ABSTRACT People living with HIV (PLWH) have higher rates of drug addiction compared with uninfected populations, and often show faster rates of disease progression, including early and rapidly progressing cognitive impairments. We have previously demonstrated that synaptic damage resulting from acute morphine administration self- repairs during drug withdrawal. These repair mechanisms were not active in gp120 transgenic mice, and synaptic repair failed during drug withdrawal. Although these observations in addition to a number of other studies that have demonstrated interactions of morphine with HIV that ultimately reduce dendritic spine density, the precise mechanisms for these interactions are not understood. Our preliminary findings suggests that the initial dendritic damage induced by morphine involves activation of a non-canonical Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP) inflammasome pathway in astrocytes that facilitates the release of EVs carrying complement C3. This complement protein is opsonized in dendritic spines and targets them for elimination by phagocytosis. The removal of morphine stops the shedding of complement C3 from astrocytes, and dendritic spines can self-repair. However, in the setting of viral infection there is a sustained activation of pattern recognition receptors on microglia with chronic activation of the classical NLRP inflammasome pathway that maintains a state of persistent inflammation, This chronic inflammatory state disallows dendritic spines to self-repair. Here we propose to use primary cell culture, EcoHIV infected mice, and conditional transgenic systems to test the hypothesis that interactions between TLRs, the inflammasome, and the complement system contribute to neuronal damage in PLHW who abuse opiates. .