Lifelong antiretroviral therapy (ART) presents formidable problems. Therefore, among the many important goals for future HIV research is the development of temporally contained therapies capable of eradicating HIV infection. The persistence of quiescent HIV infection within populations of CD4+ T cells is currently a major obstacle to eradication of HIV infection. We will continue proof-of-concept studies attempting to directly and precisely measure the induction of proviral expression from the latently infected CD4+ cell reservoir, and the depletion of infection within that reservoir. We have demonstrated the ability of the HDAC inhibitor licensed for use in oncology, suberoylanilide hydroxamic acid (Vorinostat, VOR), selective for Class I HDACs, to induce HIV expression in the resting CD4+ T cells of antiretroviral-treated, aviremic HIV-infected patients in vivo. We have established the infrastructure and assays needed to document a repeated induction of resting CD4+ T cell-associated HIV RNA in vivo following repeated doses of VOR. Clearance of this small, latent reservoir upon relatively brief proviral induction may not be possible in the absence of a robust HIV-specific immune response. We have selected 2nd proof-of-concept tool, Argos AGS-004, an autologous dendritic cell vaccine that has demonstrated the ability to induce immunity in vivo as measured by a clinically apparent reduction in rebound viremia after ART interruption. AGS-004 consists of dendritic cells (DCs) co-electroporated with in vitro transcribed (IVT) ribonucleic acid (RNA) encoding specific autologous HIV antigens (Gag, Vpr, Rev, and Nef) to achieve antigen presentation, with CD40 ligand RNA, to enhance DC functionality. We have established the infrastructure and assays needed to document the induction of an appropriately durable antiviral immune response following AGS-004. We propose a proof-of-principal study to measure the potential of VOR and AGS-004 to deplete latent infection, following administration in a carefully validated combination:
Specific Aim 1 : The frequency of detectable HIV RNA expression within resting CD4+ T cells will increase after repeated VOR exposure in vivo Specific Aim 2: AGS-004 will induce an HIV-specific immune in HIV-infected participants with durable viral suppression on ART initiated, both prior to and following VOR administration.
Specific Aim 3 : A combination of serial AGS-004 vaccinations and
Despite antiviral therapy, eradication of HIV infection is unachievable as the virus can establish latency in memory CD4+ T cells. There is a significant effort to develop agents capable of inducing expression of quiescent HIV in these cells without enhancing new infection, so that persistent viral infection may be cleared. However, recent data suggests that enhanced HIV-1 specific T cell immune responses will be a required component of any cure strategy. We hypothesize that by augmenting and broadening HIV-1-specific immunity, therapeutic immunization with AGS-004 will enhance immune-mediated clearance of virus-producing cells, as well as latent virus re-activated with the HDAC inhibitor, VOR. We will document and quantify latent infection in these cells, and test approaches to purge this reservoir of latent infection.
| Ke, Ruian; Conway, Jessica M; Margolis, David M et al. (2018) Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design. JCI Insight 3: |
| Turner, Anne-Marie W; Margolis, David M (2017) Chromatin Regulation and the Histone Code in HIV Latency?. Yale J Biol Med 90:229-243 |
