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Review
. 2022 Dec;19(6):566-579.
doi: 10.1007/s11904-022-00628-8. Epub 2022 Oct 19.

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Patricia K Riggs  1 , Antoine Chaillon  2 , Guochun Jiang  3 , Scott L Letendre  2 , Yuyang Tang  3 , Jeff Taylor  4   5 , Andrew Kaytes  4 , Davey M Smith  2 , Karine Dubé  2 , Sara Gianella  2
Affiliations
Review

Lessons for Understanding Central Nervous System HIV Reservoirs from the Last Gift Program

Patricia K Riggs et al. Curr HIV/AIDS Rep. 2022 Dec.

Abstract

Purpose of review: Deep tissue HIV reservoirs, especially within the central nervous system (CNS), are understudied due to the challenges of sampling brain, spinal cord, and other tissues. Understanding the cellular characteristics and viral dynamics in CNS reservoirs is critical so that HIV cure trials can address them and monitor the direct and indirect effects of interventions. The Last Gift program was developed to address these needs by enrolling altruistic people with HIV (PWH) at the end of life who agree to rapid research autopsy.

Recent findings: Recent findings from the Last Gift emphasize significant heterogeneity across CNS reservoirs, CNS compartmentalization including differential sensitivity to broadly neutralizing antibodies, and bidirectional migration of HIV across the blood-brain barrier. Our findings add support for the potential of CNS reservoirs to be a source of rebounding viruses and reseeding of systemic sites if they are not targeted by cure strategies. This review highlights important scientific, practical, and ethical lessons learned from the Last Gift program in the context of recent advances in understanding the CNS reservoirs and key knowledge gaps in current research.

Keywords: Brain; Central nervous system (CNS); Cure; Eradication; HIV reservoirs; Spinal cord.

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Conflict of interest statement

DS has received consulting fees outside the submitted work from Matrix Biomed; Vx Biosciences, Signant Health, Model Medicines, Kiadis Pharmaceuticals, Bayer Pharmaceuticals, and owns equity in Linear Therapies. SLL received an unrelated grant from Merck & Co. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
HIV DNA copies per 106 cells by digital droplet PCR (ddPCR) in five CNS locations from the first six Last Gift participants
Fig. 2
Fig. 2
Maximum Likelihood (ML) Phylogenies and Clonal Populations (Full Length Envelope) for two participants who both remained virally suppressed at time of death. Phylogenies were estimated using IQtree [87] from the full length (FL) HIV env sequences obtained from ante-mortem blood plasma and from tissues and PBMC collected during rapid autopsy. Circle sizes reflect level of HIV DNA. A LG05 with pronounced viral compartmentalization within brain tissues. B LG08 without compartmentalization within CNS (arrows show frontal cortex). Both participants were heavily treatment-experienced with at least 8 years of suppressive ART. Figure adapted with permission from “HIV persists throughout deep tissues with repopulation from multiple anatomical sources.” By A. Chaillon, 2020, J Clin Invest, 130(4):1699–712
Fig. 3
Fig. 3
Sankey plots showing the proportion of migration events between anatomic locations for which the adjusted Bayes factor (BF) was 3 or higher for two participants showing migration within brain sites and bidirectionally across the blood brain barrier. The source locations are depicted on the left side of the plots and the destination locations on the right side. A Participant LG03 who remained virally suppressed on ART. Plots show evidence of bidirectional migration events of HIV DNA between the frontal motor and occipital cortex and occipital cortex to peripheral blood mononuclear cells [PBMCs]. B Data for a participant LG01 who stopped ART 53 days prior to death with viral rebound (antemortem plasma HIV RNA of 280 copies/mL). Note transitions of HIV DNA from frontal motor cortex to PBMC and plasma (and vice versa). Figure adapted with permission from “HIV persists throughout deep tissues with repopulation from multiple anatomical sources.” By A. Chaillon, 2020, J Clin Invest, 130(4):1699–712
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