Blood Bacterial Profiles Associated With Human Immunodeficiency Virus Infection and Immune Recovery.

Human immunodeficiency virus (HIV) infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by antiretroviral therapy (ART). Using 16S ribosomal DNA targeted sequencing and shotgun proteomics, we showed that HIV increases bacterial translocation from the gut to the blood. HIV increased alpha diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular cross talk between the host and the translocated bacterial products could influence ART-mediated immune recovery.

Effects of Immunonutrition in Advanced Human Immunodeficiency Virus Disease: A Randomized Placebo-controlled Clinical Trial (Promaltia Study).

Background: While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear. Methods: This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/µL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and ß microbiota diversity. Results: Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/µL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/µL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints. Conclusions: In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota. Clinical Trials Registration: NCT00870363.

Neuropatogénesis inducida por el virus del sida: estrategias terapéuticas frente a la neurodegeneración inducida por la glucoproteína gp120/Tat en el sistema nervioso central / Summary. Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant in the central nervous system

La neuroinflamación constituye un proceso clave en la neuropatogénesis del virus del sida como consecuencia de la activación aberrante de receptores de quimiocinas (CXCR4, CX3CR1 y CCR5), ya que la liberación de citocinas proinflamatorias por las células infectadas amplifica la neurotoxicidad microglial y genera lipoperóxidos y especies reactivas de oxígeno que, en última instancia, dañan la neurona. Por otro lado, la neurotoxina Tat induce alteraciones dendríticas por interacción con el receptor LRP (receptor de lipoproteínas de baja densidad) e induce una excesiva estimulación de los receptores de N-metil D-aspartato. Además, la interacción aberrante de la glucoproteína gp120 con el receptor CXCR4 induce apoptosis dependiente de caspasa 3 (también libera ceramida) y activa las proteínas apoptóticas p53 y retinoblastoma como mecanismos neurotóxicos asociados a la disfunción neural en el virus de la inmunodeficiencia humana 1 (VIH-1). Asimismo, la gliosis/activación microglial y la liberación de factores virales por los monocitos infectados, y el incremento de determinadas quimiocinas en el líquido cefalorraquídeo (MCP-1 y fractalcina, entre otras), contribuyen a la neuropatogénesis del VIH-1. Por otro lado, se han detectado depósitos de alfa-sinucleína y de beta-amiloide en cerebros post mortem de seropositivos de edad avanzada. Además, se han descrito varios marcadores sistémicos relacionados con los efectos degenerativos del virus y de sus neurotoxinas en el sistema nervioso central, tales como osteopontina, CD163 y fractalcina, entre otros. Por último, se han realizado ensayos clínicos basados en estrategias protectoras relacionadas con la inhibición de proteínas apoptóticas (inhibidores de GSK-3 beta), con inhibidores de la activación microglial (minociclina), antioxidantes (selegilina) o factores tróficos (IGF-1, hormona del crecimiento o eritropoyetina), que muestran efectos beneficiosos como tratamientos complementarios a la terapia antirretroviral (AU)

Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV-1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS (AU)