Purpose <p>More than four decades of HIV/AIDS studies reveal that generation of effective vaccines against HIV infection requires understanding of a host immunity that protects our DNA against the HIV infection. An effective vaccine can elicit the host immunity to stop HIV RNA expression despite the viral DNA integrated into the host DNA.</p> Recent Findings <p>Vaccination is one of the most successful public health interventions of all time. Recent studies show that humans have an intrinsic immunity against foreign nucleotide gene expression, and we have named this the epigenetic immunity. We propose that chromatin vaccine (cVacc), a foreign DNA in chromatin format, is capable of triggering the immunity of host DNA, the epigenetic immunity, to silence the viral gene expression at its RNA transcription level. We discuss these advances in the field of host – virus interaction, specifically host immunity against the retroviral infections by silencing its gene expression, ranging from nucleotide sensors that distinguish self-nonself to the chromatin features that constrict the HIV reservoir.</p> Summary <p>Bolstered by the progress in the fields of virology, immunology and epigenetics, we propose to maneuver cutting edge technologies to develop next-generation vaccines like cVacc, not only silencing the foreign gene expression, but assimilating it to improve our DNA function as well.</p>