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    • atm inhibitor This study does have important limitations

    2022-03-11

    This study does have important limitations to consider. The utilization of a recombinant gp120 monomer (at a single concentration of 100 ng/ml) instead of live virus particles may limit the validity of our results. Moreover, extrapolation of an in vitro cell culture model to animals or humans cannot always be done with confidence. However, each structural component of the HIV virion or viral infection in itself may have a varied biological effect on cellular apoptosis, differentiation and function. To best determine which specific viral component, and the mechanism by which it modulates MSC migration, we preferentially used a panel of HIV structural proteins in our study. Numerous studies have provided supportive evidence of the bioactivity of gp120 independent of viral replication [12,[15], [16], [17], [18], [19], [20]]. Despite effective antiretroviral therapy, there continues to persistent HIV protein production in vivo; the estimated concentration of soluble gp120 in HIV-infected individuals range between 100 and 1000 ng/ml [15,47]. The use of animal and human models of HIV infection to investigate the effects of gp120 on MSCs may be inferior compared to a cell-culture based model for numerous reasons, including interspecies variability in the bioactivity of HIV gp120, and the low abundance of MSCs in animal/human tissues and its lack of specific immunophenotype which will significantly hinder the ability to identify MSCs in vivo [48]. We did not investigate gp120 atm inhibitor on CXCR4 as this has been described by other studies, and our focus was on the biological effects and mechanisms of gp120 in modulating MSC migration. Transcriptional regulation of CXCR4 is complex and not adequately elucidated to date. Initial mapping and cloning of CXCR4 promoter region revealed multiple potential binding sites for transcription factors [[49], [50], [51]]. Only two transcriptional regulators with opposing actions have been demonstrated to mainly control the basal transcription of CXCR4: Nrf1 (Nuclear Respiratory Factor 1) promotes [50] while YY1 (Ying Yang 1) inhibits its expression [52]. In addition to its basal transcription, CXCR4 is reported to be modulated by numerous stimuli positively or negatively in various cell types involving different signaling proteins and downstream transcriptional factors (reviewed in [53]). HIV gp120 has been shown to activate transcription factors such as STAT3 [54], AP-1 [55] and NFAT [56] in leucocytes and lineage commitment transcriptional factors including RUNX and PPARγ in MSCs [17,57]. However, how HIV gp120 specifically regulates CXCR4 transcription in MSCs remains unknown, and this will be the focus of future work. There is currently much hope for a cure for HIV infection using gene therapy in haemopoetic stem cells. As CCR5-tropic HIV strains are the dominant infective strains in vivo, persons who are homozygous for a 32-bp deletion (delta 32/delta 32) in CCR5 are resistant to HIV infection. Early clinical trials using zinc-finger nucleases to disrupt the CCR5 gene in stem cells of HIV-infected patients are underway [[58], [59], [60], [61]]. Our present result raises the question whether gp120 upregulation of CXCR4 could potentially jeopardize CCR5-knockout strategies to control and cure HIV infection, by providing a viral escape mechanism to facilitate HIV entry by CXCR4 instead.
    Conclusion The following are the supplementary data related to this article.
    Transparency document
    Introduction There are 36.7 million people living with HIV-1 worldwide, with 1.8 million people with acquired HIV-1 infections, and more than 1 million deaths from AIDS-related illnesses [1]. Currently, therapy with antiretrovirals is the most effective treatment for the control of HIV-1 infection. However, this therapy has serious adverse effects and viral resistance [2]. HIV-1 gp120 is the first glycoprotein to establish contact with host target cells on the CD4 receptor [3] and blocking gp120-CD4 complex formation may prevent HIV-1 infection in host CD4+ target cells [3]. Thus, neutralizing antibodies that bind to the interface of the internal and external domains of the gp120 CD4 binding site (CD4bs) can compete with CD4 receptors [4].Three-dimensional models of the quaternary structure of HIV-1 envelope proteins (gp120-gp41) in complex with broadly neutralizing antibodies (bnAbs) obtained from cryo-electron microscopy are useful resources for peptide epitopes. This utility is observed because bnAbs can neutralize the majority of circulating HIV-1 strains [5]. One useful resource for peptide epitopes is the BG505 SOSIP trimer (PDB: 3J5M), a gp120 and gp41 trimer assembly, which includes the V1/V2, V3, HR1, and HR2 domains and the CD4 binding site epitope cluster for bNAbs [6]. This assembly displays a well-ordered quaternary structure, permits a good antigenic profile and possesses the ability to discriminate between recognition by bnAbs and nonbnAbs as native gp120-gp41 trimers [7].