Altered expression of fractalkine in HIV-1-infected astrocytes and consequences for the virus-related neurotoxicity.

HIV-1 infection in the central nervous system (CNS) causes the release of neurotoxic products from infected cells which trigger extensive neuronal loss. Clinically, this results in HIV-1-associated neurocognitive disorders (HAND). However, the effects on neuroprotective factors in the brain remain poorly understood and understudied in this situation. HAND is a multifactorial process involving several players, and the complex cellular mechanisms have not been fully elucidated yet. In this study, we reported that HIV-1 infection of astrocytes limits their potential to express the protective chemokine fractalkine in response to an inflammatory environment. We next confirmed that this effect was not due to a default in its shedding from the cell surface. We then investigated the biological mechanism responsible for this reduced fractalkine expression and found that HIV-1 infection specifically blocks the interaction of transcription factor NF-κB on its promoter with no effect on other cytokines. Moreover, we demonstrated that fractalkine production in astrocytes is regulated in response to immune factors secreted by infected/activated microglia and macrophages. In contrast, we observed that conditioned media from these infected cells also trigger neuronal apoptosis. At last, we demonstrated a strong neuroprotective action of fractalkine on human neurons by reducing neuronal damages. Taken together, our results indicate new relevant interactions between HIV-1 and fractalkine signaling in the CNS. This study provides new information to broaden the understanding of HAND and possibly foresee new therapeutic strategies. Considering its neuro-protective functions, reducing its production from astrocytes could have important outcomes in chronic neuroinflammation and in HIV-1 neuropathogenesis.

HIV-1 infection and latency-reversing agents bryostatin-1 and JQ1 disrupt amyloid beta homeostasis in human astrocytes.

Since the introduction of the combined antiretroviral therapy, HIV-1 infection has become a manageable chronic disease in which patients display a life expectancy almost identical to the general population. Nevertheless, various age-related pathologies such as neurocognitive disorders have emerged as serious complications. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed to eliminate the viral reservoir in such chronically infected patients. However, the impact of LRA on the central nervous system remains elusive. Given that an increased amyloid beta (Aß) deposition is a feature of HIV-1-infected brains, we investigated the consequences of HIV-1 infection and treatment with two LRA (bryostatin-1 and JQ1) on the capacity of human astrocytes to engulf and clear Aß. We show here that HIV-1-infected astrocytes accumulate a very high amount of Aß compared to uninfected cells, but the engulfed peptide in degraded very slowly. The LRA bryostatin-1 induces a reduction in Aß endocytosis, whereas JQ1 treatment results in a very slow degradation of the ingested material associated with a reduced expression of the endopeptidase neprilysin. An exposure to JQ1 also induces a sustained release of Aß-loaded microvesicles. Thus, both HIV-1 infection and treatment with some LRA could contribute to the reported Aß accumulation in the brain of HIV-1-infected persons.

Safety, tolerance and acceptability of the Invisible Condom and its vaginal applicator in healthy women and their male sexual partners.

OBJECTIVES: The study was conducted to evaluate the safety and acceptability of the Invisible Condom when applied once or twice daily for 14 days in healthy women and their male sexual partners. STUDY DESIGN: Forty-one women and 23 men divided into three cohorts were enrolled. Cohort 1:14 sexually abstinent women applying gel twice daily for 14 days; Cohort 2:14 sexually active women with tubal ligation applying gel once daily for 14 days and their 14 sexual partners who did not use gel; Cohort 3:13 women on oral contraceptive applying gel once daily for 14 days and 9 of their sexual partners. RESULTS: No serious adverse events (AEs) were reported. Colposcopy showed no genital ulceration nor epithelial lesions. No major changes in vaginal flora or vaginal pH were detected. None of the women had to stop product application because of AEs. The majority of AEs were mild. Common AEs were itching, dryness, burning sensation, erythema and discharge. Satisfaction questionnaire showed that the gel and applicator were acceptable. CONCLUSION: The Invisible Condom and applicator were safe, well tolerated and acceptable when applied intravaginally for 14 days. Thus, expanded safety and effectiveness evaluation is warranted.