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    • Indeed in women with different causes

    2021-10-20

    Indeed, in women with different causes of epithelial layer damage, HIV infection rates have been reported to be very high [2], [3]. As observed from in vivo studies, disruption of the epithelium due to pathogens [45], [46] or chemical irritants [47], has resulted in women being at a higher risk of HIV infection. An increase in anti-proteases was observed in cervicovaginal lavage of highly exposed seronegative individuals and was associated with a protective phenotype from HIV infection [48], [49]. These in vivo observations together with the fact that HIV gp120 induces protease activity in vaginal epithelial cells, implicate that HIV would facilitate its initial entry by compromising the integrity of the host tissue. Interestingly, chemotaxis was another enriched process, observed in our study, which is fueled by chemokine activity leading to immune cell activation [33]. This observation prompts us to hypothesize that HIV gp120 mediated chemokine induction, would enhance the chemotaxis of sub-epithelial CD4 cells, accelerating viral dissemination via the sexual route. To the best of our knowledge, this is the first study to elucidate that HIV gp120 induces characteristic transcriptional gene expression signatures in vaginal epithelial cells. In the present study, we have delineated the effects of recombinant monomeric glycosylated gp120 interactions with epithelial cells; nonetheless it will also be interesting to evaluate the effects of alternate multimeric forms of the protein. The gene expression signatures reflected in the current study, included inflammation and increased proteolysis, which are recapitulated in several in vivo situations of mucosal HIV infection. The induction of proteases, may lead to direct breakdown of cell junctions and extracellular matrix proteins. Secondly, HIV gp120 also induces a proinflammatory milieu through induction of cytokines, like TNFα which would cause breaks in the epithelium. Thirdly, the increased production of chemokines would directly recruit immune h89 to sites of infection. We hypothesize that these processes would act in concert, thereby providing the virus a direct route of entry into the sub-epithelial zone, where HIV gains access to the CD4+ immune cells (Fig. 3). In this model, we propose a potential new mechanism whereby HIV uses gp120 to breach the vaginal epithelial barrier, to enhance and facilitate its own entry. Further studies are warranted in this direction to study the transepithelial resistance and permeability breaches of the vaginal epithelium following HIV gp120 binding. This study has also opened new avenues in the design of anti-HIV therapeutics/microbicides to prevent HIV induced damage to the vaginal epithelial barrier, in a bid to halt HIV in its tracks at the site of entry.
    Acknowledgments
    This work (NIRRH/M/88/13) was funded by grants from the Indian Council of Medical Research, Government of India. We are grateful to the Indian Council of Medical Research, Government of India for the Senior Research Fellowship to SEF. The microarray processing was performed at Genotypic Technology Pvt. Ltd, Bangalore, India. Author contributions: Conceived and designed the experiments: SEF DNM AHB. Performed the experiments: SEF. Analyzed the data: SEF DNM AHB. Wrote and evaluated the paper: SEF DNM AHB.
    Introduction Cardiac abnormalities are found at autopsy in two-thirds of patients with acquired immunodeficiency syndrome (AIDS). The most commonly described cardiac manifestations of AIDS include pericardial disease, myocarditis, dilated cardiomyopathy, and endocarditis [1], [2], [3]. Cardiovascular abnormalities may directly result from the human immunodeficiency virus type 1 (HIV-1) infection of cardiomyocytes or the effects of HIV-1 encoded proteins which disturb the normal cellular biological process. Cardiovascular abnormalities may also be indirectly induced by the effects of cytokines, co-infection with bacteria, autoimmunity caused by HIV infection, as well as antiretroviral toxicity [4], [5], [6], [7], [8]. Among HIV-1 encoded proteins, the HIV-1 envelope glycoprotein gp120 (gp120) has been extensively studied for its pathogenic roles in HIV-1 induced cardiovascular abnormalities. HIV-1 gp120 has biological effects on different organs and systems through regulation of multiple signaling pathways. HIV-1 gp120 can modulate various cellular processes through activating chemokine receptors CXCR4 or CCR5 on the membrane of the cells. HIV-1 gp120 can also interact with N-methyl d-aspartate receptor (NMDAR) and induce apoptosis of neuronal cells and cardiomyocytes [9], [10], [11]. HIV-1 gp120 has been implicated in causing HIV myopathies of both cardiac and skeletal muscles [12]. The studies on direct effects of recombinant gp120 using animal models and transgenic mouse models have linked gp120 to myocardial dysfunctions [13], [14], [15]. Although gp120 has been considered an inducer of apoptosis in rat cardiac cells [8], [15] the mechanisms of cardiac effects of gp120 remain poorly understood.