Therapeutic avenues for restoring the gut microbiome in HIV infection Cecilia Rosel-Pech 1,2 , Monserrat Cha´ vez-Torres 3,4 , Vilma Carolina Bekker-Me´ ndez 1 and Sandra Pinto-Cardoso 3 The interplay between the gut microbiota, the intestinal barrier and the mucosal immune system is profoundly altered in Human Immunodeficiency Virus (HIV) infection. An HIV- associated microbial dysbiotic signature has been difficult to define due to the strong impact of confounders that are intimately linked with HIV infection, namely HIV risk behaviors. When controlling for sexual preference and gender, HIV- associated microbial dysbiotic signatures are characterized by an increase in deleterious taxa and a decrease in beneficial bacteria and their respective metabolic end-products. First attempts to restore the gut microbiota of HIV subjects on Antiretroviral Therapy using Fecal Microbiota Transplantation proved to be safe and reported mild transient engraftment of donor microbiota and no effect on markers of HIV disease progression. This review focuses on the current evidence supporting a role for microbial dysbiosis in HIV pathogenesis, and reviews current microbiome-based therapeutics for restoring the gut microbiota in HIV infection. Addresses 1 Unidad de Investigacio´n Me´ dica en Inmunologı´a e Infectologı´a, Hos- pital de Infectologı´a “Dr. Daniel Me´ ndez Herna´ ndez”, Centro Me´ dico Nacional “La Raza”, IMSS, Ciudad de Me´ xico, Mexico 2 Posgrado en Ciencias Biolo´ gicas, Universidad Nacional Auto´ noma de Me´ xico, Ciudad de Me´ xico, Mexico 3 Centro de Investigacio´n en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosı´o Villegas, Ciudad de Me´ xico, Mexico 4 Seccio´n de Estudios de Posgrado e Investigacio´ n, Escuela Superior de Medicina, Instituto Polite´ cnico Nacional, Ciudad de Me´ xico, Mexico Corresponding author: Pinto-Cardoso, Sandra (sandra.pinto@cieni.org.mx) Current Opinion in Pharmacology 2020, 54:188–201 This review comes from a themed issue on Anti-infectives Edited by Leonor Huerta https://doi.org/10.1016/j.coph.2020.09.010 1471-4892/ã 2020 Elsevier Ltd. All rights reserved. Introduction Inflammatory, autoimmune, neuropsychiatric disorders, cancer and infectious diseases, all have been linked to gut microbiota alterations, and broadly report the concomi- tant increase in deleterious taxa and decrease in beneficial bacteria and their respective metabolic end-products [1,2]. Microbiome-based therapeutics (MBT) have emerged with variable success rates. MBT include direct or indirect manipulation of the gut microbiota and mainly target the bacterial component of the microbiota. Current strategies include fecal microbiota transplantation (FMT) and exoge- nous administration of live bacteria though to be beneficial (probiotics) [3]. Human immunodeficiency virus (HIV) infection is one such disease, with tremendous potential for MBT given that the interplay between the gut micro- biota, the intestinal barrier and the mucosal immune system is profoundly altered. Chronic inflammation, residual immune activation and microbial translocation are all major drivers of HIV disease progression and have been linked to increased mortality and morbidities among HIV-infected individuals [4,5]. Loss of gut mucosal immunity, gut barrier damage, gut permeability and systemic inflammation are all key features of untreated HIV infection. These are partially, but not completely, restored by antiretroviral therapy (ART) [6]. Understanding gut microbial dysbiosis in HIV infection is paramount because microbial communities interact intimately with the immune system, and HIV disrupts said system [7,8  ,9,10]. Researchers have long thought that some gut microbial communities, also referred to as pathobionts, no longer under immune surveillance, expand, exacerbating intestinal inflammation and possibly driving microbial dysbiosis. Pathobionts are resident bacte- ria that have pathogenic potential, meaning that they can induce inflammation under particular circumstances [11]. Evidentiary data supports the currently accepted paradigm linking HIV infection to gut microbiota alterations (Figure1) [7,8  ,9,10]. An HIV-associated microbial dysbiotic signa- ture has been difficult to define given the strong impact of confounders, namely HIV risk behaviors [12  ] and mecha- nisms by which microbial communities contribute to HIV pathogenesis remain poorly understood. Also, causality has not been established [7,9,10]. Attempts to target the gut microbiota in HIV infection have yielded modest results [7,13]. We will review the current MBT for restoring the gut microbiota in HIV infection, focusing on FMT. HIV infection: the loss of gut mucosal immunity coincides with gut microbial dysbiosis First, we will briefly recapitulate the effects of HIV on the gastrointestinal-associated lymphoid tissue (GALT). The Available online at www.sciencedirect.com ScienceDirect Current Opinion in Pharmacology 2020, 54:188–201 www.sciencedirect.com