ba-L, NL4-3, LAI, IIIB, and N54) and drugresistant strains of HIV-1 (IC 50 :~700 nM) with no significant effect on cell viability at doses tested. 5342191 blocks expression of four essential HIV-1 structural and regulatory proteins (Gag, Env, Tat, and Rev) without affecting total protein synthesis of the cell. This response is associated with altered unspliced (US) and singly-spliced (SS) HIV-1 RNA accumulation (~60% reduction) and transport to the cytoplasm (loss of Rev) whereas parallel analysis of cellular RNAs revealed less than a 0.7% of host alternative splicing (AS) events (0.25-0.67% by � 10-20%), gene expression (0.01-0.46% by � 2-5 fold), and protein abundance (0.02-0.34% by � 1.5-2 fold) being affected. Decreased expression of Tat, but not Gag/ Env, upon 5342191 treatment was reversed by a proteasome inhibitor, suggesting that this compound alters the synthesis/degradation of this key viral factor. Consistent with an affect on HIV-1 RNA processing, 5342191 treatment of cells altered the abundance and phosphorylation of serine/arginine-rich splicing factor (SRSF) 1, 3, and 4. Despite the activation of several intracellular signaling pathways by 5342191 (Ras, MEK1/2-ERK1/2, and JNK1/2/3), inhibition of HIV-1 gene expression by this compound could be reversed by pre-treatment with either a G-protein α-subunit inhibitor or two different MEK1/2 inhibitors. These observations demonstrate enhanced sensitivity of HIV-1 gene expression to small changes in host

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Section: Introductionmentioning

confidence: 99%

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

et al. 2020

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“…In the next experiment, we applied 8-10 months mice which resulted in isolation of 33 million cells. Moreover, the procedure of bone marrow cell isolation includes applying 70% ethanol in many protocols [20,21]. In two series of the procedures we performed, once a protocol with ethanol and the other time with PBS containing penicillin/streptomycin 2X, the result indicated that ethanol might reduce the number of cells.…”

Section: Discussionmentioning

confidence: 97%

Murine Dendritic Cells for Immunotherapy and Vaccine Development: Generation, Optimization and Transduction

Larijani

Shirazi

Ramezani

et al. 2020

vacres

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Introduction: Dendritic cells (DCs) play crucial roles in cellular immunity as the most powerful antigen presenting cells. They have been widely used for antigen delivery in vivo and in vitro. There are different ways to generate DCs and also gene transduction. In this study we introduce some optimization in order to produce high amount of well differentiated murine DCs for potential immunotherapy and vaccine development applications. Methods: Murine bone marrow cells were isolated from male BALB/c mice and the cells were cultured with complete RPMI in presence of the same ratio of IL-4 and GM-CSF. Some changes were made in the medium and the lysis buffer applications to increase the differentiation rate of the cells. Lentiviral virions were applied to transfer the genes of interest to DCs with no pre-maturation steps. CD11c, MHC-II, CD80 and CD86 were assessed by flow cytometry. Results: The optimized steps led to significant increase in number of the isolated cells. IL-4 usage in a similar dose to GM-CSF led to macrophage formation inhibition. Lentiviral virions resulted in successful gene delivery along with well-maturated DCs. Conclusion: The introduced optimized steps could be followed in different DC applications by using lentiviral virions to transduce DCs, independent of the pre-maturation steps.

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“…The envelope is highly glycosylated and thus neutralizing antibodies should prevent spatial inhibition. The interspecies differences between nonhuman primates (NHPs) and humans have become a major challenge in designing a candidate for the HIV vaccine, which is why many candidate vaccines in the model have not been succeeded (Barry, Mena Lora, & Novak, 2014;Haynes & Burton, 2017).…”

Section: Hiv Vaccinationmentioning

confidence: 99%

Memory and CAR‐NK cell‐based novel approaches for HIV vaccination and eradication

Mazarzaei

Vafaei²,

Ghasemian

et al. 2019

Journal Cellular Physiology

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Human immunodeficiency virus (HIV) is one of the critical infectious agents with thousands of newly infected people worldwide. High mutational capability and rapid diversification, inhibition of humoral and cellular immune responses, and thus inability for recognition of an immunogenic region in the viral envelope by the immune system are major challenges. Natural killer (NK) cells are multifunctional, playing a key role in the identification and elimination of HIV‐infected cells. These cells identify and eliminate virus‐infected cells in a multilateral manner, such as ligand stress, antibody‐dependent cell cytotoxicity (ADCC), T follicular helper (Tfh), and the activation of most of the stimulatory receptors. Moreover, these cells release cytokines leading to the activation of cytotoxic lymphocytes (CTLs) and dendritic cells (DCs), contributing to efficient viral elimination. Some subsets of NK cells exhibit putatively enhanced effector functions against viruses following vaccination easily expanded and identified by NK cell lines culture. Furthermore, NK cells promote the elimination of HIV‐infected cells which reduce the expression of major histocompatibility complex (MHC) molecules. Memory NK cells have higher functionality and renewable potential. A pioneering strategy to establish an efficacious HIV vaccine would include stimulation of the accumulation and long‐term maintenance of these HIV‐reactive NK cells. CAR‐NK (chimeric antigen receptor‐natural killer) cells‐based antiviral therapies have emerged as novel approaches with the ability of antigen recognition and more advantages than CAR‐T (chimeric antigen receptor‐T) cells. Recent development of induced pluripotent stem cell (iPSC)‐derived NK cells with enhanced activity and efficiency conferred a promising insight into CAR‐NK cell‐based therapies. Therefore, memory and CAR‐NK cells‐based approaches can emerge as novel strategies providing implications for HIV vaccine design and therapy.

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Trial, Error, and Breakthrough: A Review of HIV Vaccine Development

Cited by 7 publications

References 142 publications

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

An activator of G protein-coupled receptor and MEK1/2-ERK1/2 signaling inhibits HIV-1 replication by altering viral RNA processing

Murine Dendritic Cells for Immunotherapy and Vaccine Development: Generation, Optimization and Transduction

Memory and CAR‐NK cell‐based novel approaches for HIV vaccination and eradication

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