Severe immunodeficiency in HIV infection is linked to changes in the gut virome and bacterial microbiome

Human immunodeficiency virus (HIV) infection is a significant global health threat, with an estimated 35 million HIV-positive adults worldwide. HIV leads to the development of acquired immune deficiency syndrome (AIDS) by infecting and depleting CD4 T cells, a subset of white blood cells with an important role in mediating immune response. Despite great advances in understanding immune system processes in the past several decades, HIV researchers still lack a complete understanding of severe immunodeficiency and are seeking better methods of preventing and treating HIV disease.

Previous work linked HIV infection to gut bacteria in studies that observed increased intestinal translocation of microbial products, in addition to gut bacterial community changes, in HIV-positive individuals. Now, two important studies from the lab of Herbert S. Virgin from the Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis (USA), shed more light on how severe immunodeficiency relates to the gut virome and bacterial microbiome in HIV infection.

In the first study, Monaco, et al. took samples from three groups of patients in Uganda: individuals who were HIV-negative (n=40), those who were HIV-infected and being treated with antiretroviral therapy (ART) (n=40), and those who were HIV-infected and naive to ART (n=42). The researchers collected blood and stool samples and measured, among other things, the patients’ vital signs, medication history, clinical symptoms, CD4 T cell counts, and reported living conditions.

Consistent with other studies, the researchers found the group of HIV-infected subjects with low peripheral CD4 T cell counts tended to have a lower body weight. Moreover, microbial translocation in the gut (represented by plasma soluble CD14 levels) was higher in HIV-infected subjects than those without HIV, whether or not they were on ART.

The researchers found HIV-positive individuals with severe immunodeficiency (that is, peripheral CD4 T cell counts less than 200 per mm³, signifying advanced disease) showed an expansion of enteric viruses and had less phylogenetic diversity and richness in their gut bacterial microbiomes. One of the most noticeable changes in the guts of these patients was an increase in inflammation-associated Enterobacteriaceae. These changes in the enteric virome and bacterial microbiome were observed whether or not the patients were being treated with ART. From these results, the team concluded that immunodeficiency in human HIV infection is associated with alterations in both the enteric virome and the bacterial microbiome.

To get a more detailed look at gut microbiota changes during disease progression leading to AIDS, the Virgin Lab team undertook a related longitudinal study (Handley, et al.) on rhesus macaques. They aimed to find out how viral and bacterial populations changed throughout the course of infection with simian immunodeficiency virus (SIV).

In this study, the macaques were either infected or uninfected with SIV; some of the infected animals were protected by receiving the adenovirus serotype 26 (Ad26) vaccine.

Researchers observed an expansion of potentially pathogenic viruses and bacterial enteropathogens as SIV infection progressed to AIDS in these macaques. Advanced SIV disease is normally associated with more gastrointestinal disease; this team observed that specific enteropathogenic viruses spiked with increases in gastrointestinal disease and AIDS-related mortality. These pathogens, both bacterial and viral, were largely absent in animals protected by the vaccine.

The researchers say expansion of the enteric virome may be a biomarker for severe deficiency in the capacity of an animal’s gut immune system. And taken together with the previous study in humans, they say it is likely that severe immunodeficiency is the mechanism accounting for the dramatic changes in the makeup of the gut microbiota during HIV disease.

Further experiments may explore microbiota manipulation as a way to discover whether the gut microbiota have an active (causal) role to play in HIV disease progression leading to AIDS. A recent review by Williams, et al. noted that “modification of commensal microbial communities likely represents an important therapeutic adjunct to treatment of HIV”. Already, some researchers are investigating ways to alter microbial communities in HIV disease; so far, attempts to change gut microbiota of HIV-infected humans through fecal microbiota transplantation have not yielded promising results (although this comes from preliminary data in a trial that is still recruiting). More controlled approaches using characterized strains of bacteria (i.e. probiotics) show initial promise, but require further investigation.

A recently published workshop report authored by Moyes, et al. also noted increasing evidence for significant changes in the oral microbiota of HIV-infected individuals as infection progresses. Future work may clarify whether these changes in the oral microbiota are linked to the changes further down the gastrointestinal tract.

REFERENCES:

Handley SA, Desai C, Zhao G, et al. SIV infection-mediated changes in gastrointestinal bacterial microbiome and virome are associated with immunodeficiency and prevented by vaccination. Cell Host & Microbe. 2016; 19(3):323-335.

Monaco CL, Gootenberg DB, Zhao G, et al. Altered virome and bacterial microbiome in human immunodeficiency virus-associated acquired immunodeficiency syndrome. Cell Host & Microbe. 2016; 19(3):311-322.

Moyes DL, Saxena D, John MD, Malamud D. The gut and oral microbiome in HIV disease: a workshop report. Oral Diseases. 2016; 22(1): 166-170.

Williams B, Landay A, Presti RM. Microbiome alterations in HIV infection a review. Cellular Microbiology. 2016; 18(5): 645–651.