The outbreak of the novel SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) responsible for coronavirus disease 2019 (COVID-19) has developed into an unprecedented global pandemic. Clinical investigations in patients with COVID-19 has shown a strong upregulation of cytokine and interferon production in SARS-CoV2-induced pneumonia, with an associated cytokine storm syndrome. Thus, the identification of existing approved therapies with proven safety profiles to treat hyperinflammation is a critical unmet need in order to reduce COVI-19 associated mortality. To date, no specific therapeutic drugs or vaccines are available to treat COVID-19 patients. This review evaluates several options that have been proposed to control SARS-CoV2 hyperinflammation and cytokine storm, eincluding antiviral drugs, vaccines, small-molecules, monoclonal antibodies, oligonucleotides, peptides, and interferons (IFNs).

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The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication.

We previously demonstrated that a commercially available natural product preparation with high content (>90%) of theaflavin derivatives (TFmix) exhibited potent anti-HIV activities. Here we developed a TFmix gel formulation as a topical microbicide candidate. The effect of TFmix on the amyloid fibril formation of semen-derived enhancer of virus infection (SEVI) peptide was detected by transmission electron microscopy. The toxicity of the TFmix gel was evaluated using human vaginal and cervical epithelial cell lines and rabbit vaginal irritation models, respectively. Levels of proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) and immunoregulatory cytokines (IL-10 and GM-CSF) in cervicovaginal lavages (CVLs) were measured by ELISA kits. Proliferating cell nuclear antigen (PCNA) immunostaining was performed to evaluate inflammation in the vaginal tissues. TFmix gel could degrade SEVI-specific amyloid fibrils and showed low cytotoxicity to epithelial cells of the female reproductive tract. No apparent cervicovaginal toxicity was observed at any time point evaluated following the intravaginal administration of TFmix gel to rabbits, whereas application of N-9 gel resulted in damage to the vaginal epithelium. Neither proinflammatory nor immunoregulatory cytokine production was triggered by TFmix gel. Only low expression of PCNA was observed in vaginal tissues of TFmix gel-treated rabbits. The concentration of TFmix in plasma was very low (below the lower limit of quantitation) 1 h after a single vaginal administration of TFmix gel. However, TFmix was still detected in the cervicovaginal lavages (CVLs) 6 h after treatment, indicating that it could be retained in the vaginal cavity for a long period of time. With its potent anti-HIV-1 activity, marked stability at acidic condition, low mucosal toxicity, and lack of systemic absorption, TFmix gel can be considered as an inexpensive and safe microbicide candidate for the prevention of HIV sexual transmission.