Nominated From: University of Hawai’i
Research Site: Thailand
Research Area: Infectious Disease
Primary Mentor: Lishomwa C. Ndhlovu
Mucosal Myeloid Inflammation in Chronic HIV infection— Implications for HIV Associated Neurocognitive Disorders
With the advent of combinational antiretroviral therapy (cART), HIV infection is now managed as a chronic disease. However, despite the unquestioned success of cART in treatment and prevention, limitations persist. As compared to matched HIV-uninfected adults, successfully treated HIV-infected adults have a higher risk and prevalence of a number of non-AIDS defined conditions, including neurocognitive disorders. The prevalence of HIV-associated neurocognitive disorder (HAND) remains high (estimated 30-50%) and persists despite plasma HIV RNA suppression with potent cART (1). Inflammation and persistent immune activation have been linked as a potential mediator to this increase in non-AIDS-related mortality and morbidity however the underlying mechanisms involved are unresolved. To date, there are no clinically proven therapies for HAND for individuals already on stable, virologically suppressive anti-HIV regimens (2).
Peripheral monocytes and tissue macrophages are part of the innate immune response and represent an important source of inflammatory cytokines and chemokines (3, 4) that have been associated with an increased risk of mortality in cART treated HIV-infected individuals (5). Furthermore, circulating monocytes play a critical role in many inflammatory diseases, including in chronic HIV infection (3, 4, 5). Studies in the Ndhlovu Laboratory reveal that circulating inflammatory monocyte levels (CD16+ levels) with polyfunctional cytokine activity (IL-1β, IL-6, IL-8) remain elevated among cART treated HIV subjects compared to HIV uninfected donors (5, 7, 8). An increase in these markers correlates with increased lipopolysaccharide (LPS), levels in the blood, a biomarker of microbial translocation (5, 7, 8, 9). High levels of monocyte derived inflammatory biomarkers appear contributory to the pathogenesis of HAND and associated with an increased risk of mortality in cART-treated HIV-infected individuals (4, 6, 7,10). The role of gut macrophage perturbations in cART treated HIV subjects remains unknown and would be relevant to understanding the pathogenesis of non-AIDS defined comorbidities such as HAND. Recent studies from Schuetz Laboratory reveal that Th17 cell depletion in the days soon after HIV acquisition were associated with local and systemic immune activation (11). In chronic HIV infection, Th17 frequencies are lower in the sigmoid colon of individuals with higher plasma LPS levels (11).
Therefore, gut, mucosal and peripheral inflammatory profiles from chronically treated HIV-infection need to be further studied as apart of forming a comprehensive understanding of inflammatory immunodynamics and be considered in context of HAND pathogenesis.
This study proposal seeks to investigate inflammatory profiles of myeloid gut tissue from five HIV-infected and five HIV-uninfected matched Thai donors as part of the RV304/SEARCH013 clinical cohort study of chronic HIV infection and gut mucosal immunobiology in Bangkok. These data will be compared with mucosal Th17 activity and examined in context with subject’s neurocognitive assessments.
- Specific Aim 1: To examine gut macrophage inflammation during chronic HIV infection compared to HIV uninfected Thais and determine the relationship to peripheral monocyte inflammation (CD16+, TNF-α, IL-1β, IL-6) and mucosal Th17 cells.
- Hypothesis 1: A gut macrophage inflammatory profile (HLA-DR, CD206, CD14 frequencies) will be increased in HIV Thai subjects compared to HIV uninfected matched donors.
- Hypothesis 2: An increase in gut macrophage inflammation will be related to the degree of loss of mucosal Th17 cells and to increased peripheral monocyte inflammation
- Specific Aim 2: To characterize neurocognition through neurophyschological test assessments in chronic HIV infected and HIV uninfected Thai subjects
- Hypothesis 1: Neurocognitive impairment (NCI) will be more prevalent amongst chronic HIV infected Thai subjects in comparison to matched HIV uninfected subjects.
- Hypothesis 2: The levels of NCI will be associated with increased gut macrophage and monocyte inflammation and decreased mucosal Th17 frequencies.
With increased survival rate of HIV-infected individuals, rates of chronic non-AIDS comorbidities has become a major problem, and a novel strategy to manage the persistent immune activation as the underlying cause of these comorbidities needs to be addressed. The study will provide key information about the gut myeloid inflammatory profile in HIV-infected and matched HIV-uninfected subjects in Thailand. The results from this study may be crucial to developing new immunomodulatory approaches to HIV-associated neurocognitive disorder (HAND) and has the potential to identify implications in other comorbidities of chronic HIV infection.
- Lishomwa C. Ndhlovu, University of Hawaii
- Alexandra Schuetz, Armed Forces Research Institute of Medical Sciences
- Robert J. O’Connell, Armed Forces Research Institute of Medical Sciences