Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Abstract

Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

Insight into treatment ofHIVinfection from viral dynamics models

“…Now that the role of proliferation in maintaining the reservoir has been established, there is renewed interest in developing “antiproliferative” therapies for HIV, which would reduce the ability of latently infected cells to self‐renew. Mathematical models have been developed to predict how effective these treatment strategies are likely to be . Two recent papers used a similar approach which we will summarize here.…”

“…However, the effect of interventions on these parameters strongly depends on their underlying values, and while the observed half‐life of the reservoir tells us about δ (=log(2)/44 mo = .2/y), it is extremely difficult to estimate the relative contribution of each process. Petravic et al., examined how these uncertainties effect estimates of efficacy for interventions on a , while Reeves et al., explored similar questions for p . In Figure , we show examples of some output from their models.…”

“…Mathematical models have been developed to predict how effective these treatment strategies are likely to be. 121,122 Two recent papers used a similar approach which we will summarize here. If it is assumed Red and blue lines are for alternate parameter sets.…”

Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design

“…However, latency reversal is a dynamic process potentially affected by many processes, including activation of HIV gene expression and subsequent expression of HIV antigen, clearance of induced cells, reestablishment of latency after HIV expression (22), and cell proliferation (28)(29)(30). Therefore, a quantitative framework that might integrate these processes is needed to formally evaluate the efficacy of candidate LRAs and improve the design of further studies (31,32).…”

Impact of Early Antiretroviral Therapy on Detection of Cell-Associated HIV-1 Nucleic Acid in Blood by the Roche Cobas TaqMan Test

“…More recent approaches to viral cure and efforts to eradicate the reservoir have combined early ART treatment with targeted killing of latently infected cells (23). These approaches include therapeutic vaccines that elicit broad immune responses and shock-and-kill strategies by activating latently infected cells with HIV latency-reversing agents (LRAs) and then employing drugs, broadly acting monoclonal antibodies, or other immune-mediated cell killing mechanisms (24)(25)(26)(27). Assessments to determine whether interventions have resulted in HIV remission or eradication require carefully controlled analytic treatment interruptions (ATIs).…”