COMMENTARY

Deciphering how HIV-1 weakens and cracks the bone COMMENTARY Ighovwerha Ofotokuna,1

Globally, life expectancy for HIV-infected individuals is increasing and many are living into their old age, largely due to the success and increased use of combination antiretroviral therapy (cART) (1). Among the debilitating features of aging are the development of osteoporosis and loss of immune competence (2). Notably, both osteoporosis and immune compromise are also features of HIV infection, fueling speculations that HIV may lead to a form of premature aging. In fact, over half of HIV-infected individuals exhibit some degree of clinically appreciable bone loss (3). The skeletal effects of HIV infection are further com- pounded by additional bone mineral density (BMD) A loss at fracture-prone anatomical sites mostly within Fig. 1. ( ) Indirect bone effect of HIV. HIV-1 acts either through a suppressive effect on B cells or through disruption of T cell costimulation of B cells, leading 48 wk of cART initiation (4). The clinical significance to a decline in B cells secretion of OPG and an increase in B cells secretion of of HIV bone loss was for long unappreciated and ev- RANKL. This results in an increase in the RANKL/OPG ratio that is permissive for idence for a higher fracture rate in HIV-infected indi- osteoclastogenesis, contributing to bone loss and the elevated bone fracture viduals relative to the general population has until risk. Adapted with permission from ref. 18. (B) Direct bone effect of HIV. recently been anecdotal. However, a series of large HIV-1 directly infects circulating osteoclast precursors, enhancing their differentiation and migration to bones, and also alters the structure and function observational studies have now unambiguously shown of the osteoclast SZ, the resorption apparatus of the bone. These changes lead to a dramatic rise in fracture rate with HIV infection that is enhanced osteoclast adhesion and osteolytic activities resulting in accelerated particularly pronounced with advancing age. Overall, bone degradation. Adapted from Raynaud-Messina et al. (8). fracture rate with HIV infection is two- to sixfold higher than the general population (5, 6), and hip fracture risk dynamic organ that is continually renewed by the ninefold higher has been reported (7). These data coordinated removal of worn out bone by osteoclasts forewarn of a looming epidemic of fragility fracture and the deposition of new bone by osteoblasts, the cells in the aging HIV population and provide a compelling responsible for bone formation (9). While osteoblasts rational to explore in greater depth the pathophysiol- develop primarily from cells of mesenchymal origin, ogy of this phenomenon, to inform the search for the precursors of osteoclasts derive from cells of the effective preventive and therapeutic strategies. In , specifically those of monocytic lineage. PNAS, Raynaud-Messina et al. (8) make significant Under the influence of the key osteoclastogenic inroads into this quest, adding to our current under- , activator of NF-κB ligand (RANKL), standing of the mechanisms of HIV-induced bone loss. They demonstrate for the first time that HIV-1 is capa- and the presence of permissive amount of macro- ble of infecting the bone resorbing cell, the osteoclast, phage colony stimulating factor, monocytes differen- thereby directly modifying the structure and the func- tiate into osteoclasts. The activity of RANKL is moderated tion of the osteoclasts bone resorption apparatus, by its physiological decoy receptor known as the “sealing zone” (SZ), leading to enhanced (OPG) (10). Thus, the ratio of RANKL to that of OPG in adhesion and osteolytic activity. the bone microenvironment is the key determinant of the To put these findings in context and to better rate of osteoclast differentiation and consequently of appreciate the cellular and molecular events of bone bone resorption in the body. Of note, osteoclastogenis homeostasis, one must recognize that the skeleton is a is further potentiated by other inflammatory ,

aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30303 Author contributions: I.O. wrote the paper. The author declares no conflict of interest. Published under the PNAS license. See companion article on page E2556. 1Email: [email protected]. Published online March 1, 2018.

www.pnas.org/cgi/doi/10.1073/pnas.1801555115 PNAS | March 13, 2018 | vol. 115 | no. 11 | 2551–2553 Downloaded by guest on October 2, 2021 including TNF-α and IL-17 that amplify RANKL activity and promote HIV-induced disruption of the ISI acts indirectly via alteration in its secretion (11). immune cellular secretion of key osteoclastogenic regulatory fac- It is now evident that skeletal health is strongly influenced by tors to accelerate bone resorption and promote bone loss. the immune system, a consequence of deep integration and In addition to the indirect effects of ISI disruption on osteo- centralization of common cell types and cytokine mediators, clastogenesis described above, new findings by Raynaud-Messina which is now referred to as the “immuno-skeletal interface” (ISI). et al. (8) in PNAS indicate that HIV-1 also mediates a direct dis- Not only are osteoclast precursors derived from cells of monocytic ruptive effect on osteoclast structure and function. Using in vivo lineage, but under inflammatory conditions, such as rheumatoid humanized mice and ex vivo human joint tissue, the authors arthritis, periodontitis, and during estrogen deficiency, activated demonstrate that osteoclast precursors can be directly in- B and T lymphocytes secrete osteoclastogenic cytokines, including fected with HIV-1 and that osteoclast precursor infection oc- RANKL, TNF-α, and the RANKL-independent osteoclastogenic fac- curs at different stages of osteoclastogenesis, either via cell- tor, secreted osteoclastogenic factor of activated T cells (12). free viruses or more efficiently by transfer from infected T cells. Furthermore, B cells are a major source of OPG, the key regulator of RANKL, and OPG production is sustained by Raynaud-Messina et al. provide the first direct interactions with T cells, in part via CD40:CD40 ligand (CD40L) evidence of osteoclasts as a reservoir for the HIV costimulation (13, 14). Thus, under basal conditions, B cells act as virus and of the direct damaging effects of HIV critical stabilizers of peak BMD, and animal models of B cell de- ’ ficiency, T cell deficiency, and CD40 and CD40L deficiency display infection on the bone s resorption machinery. diminished B cell OPG production and severe bone loss (15). HIV-1–infected osteoclast precursors display enhanced migratory Although CD4 T cell depletion is the hallmark of HIV infection, the ability and thus have enhanced ability to recruit and concentrate in humoral immune response is also markedly denuded, with signifi- the bones. Importantly, the authors show that infection of osteoclasts cant depletion in resting memory B cells, along with a concomitant by HIV-1 disrupts the structure and the function of the SZ, the re- increase in activated and exhausted memory B cell populations and sorption apparatus of the osteoclast. Not only is the size of the SZ an increase in the frequency of immature/transitional B cells (16). increased, their ability to secrete tartrate-resistant acidic phospha- Given these observations, it has been proposed that HIV infection could disrupt the ISI and adversely impact bone health. tase, demineralize, and degrade larger bone areas is enhanced. Consequently, our group recently investigated RANKL and OPG Furthermore, there is enlargement of the SZ podosomes, the struc- cellular kinetics in animals (using the HIV-transgenic rats) and ture involved in cell adhesion, mechanosensing, and cell migration. in clinical studies in HIV-infected individuals. As predicted, we The net effects of these changes are enhanced adhesion and observed marked elevation in RANKL production concurrent with osteolytic activities of human osteoclasts with a consequent increase a marked depletion in OPG production by B cells in the setting of in bone degradation. These bone effects of HIV-1 were shown to be HIV infection. This alteration in B cell secretory function led to a mediated by the viral protein, Nef, partly through the activation of significant elevation in RANKL/OPG ratio, resulting in enhanced Src, a regulator of the podosomes and of their assembly into the SZ. bone resorption with marked reduction in BMD at key fracture- Raynaud-Messina et al. provide the first direct evidence of osteo- prone sites in both the animal model and human subjects (17, 18). clasts as a reservoir for the HIV virus and of the direct damaging Chakravarti et al. (19) similarly reported that serum OPG concen- effects of HIV infection on the bone’s resorption machinery. trations are diminished in HIV-infected patients and speculated Although, the findings by Raynaud-Messina et al. (8) need to that human peripheral blood T cells may also be a potential be validated in clinical studies involving HIV-infected participants, source of OPG. Interestingly, they noted that treatment of periph- the significance of this and other related work cannot be over- eral blood CD4 T cells in vitro with the HIV-1 gp120 caused a stated. With expanding uptake of cART, lifespan with HIV infec- decline in T cell OPG production. In subsequent studies, our tion is expected to continue to increase and age-related group confirmed these findings in vivo in HIV-infected patients, comorbidities, including fragility bone disease (osteoporosis and demonstrating that similar to B cells, T cells are also a source of fractures), will continue to rise. There are reasons to be concerned OPG in humans, and that HIV infection leads to a marked reduc- that age-related bone loss will synergize with HIV-induced skeletal tion in T cell OPG production and an increase in the T cell RANKL/ assault to precipitate an epidemic of fracture in the aging HIV OPG ratio that correlated significantly with BMD z-scores in the population. A clearer understanding of the pathophysiology of hip and lumbar spine in HIV-infected patients with CD4 T cell the HIV bone effects is therefore warranted to aid in constructing counts ≥ 200, concurrent with increases in T cell RANKL produc- effective remedies. Based on emerging data, such efforts can now tion (20). Another central cytokine involved in the ISI is IFN-γ. reasonably be targeted, either at mitigating the impact of HIV-1 Under inflammatory conditions, IFN-γ promotes bone loss by on the ISI or purging/protecting osteoclasts from direct viral up-regulating the activity of antigen-presenting cells (especially invasion and disruption. HIV-1 disruption of osteoclastogenesis macrophages), leading to T cell activation and osteoclastogenic either indirectly via alterations in the ISI or directly through cytokine production (21). Taken together, these data suggest that infection of osteoclasts is represented in Fig. 1 (8, 18).

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