Durable suppression of HIV viral activity and the restoration of immune function are the primary goals of anti-retroviral therapy (ART), nutritional status and intestinal mucosal integrity may have an impact on these goals. A "healthy" intestinal microbiota both promotes nutritional status and preserves intestinal integrity. However, HIV infection, malnutrition, and altered dietary intake may adversely affect the intestinal microbiota, resulting in altered intestinal integrity and potentially, an increase in translocation of intestinal bacteria or their products into the systemic circulation. Our group is conducting a study of intestinal mucosal integrity (determined by lactulose:mannitol permeability) in HIV-infected individuals before and after they initiate ART, in rural Tamil Nadu, where rates of HIV prevalence are the highest in India. Based on this proposal, we will examine the role that alterations in the intestinal microbiota play in nutritional status, immune and virologic status, bacterial translocation and systemic inflammation and how these alterations respond to the initiation of ART. The study will be performed in two subgroups of HIV infected individuals from this parent study, one with normal and one with increased intestinal permeability, The overall hypothesis is that HIV infection and disruption of intestinal permeability will be associated with an intestinal microbiota profile which is "less healthy", i.e. less abundant and diverse, than that in HIV negative subjects of similar age and gender from the same community. We postulate that the "less healthy" intestinal microbiota will be associated with a greater inflammatory burden. Identification of these differences will allow us to further understand the pathogenesis of inflammation in HIV and allow us to develop and test targeted interventions, such as the use of pro- or pre-biotics or dietary interventions that may promote restoration of the profile of the intestinal microbiota and result in beneficial changes in intestinal integrity and improved nutritional status.
The specific aims of this proposal are to: 1. Elucidate the associations between the intestinal microbiota profile and immune, virologic and nutritional status in HIV-infected patients with normal and increased intestinal permeability, immediately prior to the initiation of ART, compared to that of non-HIV-infected controls of similar age and gender from the same community with normal permeability. Intestinal microbiota profiles (determined by pyrosequencing of bacterial 16s rRNA) will be assessed by abundance and diversity. Principal co-ordinates analysis (PCA) of the phylogenetic distances from each sample will be used to generate clusters of related microbiota profiles, which will be queried for association with i) CD4 count, ii) viral load, iii) body mass index (BMI), iv) mid-upper arm circumference (MUAC), v) bacterial translocation (plasma 16S rRNA) and vi) systemic inflammation (serum hsCRP) and 2. to investigate changes in the intestinal microbiota profile 6 months after the initiation of ART in both HIV infected groups and the non-HIV infected controls and determine the associated changes in i) CD4 count, ii) viral load, iii) BMI, iv) MUAC, v) plasma 16S rRNA levels and vi) hsCRP levels.
We propose to study the association of the intestinal microflora, as characterized by new sequencing technology, with intestinal integrity, nutritional status and inflammation in HIV infected individuals in South India. The results of this study will allow us to develop novel and targeted interventions that are appropriate to the resource limited setting which may lead to changes in not only nutritional status but also long-term outcomes in HIV infection.