Research Project
9727915
PROJECT SUMMARY To eliminate the latent HIV-1 reservoir, it is essential that HIV-infected cells are killed following viral reactivation by histone deacetylase inhibitors (HDACis) such as romidepsin. However a recent study found that pre- stimulation of cytolytic T-lymphocytes (CTLs) with HIV-1 gag peptides leads to a more rapid and effective clearance of HIV-infected cells reactivated from latency. Therefore, boosting CTL responses through immunotherapy prior to virus reactivation may be essential for HIV-1 eradication strategies. We observed in a two-step clinical trial enrolling aviremic HIV-1 infected adults on effective antiretroviral therapy that: Part A) multidose romidepsin produced an increase in cell-associated HIV RNA (CA HIV RNA) and plasma viremia during romidepsin therapy; and Part B) prior therapeutic HIV-1 vaccination with Vacc-4x (containing gag-specific peptides) followed by multidose romidepsin therapy revealed an increase of CA HIV RNA during romidepsin therapy and a significant decline in HIV DNA levels and replication-competent virus for 6 evaluable participants. Importantly, the decrease in HIV DNA levels was greatest in those individuals with CD8 T cell response to HIV antigens at baseline. However, all participants in Part B experienced viral rebound at various timepoints during a planned analytical treatment interruption post Vacc-4x and romidepsin therapy. Given these findings we will answer two significant questions in the proposed study: 1) Does romidepsin treatment broadly activate latent proviruses that contribute to increases in plasma RNA? To address this question, we will examine the genetic composition and diversity of CA HIV RNA and DNA from CD4+ T cells of participants prior to and following multi-dose romidepsin treatment and compare this with plasma-derived HIV-1 RNA sequences during romidepsin treatment. 2) Does Vacc-4x/GM-CSF immunization prior to romidepsin treatment enhance immune recognition and elimination of cells reactivated by romidepsin? To address this question the genetic composition and diversity of CA HIV RNA and HIV DNA from CD4+ T cells of patients prior to, during and following Vacc-4x and romidepsin combination therapy will be examined. In addition, the genetic diversity of the intracellular HIV RNA and DNA will be correlated with total HIV DNA levels and immune responses. We expect this exploratory study will reveal romidepsin-induced HIV-1 RNA transcripts contribute to viremia. If so, then replication-competent virus is maintained in peripheral blood CD4+ T cells of HIV-infected individuals on effective antiretroviral therapy and these cells are an important reservoir of latent virus that should be prioritised in remission and curative strategies. We also expect this exploratory study will reveal clonal expansion of CA HIV RNA and a decrease in genetic diversity which correlates with a decrease in HIV DNA levels in CD4+ T cells of HIV-1 infected participants treated with a therapeutic vaccine and HDACi. We expect that the effects of Vacc-4x and romidepsin therapy will be most pronounced in those participants who elicited a CD8 T cell response to HIV antigens at baseline. If so, then boosting cytolytic T-lymphocyte-response with a therapeutic vaccine prior to viral reactivation by an HDACi leads to the efficient killing of HIV-1-infected cells and the reduction of latent HIV-1 reservoirs.
