Osteoporosis and bone fractures are established complications of HIV/AIDS and two of every three patients with HIV-infection are osteopenic or osteoporotic leading to a fracture incidence up to 4 fold higher in HIV patients over a wide age range. This is especially pertinent to men where fracture risk is typically low until advanced age. This substantial increase in fracture prevalence in relatively young adults is a significant public health concern as fractures can be debilitating and are frequently associated with devastating outcomes. With the advancing age of this population due to the success of antiretroviral therapy (ART), a synergy between HIV- and age-related skeletal decline could precipitate an epidemic of bone fragility disease. Another major conundrum in this field is that ART exacerbates rather than ameliorates bone loss. Interestingly, the skeletal effects of ART, though varied in magnitude, appear universal regardless of regimen. While a wealth of data now supports the notion of ART-induced bone loss, exactly when after ART initiation bone resorption begins and abates is unclear, and the underlying mechanism remains enigmatic. This dearth of knowledge has handicapped the design and implementation of strategies to limit further bone loss in patients who already exhibit an impoverished skeleton resulting from direct HIV assault. To begin to explore these issues, we recently examined bone turnover in patients initiating ART and documented a surge in bone resorption in virtually all patients starting as early as 2 weeks after ART initiation, peaking by 12 weeks, and remaining significantly elevated for up to at least 24 weeks. Importantly, T-cell recovery with ART reaches a significant magnitude at 12 weeks, the same time point at which this surge in resorption peaked, suggesting a possible link between immune recovery and ART-induced bone loss. In fact, it is now well established that bone remodeling, the process responsible for skeletal renewal, is strongly influenced by the immune system. This is the result of a deep integration and centralization of common cell types and cytokine mediators that we have termed the """"""""immuno-skeletal interface"""""""". Based on our preliminary data demonstrating that T-cell reconstitution in animals elicits a rapid and robust bone loss and our clinical studies demonstrating a temporal relationship between ART initiation, immune-reconstitution, and bone resorption, we hypothesize that immune- reconstitution, a consequence of ART-induced disease reversal, leads to robust, but acute, bone loss during the early period of ART. We propose 2 Specific Aims to further address this hypothesis:
Specific Aim 1 : To elucidate the mechanisms by which T-cell reconstitution drives skeletal deterioration;
and Specific Aim 2 : To demonstrate that skeletal deterioration associated with ART in humans, is a rapid, but relatively acute event, associated with T-cell reconstitution and immune regeneration, as a consequence of ART-induced disease reversal. These mechanistic studies into the pathophysiology of ART-induced bone loss will set the stage for future clinical studies to explore therapeutic approaches to preventing ART-induced bone loss.
Osteoporosis is a well known complication of antiretroviral therapy (ART), but the mechanisms remain poorly defined. This proposal investigates novel hypotheses regarding therapeutic approaches to, and temporal and mechanistic aspects of, the skeletal deterioration associated with initiation of antiretroviral therapy (ART) in patients with human immunodeficiency virus 1 (HIV-1) infection/acquired immunodeficiency syndrome (AIDS).
| Titanji, Kehmia; Vunnava, Aswani; Foster, Antonina et al. (2018) T-cell receptor activator of nuclear factor-?B ligand/osteoprotegerin imbalance is associated with HIV-induced bone loss in patients with higher CD4+ T-cell counts. AIDS 32:885-894 |
| Roser-Page, Susanne; Vikulina, Tatyana; Yu, Kanglun et al. (2018) Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice. Rheumatology (Oxford) 57:1105-1114 |
| Moran, Caitlin A; Weitzmann, M Neale; Ofotokun, Ighovwerha (2017) Bone Loss in HIV Infection. Curr Treat Options Infect Dis 9:52-67 |
| Weitzmann, M Neale (2017) Bone and the Immune System. Toxicol Pathol 45:911-924 |
| Neale Weitzmann, M; Pacifici, Roberto (2017) Parathyroid Diseases and T Cells. Curr Osteoporos Rep 15:135-141 |
| Li, Jau-Yi; Chassaing, Benoit; Tyagi, Abdul Malik et al. (2016) Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J Clin Invest 126:2049-63 |
| Weitzmann, M Neale; Ofotokun, Ighovwerha; Titanji, Kehmia et al. (2016) Bone Loss Among Women Living With HIV. Curr HIV/AIDS Rep 13:367-373 |
| Weitzmann, M Neale; Ofotokun, Ighovwerha (2016) Physiological and pathophysiological bone turnover - role of the immune system. Nat Rev Endocrinol 12:518-32 |
| Moran, Caitlin A; Weitzmann, M Neale; Ofotokun, Ighovwerha (2016) The protease inhibitors and HIV-associated bone loss. Curr Opin HIV AIDS 11:333-42 |
| Ofotokun, Ighovwerha; Titanji, Kehmia; Vunnava, Aswani et al. (2016) Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS 30:405-14 |
Showing the most recent 10 out of 35 publications
