Monocytes, macrophages, and microglia, play multiple roles in the pathogenesis of HIV infection. In addition to providing a tissue reservoir of infection, HIV infected and non-infected macrophages enter and accumulate in the Central Nervous System, where virus infection spreads to resident glial cells including astrocytes and microglia. This process contributes to the secretion of toxic molecules and inflammatory cytokines, which contribute to neuronal damage and promote a spectrum of HIVassociated neurological disorders ranging from HIV dementia to asymptomatic neurocognitive impairment. There appears to be an alteration in the dynamics of monocyte/macrophage subsets as a result of HIV infection, with resulting alterations in immune polarization status. It is likely that such alterations contribute to T cell dysfunction in HIV infection and may present important challenges to immune therapeutic and vaccine-based eradication strategies. As the macrophage/microglial reservoir of HIV infection is long-lived and not susceptible to the direct action of current anti-retroviral compounds (as cells already infected), this reservoir likely accumulates in infected persons over-time and may thereby provides an important target for therapeutic strategies aimed at HIV eradication and/or the treatment of HIV associated neurocognitive disorders. In the articles of this issue, experts have provided insights and perspectives regarding host-viral interaction mechanisms and specific molecular pathways involved in HIV induced inflammation, oxidative stress and neuronal injury. The articles within this Hot Topic issue, represent a series of review articles as well as original research papers. The areas covered represent diverse, yet related areas of investigation regarding HIV infection, virus induced alterations gene expression in infected cells, effects on cells of the blood brain barrier, neural injury and protection, and identify new avenues for therapeutic intervention. The monocyte/macrophage lineage, including microglia, are infected by HIV by a process that predominantly involves “R5” virus, interacting with the cellular coreceptor CCR5. The inability of X4 viruses to transmit de novo are unclear, but their appearance during the course of disease progression might suggest they are immunologically unfit and immune dysregulation would be required for successful CXCR4 tropic virus propagation in vivo. If this is the case, effects of HIV in polarizing macrophages toward M2 function may be a critical step in viral pathogenesis as well as persistence. As R5 virus appears critical for transmission and prominent in the pathogenesis of HIV induced CNS disease, the identification of determinants involved in infection through various coreceptors are of major importance, particularly in view of the association with evolution toward X4 tropic virus with AIDS progression. In the paper by Aiamkitsumrit, bioinformatics approaches to the prediction of viral tropism are discussed . The processes whereby monocytes differentiate into specific subsets appear to be dysregulated in AIDS, promoting altered immune polarization and expansion of CD16+ monocytes. CD16+ monocytes are preferentially infected by HIV and have increased capacity to cross the blood barrier, responding to specific cytokines and promoting CNS dysfunction, as review by Williams et al. . HIV encephalitis and consequent neuronal injury has been studied by a number of laboratories and it is clear that virus infection, macrophage/microglial activation, as well as macrophage transmigration of the blood brain barrier are important in the disease progress. It has been poorly understood, however, to what extent, alterations in macrophage/microglial activation and/or trafficking lead to minor neurocognitive impairment in HIV infection. This is currently an important issue, where minor neurocognitive impairment remains prominent in the setting of antiretroviral therapy. Results from Tavazzi et al.  here demonstrate that inflammation, in the absence of any obvious CNS infection is evident in both morphologic and phenotypic markers in CNS tissue from patients with minor neurocognitive disorders. The findings emphasize the likely importance of the physical interface, i.e. the blood brain barrier and perivascular region, between the CNS and the periphery in neuroAIDS in the current era of antiretroviral therapy. It will be also be of interest to determine how microglial activation reflects some of the altered dysregulation pathways described in this issue. Once inside target cells, HIV induced dysregulation of host gene expression plays an important role in the disease progress, amplified by autocrine and paracrine mechanisms. The paper by Lynn Pulliam  suggests the dual role of virus induced interferon alpha as an important initiator of the immune response, but also having deleterious effects in the setting of chronic infection. Thus, the activation of type I interferon, to which HIV appears to be resistant, may be an important aspect of immune dysregulation during the chronic phase of HIV infection. Interferon alpha secretion leads to a specific “alarm signature” which is likely important for further investigation regarding pathogenesis, development of diagnostics, as well as new targets for therapy. 76 Current HIV Research, 2014, Vol. 12, No. 2 Editorial One mechanism which may account for the indirect effects of HIV infection leading to neuronal injury, appears to be involved in the increased production and secretion of potentially neurotoxic cathepsin B, with altered interactions of cystatin B in patients with HIV infection and neurocognitive disorders, as reviewed by Rivera et al. . Another inflammatory mediator likely involved in the pathogenesis of HIV infection and CNS disorders via microglial production and receptor interactions appears to be mediated by the neurokinin, substance P (SP). As substance P appears to have immune polarizing properties on the myeloid lineage, and promotes inflammation and virus replication, it likely plays a role in both immune dysfunction and neuroAIDS. The modeling and simulation to support clinical investigation with an SP antagonist are discussed in the paper by Barrett et al. . Altered macrophage biology in HIV infection obviously presents unique opportunities for therapeutic intervention. In view of the topics and issues raised by the authors contributing here in Part I and in the next issue, Part II, of this Hot Topic issue, it is likely that strategies targeting monocytes/macrophages and microglia will have broad implications with relevance to AIDS, as well as a wide range of end-organ diseases. We hope that the research and review articles in this two-part issue will promote significant interest in further research in this area.