Contemporary viruses can be organized in an evolutionary tree ranging from the RNA world to the DNA world, from ribozymes, via viroids, DNA-ribozymes, Influenza, retro-and para-retroviruses to DNA viruses - supporting a „virus-first“ hypothesis. Retroviruses have shaped or may have even built the human genome, where up to 50% are retrovirus-related sequences to which increasing and decreasing complexities contributed. Rudimentary reverse transcription from RNA to DNA is still ongoing today in telomeres during embryogenesis and cancer [1]. Sequence analysis of the human genome witnesses our past, indicating how long HIV-like viruses, reverse transcriptase and RNases H have been around. Endogenization of retroviruses is actively ongoing in animal models and may allow a prediction on the future of HIV in people. Evolution of HIV takes place during antiretroviral therapies. An HIV suicide approach circumvents mutagenesis and escape mutants [2, 3]. Co-evolution or crossing arms, also known from phage and bacteria, can be deduced from structural and functional similarities of retroviral replication and the siRNA-mediated antiviral defense machineries [4]. An evolutionary relationship between siRNA and interferon can be constructed by comparing their pathways. SiRNA involving dicer as well as inter-feron are active antiviral defense mechanisms in mammalian cells, tested by dicer and interferon knockdown analyses [5, 6]. The systems differ in strength and sequence specificities.