Neurocognitive impairment (NCI) of mild or moderate severity occurs in up to half of people living with HIV and is rising in prevalence, despite widespread and earlier initiation of combination antiretroviral therapy (ART) that can effectively suppress viral replication. NCI, for which no treatments are currently available, occurs prematurely in HIV-positive (HIV+) individuals for unclear reasons, reducing quality of life and functional status, NCI in the ART era is strongly linked to mitochondrial dysfunction in the brain, and growing evidence implicates chronic ART toxicity in NCI. Older ART regimens with serious mitochondrial toxicities have been replaced by less overtly toxic antiretroviral (ARV) drugs, but mitochondrial effects of these newer, first-line ARVs, and the mechanisms underlying these effects, have not been sufficiently well studied. Overlap of ARV-induced mitochondrial defects with chronic inflammation, due to the inability of ART to eliminate latent virus from the central nervous system (CNS), and the mitochondrial effects of HIV itself, may account for ?inflamm-aging? in the brain, culminating in NCI. As clinical guidelines recommend initiating ART in all HIV+ persons at diagnosis, unprecedented numbers of HIV+ individuals, including the very young, will be exposed to the mitochondrial consequences of lifelong ART in the CNS. Systematic characterization of the mitochondrial effects of newer ARVs in the HIV+ CNS is therefore urgently needed. This proposal addresses knowledge gaps with regard to the effects of (newer) ARVs, alone and in combination, on mitochondrial function in human macrophages/microglia in the presence and absence of latent HIV, and also the role that cellular iron dysregulation, mediated by ARVs, HIV, or HFE gene mutations, may play.
The aims of the project are to 1) Elucidate the specific mitochondrial defects induced by commonly used ARV drugs and drug classes in human neuronal and microglial cell lines, in the presence and absence of latent HIV, 2) Determine how altered cellular iron regulation impacts ARV-mediated defects in both mitochondrial function and mitochondrial biogenesis in macrophages/microglia in the presence and absence of latent HIV, and 3) Assess the ability of mitochondrial function-enhancing agents or cell-culture models to mitigate ARV-induced cellular mitochondrial defects in the presence and absence of latent HIV. Our central hypothesis is that cognitive decline during suppressive ART results in part from sustained ARV-induced mitochondrial dysfunction, and that iron-modulating agents with neuroprotective potential in our preliminary studies (e.g., H-ferritin), or other agents that enhance mitochondrial function (e.g., Co-Q10), can prevent or reduce these effects. These studies will form the basis for future work to further identify a common linchpin mitochondrial target or targets, which might be exploited for the design and testing of novel therapeutic interventions to lessen the adverse effects of contemporary ART.
The proposed research is relevant to public health, because it will identify one or more novel mechanism(s) by which currently used antiretroviral drugs affect cellular energy metabolism and cause the cognitive difficulties that are observed in HIV+ individuals who take these medications. Thus, the proposed research is relevant to the part of NIH?s mission to develop fundamental knowledge in an attempt to reduce morbidity and mortality.
