HIV Reservoir Group

This paper presents the innovative Full-Length Individual Proviral Sequencing (FLIPS) assay which sequences full-length HIV DNA from cells to evaluate its potential replication-competency—a critical piece in the puzzle for an HIV cure as cells with genetically-intact HIV can produce virus. This ground-breaking study revealed that genetically-intact HIV is concentrated in effector memory T cells derived from participants on effective HIV therapy, indicating these cells must be targeted to cure HIV infection.

Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE, Lee E, von Stockenstrom S, Odevall L, Milush JM, Liegler T, Sinclair E, Hoh R, Boritz EA, Douek D, Fromentin R, Chomont N, Deeks SG, Hecht FM, Palmer S

Viral rebound upon stopping HIV therapy poses a major barrier for curing HIV. In conducting this study, the genetic composition of HIV within different cellular and anatomical compartments during therapy was compared to rebound plasma viruses sampled during a planned treatment interruption for 11 HIV-infected individuals. These extensive analyses based on the largest and most in-depth sequencing data of persistent HIV revealed that rebound virus originates from several anatomical compartments after treatment is stopped indicating these anatomic sites must be targeted by curative strategies.

De Scheerder MA, Vrancken B, Dellicour S, Schlub T, Lee E, Shao W, Rutsaert S, Verhofstede C, Kerre T, Malfait T, Hemelsoet D, Coppens M, Dhondt A, De Looze D, Vermassen F, Lemey P*, Palmer S*, Vandekerckhove L*                                   *Co-senior authors

Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them.

Morcilla V, Bacchus-Souffan C, Fisher K, Horsburgh BA, Hiener B, Wang XQ, Schlub TE, Fitch M, Hoh R, Hecht FM, Martin JN, Deeks SG, Hellerstein MK, McCune JM, Hunt PW, Palmer S

This study presents the innovative IMmunoinformatics Analysis Pipeline (IMAP) for identifying the HIV peptides described in the research proposal. As depicted in this paper, during the SARS-CoV-2 pandemic, the IMAP was converted to define SARS-CoV-2 immunogenic peptides within structurally important regions of the nucleocapsid and spike proteins. Importantly, CD8 T cells derived from SARS-CoV-2 survivors exhibited polyfunctional effector responses to these novel peptides, providing a proof of concept that the IMAP identifies novel immunogens that are currently included in the mRNA constructs developed by our collaborators.

Lee E, Sandgren K, Duette G, Stylianou VV, Khanna R, Eden JS, Blyth E, Gottlieb D, Cunningham AL, Palmer S

By applying the Full-Length Individual Proviral Sequencing (FLIPS) to cells from 24 HIV-infected individuals during HIV therapy, this pioneering study revealed the proportion of genetically intact HIV DNA was higher and persisted over time in effector memory CD4 T cells when compared to other cellular subsets. This study also provided critical evidence that the HIV protein, Nef, contributes to the persistence of genetically intact HIV by superior Nef-mediated MHC-I downregulation in effector memory T cells relative to other T cells. This study revealed differential immunoevasion as a cell-intrinsic property influencing HIV persistence, and highlights Nef as a therapeutic target for HIV curative strategies.

Duette G, Hiener B, Morgan H, Mazur FG, Mathivanan V, Horsburgh BA, Fisher K, Tong O, Lee E, Ahn H, Shaik A, Fromentin R, Hoh R, Bacchus-Souffan C, Nasr N, Cunningham AL, Hunt PW, Chomont N, Turville SG, Deeks SG, Kelleher AD, Schlub TE, Palmer S.