Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents

S Telwatte, P Kim, TH Chen, JM Milush, M Somsouk… - Aids, 2020 - journals.lww.com
S Telwatte, P Kim, TH Chen, JM Milush, M Somsouk, SG Deeks, PW Hunt, JK Wong, SA Yukl
Aids, 2020journals.lww.com
Objective: While latently HIV-infected cells have been described in the blood, it is unclear
whether a similar inducible reservoir exists in the gut, where most HIV-infected cells reside.
Tissue-specific environments may contribute to differences in the mechanisms that govern
latent HIV infection and amenability to reactivation. We sought to determine whether HIV-
infected cells from the blood and gut differ in their responses to T-cell activation and
mechanistically distinct latency reversing agents (LRAs). Design: Cross sectional study …
Abstract
Objective:
While latently HIV-infected cells have been described in the blood, it is unclear whether a similar inducible reservoir exists in the gut, where most HIV-infected cells reside. Tissue-specific environments may contribute to differences in the mechanisms that govern latent HIV infection and amenability to reactivation. We sought to determine whether HIV-infected cells from the blood and gut differ in their responses to T-cell activation and mechanistically distinct latency reversing agents (LRAs).
Design:
Cross sectional study using samples from HIV-infected individuals (n= 11).
Methods:
Matched peripheral blood mononuclear cells (PBMC) and dissociated total cells from rectum±ileum were treated ex vivo for 24 h with anti-CD3/CD28 or LRAs in the presence of antiretrovirals. HIV DNA and ‘read-through’, initiated, 5′ elongated, completed, and multiply-spliced HIV transcripts were quantified using droplet digital PCR.
Results:
T-cell activation increased levels of all HIV transcripts in PBMC and gut cells, and was the only treatment that increased multiply-spliced HIV RNA. Disulfiram increased initiated HIV transcripts in PBMC but not gut cells, while ingenol mebutate increased HIV transcription more in gut cells. Romidepsin increased HIV transcription in PBMC and gut cells, but the increase in transcription initiation was greater in PBMC.
Conclusion:
The gut harbors HIV-infected cells in a latent-like state that can be reversed by T-cell activation involving CD3/CD28 signaling. Histone deacetylation and protein kinase B may contribute less to HIV transcriptional initiation in the gut, whereas protein kinase C may contribute more. New LRAs or combinations are needed to induce multiply-spliced HIV and should be tested on both blood and gut.
Background
Latent HIV infection is widely regarded as the main barrier to curing HIV. While latent infection was originally described in blood CD4+ T cells [1–3], most HIV-infected cells reside in tissues such as the gut [4, 5], where differences in infected cell types [6], immune activation [4, 7, 8], and other factors could influence HIV latency. We recently showed that the blocks to HIV expression differ between gut and blood, with blocks to HIV transcriptional completion and splicing in both sites but 10-fold less HIV transcriptional initiation in the gut [9, 10]. While ex-vivo T-cell activation has been shown to reverse HIV latency in blood cells [1–3], it is unclear to what degree activation can reverse the blocks to virus expression in the gut, where a much higher proportion of CD4+ T cells show constitutive markers of ‘activation’[4, 7]. Likewise, it is unclear which cellular mechanisms govern the different blocks to HIV transcription, or whether agents aimed at reversing latency will show differing effects in the gut or between gut regions [4, 11].
Lippincott Williams & Wilkins