Reactivation of simian immunodeficiency virus reservoirs in the brain of virally suppressed macaques

Abstract

Objective:Resting CD4+ T cells have been recognized as the major cell reservoir of latent HIV-1 during antiretroviral therapy (ART). Using an simian immunodeficiency virus (SIV)/macaque model for AIDS and HIV-related neurocognitive disorders we assessed the contribution of the brain to viral latency and reactivation.Design:Pigtailed macaques were dual inoculated with SIVDeltaB670 and SIV17E-Fr and treated with an efficacious central nervous system-penetrant ART. After 500 days of viral suppression animals were treated with two cycles of latency reversing agents and increases in viral transcripts were examined.Methods:Longitudinal plasma and cerebrospinal fluid (CSF) viral loads were analyzed by quantitative and digital droplet PCR. After necropsy, viral transcripts in organs were analyzed by PCR, in-situ hybridization, and phylogenetic genotyping based on env V1 loop sequences. Markers for neuronal damage and CSF activation were measured by ELISA.Results:Increases in activation markers and plasma and CSF viral loads were observed in one animal treated with latency reversing agents, despite ongoing ART. SIV transcripts were identified in occipital cortex macrophages by in-situ hybridization and CD68+ staining. The most abundant SIV genotype in CSF was unique and expanded independent from viruses found in the periphery.Conclusion:The central nervous system harbors latent SIV genomes after long-term viral suppression by ART, indicating that the brain represents a potential viral reservoir and should be seriously considered during AIDS cure strategies.

Novel Latency Reversal Agents for HIV-1 Cure

“…Ingenol-3-mebutate (also known as ingenol-3-angelate) is FDA-approved as a topical therapy for actinic keratosis(49) and has demonstrated efficacy in multiple HIV-1 latency systems(46; 50). Ingenol B has recently been administered to non-human primates in combination with vorinostat (51). One of the two rhesus macaques exposed to ingenol B and vorinostat demonstrated increased SIV viral loads in both the central nervous system (CNS) and the periphery in response to LRA treatment, and also developed markers of systemic and CNS inflammation.…”

“…One of the two rhesus macaques exposed to ingenol B and vorinostat demonstrated increased SIV viral loads in both the central nervous system (CNS) and the periphery in response to LRA treatment, and also developed markers of systemic and CNS inflammation. A recent in vitro study of the effects of prostratin and bryostatin-1 on the central nervous system (CNS) identified that these agents may impair the integrity of the blood-brain barrier and increase trafficking of pro-inflammatory immune cells into the CNS(52), which may help to explain the results of the study by Gama and colleagues(51). …”

Pharmacologic HIV-1 Nef blockade promotes CD8 T cell–mediated elimination of latently HIV-1–infected cells in vitro

“…However, to our knowledge, no single intervention to date has resulted in a significant reduction of the viral reservoir in vivo while various adverse effects have been observed (62,63). Of particular concern is the observation that some LRAs could disrupt the blood brain barrier and induce hyperinflammation of neural tissue, which has been shown to correlate with HIV-1 progression (64,65). Additionally, some HDACi impair HIV-specific CD8 T cell function as measured by a reduced capacity to eliminate HIV-1-infected cells (66).…”

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

“…Compare to chemical activating agents, CRISPR/Cas9 system is safer and more efficient though, the balance of "shock" and "kill" is difficult to master. A recent study reveals a severe inflammatory response in central neural system after chemical activation of simian immunodeficiency virus (SIV) reservoirs in the pigtailed macaques (ongoing HAART) [30]. Therefore, the clinical application should be considered deliberately to avoid catastrophic consequence of extensive activation without proper eradication.…”