Researchers around the world are making advances in understanding how HIV becomes latent and seeking out vulnerabilities that could provide routes to targeting reservoirs and eliminating them. The virus persists in some cells after infection despite antiretroviral therapy (ART) and these contain inactive proviruses that can replicate and trigger the disease.
At a session at the 2022 AIDS Conference, "The view from the bench: Advances in HIV basic and translational research," Alberto Bosque, associate professor in the Department of Microbiology, Immunology and Tropical Medicine at George Washington University, introduced three new pieces of research into latent HIV.
Bosque's group has discovered that a retinol derivative isotretinoin enhances the activity of the latency-reversing agent (LRA) IL-15, which could help to target HIV reservoirs.
Building on this, researchers have designed so-called STESK strategies, such as the one presented by Bosque's colleague Jacqueline Howard in her talk 'Pharmacological enhancement of IL-15 signaling to improve shock-and-kill strategies against latent HIV.' STESK stands for Shock of latent HIV, Translation of viral transcripts, enhancement of Effector function of the immune system, Sensitization of reactivated cells to apoptosis, and Killing the latent HIV reservoir.
Reservoir latency can be reversed with IL-15, or the IL-15 superagonist IL-15 (nogapendekin alfa), which reactivates latent HIV ex vivo and in vivo. However, the activity of this LRA is limited, since cytokine signaling is transient. A second LRA discovered earlier by Bosque's team, called HODHBT, improves the activity of IL-15.
Howard described using connectivity maps to find another five HODHBT-like molecules that are clinically relevant and already approved by the FDA. Of these, isotretinoin has a transcriptional profile in CD4 T cells similar to that of HODHBT. This retinoid has two of the functions of STESK strategies. It helps IL-15 reactivate latent HIV and initiates cell death of latent HIV reservoirs.
Bosque's laboratory is now investigating other retinoid structural analogues and their possible LRA activity.
Tinus Schynkel of the HIV Cure Research Centre at Ghent University, Belgium, presented the 'Interactome of HIV proteins and their host RNA interaction partners', describing his work in uncovering how long noncoding RNAs regulate HIV latency through building interaction maps of human RNA and HIV proteins, a new field of research with potential for the discovery of new therapeutic targets.
HIV sequesters noncoding cellular RNA molecules to encode its proteins, complete its cycle or establish latency. By RIP-seq assay, Schynkel and his colleagues have identified 1,162 interactions between 8 HIV proteins and host RNA. Most of these interactions occur via mRNA (55%), tRNA (7%), pseudogenes (25%) or long noncoding RNAs (3%). In addition, the researchers have identified the interactors of the viral proteins Matrix, Gag, Rev and Tat.
Understanding how HIV manipulates host RNA during infection to establish and maintain latency is an important step in finding LRAs for STESK strategies. Schynkel said future research will focus on assessing the effect of these interactions on HIV infection and latency.
Marta Massanella, principal investigator at the Institut de Recerca de la Sida, Barcelona, Spain, discussed her research on the accelerated immunoaging of HIV-infected ART-treated infants in her talk, 'Inducibility and distribution of HIV proviruses in early treated Thai children on suppressive ART'. Massanella has evaluated the distribution and inducibility of HIV provirus in CD4 T cells over time in 8 children, who were vertically infected, and who started ART at 5 months of age.
Massanella's study is based on the frequency of CD4 T cells that produce mRNA and viral p24 protein (as an indicator of infection) after promoting the proliferation of these cells by PMA (phorbol 12-myristate 13-acetate) and ionomycin. She has observed that HIV reservoirs in children have a composition like that of adults and are found mainly in central memory cells.
Nevertheless, despite the high levels of HIV genomes in memory cells, naive cells are rarely infected and detectable levels of p24 protein are not produced after stimulation. The latent reservoir of these children is poorly inducible, and this does not change over time, after 2.6 years of treatment.
"Since infant and adult immune systems differ, it is essential to study reservoir composition and dynamics in children to facilitate a cure," said Sherazaan Ismail, a postdoctoral fellow at the University of Cape Town, South Africa, commenting on the significance of Massanella's findings. "Further studies into the mechanisms underlying the refractory nature of reservoir cells in children are needed," she said.