Our work focuses on transforming existing anti-human immunodeficiency virus (HIV) drugs into potent long-acting nanoformulated antiretrovirals (nanoART) together with the development of agents that boost drug depots by affecting autophagy. The sustained release products (SRP) were shown in our prior works to attenuate viral infection with dosing intervals of once a month or longer. The chemical process involves conversation of hydrophilic antiretroviral drugs (for example entry, nucleoside and nonnucleoside reverse transcriptase inhibitors) into crystalline hydrophobic prodrugs. Drug encapsulation into decorated (cell targeted) nano particles are carried in mononuclear phagocytes (MP: monocytes, perivascular and tissue macrophages) autophagosomes. The end result are anti-HIV SRPs with prolonged half-lives. Drug pharmacokinetics (PK) are governed by rate of antiretroviral drug (ARV) crystal particle dissociation and drug hydrolysis. This directive can circumvent drug toxicities, improve regimen compliance and facilitate penetrance into viral reservoirs [notably gut, lymphoid organs and the central nervous system]. Reduction in residual infection was shown through pharmacodynamic tests. MPs are the depots and enabler of drug transport to tissue reservoirs. The ARV particles can readily be delivered to subcellular sites of viral replication. The goal of ARV transformation into SRP products will be step-wise. The first part rests in making the drug libraries. The second encases prodrugs into decorated poloxamers. The third characterizes the SRPs to optimize its size, shape, polydispersity and particle integrity. Antiretroviral responses and drug endosomal trafficking will be discussed. Our use of SRP boosting agents for sustaining intracellular depots with autophagy drugs that facilitate particle autophagosomal depots have been shown to improve ARV biodistirbution. Discussion of “state of the art” tools to improve nanoART access for human use will be discussed.