Background
There is a critical need to understand HIV-1 and host immune dynamics in deeper tissues early during analytical treatment interruption (ATI). Non-invasive methods to ascertain viral-host responses across the whole body and identify the location of viral reservoirs that lead to HIV-1 recrudescence are urgently needed.
Methods
We first performed longitudinal PET imaging using [89Zr]-VRC01 to detect HIV-1 gp120 in 3 participants participating in an ATI study (2 days prior to first detectable HIV-1 plasma RNA, during viral rebound [VL 381], and 18 days following ART re-initiation in a person who controlled virus). We then performed [18F]-FaraG PET MR imaging (a tracer specific to activated/cycling T cells) prior to ATI followed by another administration a median of 9 days after stopping ART (N=4, range 7-13 days). Standardized uptake values (SUV) were calculated for tissue regions of interest (ROI)
Results
We observed an increase in [89Zr]-VRC01 uptake in inguinal lymph nodes (mean tissue-blood ratio SUVmax: 0.33 vs 0.15), colorectal tissue (0.5 vs 0.21), femoral bone marrow (1.09 vs 0.4), and peri-vascular brain parenchyma (frontal cortex [ 0.31 vs 0.1 ], cerebellum [0.8 vs 0.09 ]) in the 2 pre-/peri-rebound participants compared to previously reported SUV for PWH on ART. In contrast, the controller imaged after ART reinitiation had similar VRC01 SUVs to PWH on ART. In the longitudinal [18F]-FaraG PET MR imaging study, repeat PET scanning during ATI was performed 5 to 35 days prior to detectable plasma HIV-1 RNA, and we observed an up to 2.3-fold increase in tracer uptake from pre-ATI baseline in various inguinal lymph nodes in 3 of 4 participants; the highest levels were measured in a participant that experienced viral rebound 35 days following PET. We also observed a ~1.5-fold increase in brain uptake (frontal, temporal, cerebellum, pons) in one individual during ATI 17 days prior to first detectable viral load compared to pre-ATI imaging.
Conclusions
We directly visualized tissue-based HIV and immune activation during ATI even before virus was detectable in plasma. Sources of viral rebound appear specific to variable foci within lymphatic tissue, gut, brain and bone marrow. We also observed activation of T cells in the lymphoid system and CNS in this same post-ART pre-rebound period. These data suggest that PET imaging approaches may be powerful tools to understand whole-body dynamic viral-host responses, especially with respect to active reservoirs and tissue foci of HIV-1 rebound.
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