James McMahon

This session encompassed 2 key themes: 1) new data on HIV reservoirs including tissue macrophages, tissue resident memory T-cells and new markers for the transcriptionally active reservoir, and 2) Potential targets for new interventions studied in cellular and animal models

Firstly, HIV is present in urethral macrophages, is replication competent and inducible. Eloquent description of differences between HIV in CD4+ T-cells and macrophages yet questions remain: how macrophage infected cells persist? self-renewal or ongoing replication? Maria Buzon focussed on tissue resident memory T-cells and the ‘active’ HIV reservoir (transcriptionally active cells in ART-suppressed patients). Describing CD20, classically a B-cell marker, co-expressed on CD4+ T-cells marking them as more likely to be ‘active’. Then, the SMAC mimetic AZD5582 reversing latency operating via a ‘non-canonical’ nfKappa-B pathway activating fair fewer cellular genes than other LRAs. AZD5582 tested in mouse and monkey models reactivated HIV (considerable viremia in monkeys) without broad CD4+ T-cell activation. Ya-Chi Ho described how HIV integration drives transcription and identification of upregulated genes supporting transcription (IMPDH1 and JAK1). Drug screening identified targets: spironolactone, JAK1 inhibitor Filgotinib, IMPDH inhibitor Mycophenolic acid which all decreased transcription in cell lines

The session provides evidence that tissue-resident macrophages are an HIV reservoir for replication competent and inducible HIV, and how ‘shock and kill’ strategies should also consider macrophage-specific interventions like TLR4 agonists. Description of the ‘active’ reservoir which may be the first to re-seed the reservoir and trigger immune activation, how CD20 marks this reservoir on CD4+ T-cells and how the anti-CD20 molecule rituximab can impact this cell population. Additional promising interventions for future trials are the SMAC mimetic LRA AZD5582 already through a monkey study and drugs that can inhibit cellular factors supporting HIV transcription in cell based models.

Elizabeth Wonderlich

This session was chaired by Drs. Linos Vandekerckhove and Alberto Bosque and featured four presentations where researchers aimed to characterize cell types, locations, and reactivation of the HIV-1 reservoir with the ultimate goal of influencing and generating an HIV-1 cure.

Dr. Yonathan Ganor presented HIV-1 persistence in tissue resident macrophages in urethral explants from ART-suppressed individuals through confocal and electron microscopy and HIV-1 outgrowth assays. Dr. María J. Buzón discussed her work defining tissue resident memory CD4+ T cells as a cellular reservoir for HIV-1, while also working to identify host cell surface markers specific for HIV-1 transcriptionally active cells. Dr. David M. Margolis presented data on efficient HIV-1 latency reversal utilizing HDAC-inhibitors and SMAC mimetics in animal models for HIV-1 infection and clinical trial participants. Finally, Dr. Ya-Chi Ho presented data showing that through a combination of HIV SortSeq leading to single-cell RNAseq reveals the HIV-1 promoter silences upstream host gene promoters and causes aberrant downstream transcription that may be related to clonal expansion and proliferation of infected cells.

The data presented in this session highlighted the need to explore alternative methods of latency reversal to reactivate HIV-1 across a wide range of cell types and tissues. Further research and analysis is needed to define if tissue resident macrophages contribute to viral rebound, the long term effects of HDAC inhibitors and SMAC mimetics on immune responses, and host factor analyses in the HIV-1 reservoir in the absence of mitogen-induced cellular remodeling. This session featured the complexity of an eventual curative solution and emphasized the extensive commitment required to discover an HIV-1 cure.