Imaging glucose brain metabolism changes in SIV chronically-infected macaques upon starting or stopping antiretroviral therapies

Objectives There have been multiple studies examining CNS changes occurring in HIV+ patients after starting anti-retroviral therapy (ART), generally showing favorable outcomes. On the other hand, only a few studies assessed CNS changes after ART interruption with conflicting results. Elucidating the potential effects of those treatment modification approaches on the CNS can shed light on the pathophysiology of disease. The purpose of our study was to assess changes in brain metabolism associated with starting or interrupting ART in chronically infected SIV rhesus macaques using 18F-FDG and to correlate those changes with CSF cytokine levels and plasma viral loads.

Methods The animals were imaged in a prone position under anesthesia. Brain scans were obtained 70 minutes after the administration of ~5 mCi of 18F-FDG. Besides baseline scanning, follow up scans were obtained at 1, 3-5, and 6-7 months after treatment modifications. One macaque had two follow-up scans obtained one and four months following the original scan. Mean regional SUV (from multiple brain regions) and whole brain mean SUV values were obtained and compared longitudinally. Viral loads in the plasma and cytokine levels (IL-8, MCP-1, MIP-1) in the CSF were measured close to the time of imaging.

Results In the two macaques that were started on treatment, both MCP-1 levels in the CSF and plasma viral loads decreased one month following the onset of therapy. Whole brain and regional FDG uptake in the first animal decreased slightly at one month after the start of therapy but then increased at six months, corresponding to an increase in MCP-1 levels in the CSF. In the second treated animal, FDG uptake increased rather than decreased one month after starting therapy however in the long term decreased in comparison to baseline values. This corresponded to long term stabilization of viral load and MCP-1 CSF levels. In the two macaques that underwent treatment interruption, we observed an increase in viral load with increased FDG uptake at one month after stopping therapy. Between 4 and 6 months following interruption of drugs, both animals showed persistently increased FDG uptake compared to baseline that were associated with fluctuations in CSF MCP-1 levels and plasma viral loads.

Conclusions These results demonstrate the variability in the response of chronically SIV infected animals to starting or interrupting ART. FDG uptake appeared to generally trend with viral load and change in treatment status, however changes in MCP-1 concentration in the CSF seemed to play a role, probably indicating reactivation of inflammatory process with secondary increased FDG uptake. One interpretation of our results would suggest that the changes in glucose metabolism are labile and seem to not only be affected by peripheral viral replication but also by inflammatory changes in the brain as well. The balance between the development of encephalitis, neurological symptomatology, viral load changes, cytokine levels and brain metabolism needs to be further explored.

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