Gene-based therapies represent a promising therapeutic paradigm for the treatment of HIV-1, as they have the potential for sustained viral inhibition via reduced treatment interventions. Such an option may represent a long-term treatment alternative to highly active antiretroviral therapy. We have previously described a therapeutic approach, referred to as transcriptional gene silencing (TGS), where small noncoding RNAs directly inhibit the activity of HIV-1 by targeting sites within the 5’ LTR promoter/enhancer region - a feature characterized by concomitant silent-state epigenetic marks on histones and DNA. In order to deliver TGS-inducing RNAs, we developed chimeric molecules based on the previously reported dual function of the gp120 (A-1) aptamer and anti-HIV siRNA. We show that such a system is capable of producing processed guide RNAs that could localize to the nucleus and transcriptionally repress HIV expression in infected cells and in vivo in HIV-infected humanized Rag2-/-yc-/-(RAG-hu) mice. This is the first known study to demonstrate robust silencing of an existing viral infection in vivo following systemic drug administration of TGS-inducing RNAs. We further show that the viral enhancer region at the same targeting site is ideally suited for a “latency reactivation” strategy using RNA-guided CRISPR/dCas9 activation modules. We show that activation is robust, specific and consistent across multiple different latency models when compared to known chemical latency activators such as Vorinostat, Prostratin and TNFa. Further studies will reveal the durability and specificity of suppression/activation and the potential to add selective pressure on conserved promoter elements to evolve less pathogenic variants of HIV-1