Predictors of Antiretroviral Immunereconstitution Bone Loss - the Gut and the Microbiome - The premise of this work is anchored on the observation by our group and others that: a) prior to treatment the
HIV virus inflicts bone loss in persons living with HIV (PWH); b) Antiretroviral therapy (ART) inflicts additional
acute bone loss, but the magnitude of this loss varies widely from person to person, ranging from mild to
profound, and occurs within a defined window (~6 months) following ART initiation and; c) As PWH age,
HIV/ART-bone loss is compounded by natural aging bone loss. We contend that the acute ART-induced bone
loss is due to immune reconstitution and is driven by T cell activation in response to microbial antigens and
intensified by HIV-induced gut damage and microbial translocation. Importantly, as this acute bone loss is
driven by immune activation, even newer ART drugs cause severe bone loss in susceptible patients.
Of note, immune activation driving inflammation is antigen-dependent. T cells recognize antigens via a vast
repertoire of unique T cell receptors (TCRs). Although ART leads to partial T cell recovery, as the adult thymus
is atrophic, T cells repopulate mainly via homeostatic expansion of preexisting memory T cells rather than de
novo. ART, thus, likely expands T cell clones that have survived HIV as they are hyper-reactive to persistent
self- and foreign-antigens. Microbial translocation due to HIV-induced gut damage may intensify inflammation.
Another interesting feature of the gut-immune interaction is Th17 T cell expansion and translocation to the bone
marrow where they secrete the osteoclastogenic effector RANKL, as well as IL-17A and TNF, both potent
inducers of RANKL. Further, LPS, a marker of gut permeability, is an inflammatory product that promotes bone
loss through osteoclastogenic cytokines, including IL-1, IL-6, TNF, and/or direct osteoclast effects via Toll-like
receptors including TLR4. It is therefore likely that HIV-induced gut damages enhance inflammatory bone loss.
Gut-immune interaction may thus explain the inter-subject variability noted in immune reconstitution bone loss
(IRBL) as gut leakiness and microbiome profile vary widely among PWH.
In this application, we therefore propose a mechanistic animal study to establish a role for antigen presentation
and microbiota in a mice model of IRBL (Aim 1), and a complimentary human clinical study to validate the role
of microbiota, Th17 cells, and gut permeability in ART-induced IRBL in PWH (Aim 2). Upon completion, we
expect to establish strong relationships between gut leakiness, intestinal microbiota, immune activation and
IRBL and demonstrate that these relationships vary widely from person to person. Findings from this work will
contribute to ongoing efforts aimed at identifying PWH at risk for severe IRBL and provide strong rationale for
exploring targeted preventive interventions including probiotics and/or CD4+ Th17/IL-17A inhibitors.
