Complexities of Gut Microbiome Dysbiosis in the Context of HIV Infection and Antiretroviral Therapy

Abstract

Human immunodeficiency virus (HIV) infection is associated with an altered gut microbiome that is not consistently restored with effective antiretroviral therapy (ART). Interpretation of the specific microbiome changes observed during HIV infection is complicated by factors like population, sample type, and ART-each of which may have dramatic effects on gut bacteria. Understanding how these factors shape the microbiome during HIV infection (which we refer to as the HIV-associated microbiome) is critical for defining its role in HIV disease, and for developing therapies that restore gut health during infection.

© 2016 American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1. The myriad of variables in HIV microbiome studies may confound study results

Many factors influence the intestinal microbiome throughout the course of HIV infection and treatment. An individual’s microbiome at baseline, before infection, will influence HIV-associated changes. These HIV-associated alterations themselves are influenced by the course of infection as well as any co-infection and treatment. In turn, these changes are further influenced by each patient’s course of ART. As a result, these confounding factors may hide ART-associated microbiome changes.

Figure 2

Studies of the HIV-associated microbiome have not been published in the populations most impacted by HIV.

Figure 3. Microbiome influence through all stages of HIV infection

The microbiome has the potential to have an influence throughout the entire natural history of HIV disease. Transmission: Since HIV preferentially infects activated T cells, dysbiotic microbiomes that activate CD4+ T cells can enhance disease transmission at mucosal sites. Disease Progression: The translocation of gut microbes through the intestinal barrier is thought to drive immune activation and disease progression. Chronic Infection: The gut microbiome differs from that of HIV-negative controls in chronic infection, and the myriad of health effects that may result from this dysbiotic microbiome are not understood. AIDS: Even more dramatic gut microbiome differences from healthy controls may occur with AIDS. Diarrhea, malabsorption, wasting and opportunistic infections that originate in the gut are common. ART: The gut microbiome of HIV-infected individuals on ART still differs from that of healthy controls. The effects of this dysbiotic microbiome on the health of individuals living a long time with HIV on ART are unknown, but many diseases that HIV-positive individuals on ART suffer from at increased incidence have been linked with gut microbiota compositional differences in HIV-negative individuals.

Figure 4. Gut health during HIV infection

1) A healthy gut is characterized by homeostasis between the immune system and the microbiome. 2) Though the impact of the baseline microbiota on HIV infection is unknown, it is possible that gut microbes could impact (A) transmission, potentially by activating CD4+ T cells. (B) HIV infection leads to CD4+ T cell death and immune depletion, and loss of immune regulation of gut bacteria, resulting in a dysbiotic microbiome. (C) Translocation of dysbiotic bacteria leads to (D) immune activation and further HIV infection of activated CD4+ T cells. 3) ART suppresses viral replication but does not fully restore gut immunity; dysbiosis is sustained during ART and microbial translocation continues to cause chronic immune activation. 4) A healthy gut may be restored by supplementing ART with pro/prebiotics or diets that encourage growth of beneficial bacteria, and with immunotherapy that could help reconstitute gut immunity and restore immune regulation of the microbiome.