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Current HIV Research


ISSN (Print): 1570-162X
ISSN (Online): 1873-4251


Editorial (Thematic Issue: The Monocyte/Macrophage in the Pathogenesis of AIDS: The Next Frontier for Therapeutic Intervention in the CNS and Beyond: Part II)

Author(s): Jay Rappaport

Volume 12, Issue 3, 2014

Page: [163 - 163] Pages: 1

DOI: 10.2174/1570162X1203140804105508


In the previous issue of Current HIV Research, we introduced a series of research and review articles (Part I) emphasizing the role of macrophages in the pathogenesis of AIDS and CNS diseases, as well as implications for therapeutic intervention. We present several additional articles, in Part II of this issue, further emphasizing the importance of host-virus interactions in disease and consideration for avenues of therapy and new investigation. An interesting mechanism of host dysregulation of gene expression is demonstrated here by Duan et al. where HIV-1 Tat protein impairs factalkine gene expression, leading to impaired microglial-neuronal interactions and concomitant activation of inflammation (i.e. the NFkB pathway) [3]. It is interesting to speculate that Tat, through fractalkine dysregulation, may alter the retention and migration properties of peripheral derived macrophages, and thereby contributes to the pathogenesis of HIV in CNS as well as the reservoir of infection. At the same time, down-modulation of the host-factor, heme oxygenase (HO-1), permits increased release of macrophage derived glutamate, which in turn can exert toxic effects on neurons. This mechanism, as well as pharmacological modulation of HO-1 and neurotoxicity, suggests that pharmacological HO-modulation may have therapeutic efficacy, as discussed in the paper by Ambegaokar [2], in HIV induced CNS disorders as well as in other diseases associated with neurotoxicity. The monocyte/macrophage system is of interest in the context of HIV replication as macrophages provide an important reservoir of HIV infection and contribute to immune dysregulation. Upon differentiation macrophages become highly susceptible to HIV infection, relative to monocytes. The paper by Alijawai et al. demonstrates how modulation of the Wnt/ßcatenin signaling pathway can serve as a restriction mechanism in monocytes, with down-modulation of ß-catenin upon differentiation [1]. The authors further pointed out that Wnt ligands could be involved in the suppression of post integration HIV replication events in macrophages exposed to soluble factors produced by monocytes. As such, pharmacological intervention with the Wnt/ß-catenin signaling pathway could be used to suppress HIV replication, or alternatively, to activate latent reservoirs of HIV infection. Peripheral derived monocytes/macrophages and/or activated microglia play prominent roles in the pathogenesis of HIV in CNS, as discussed throughout part I and II of this thematic issue. The alteration of the myeloid lineage in the setting of HIV infection and increased organ invasion is not limited to the CNS, at least in the setting of encephalitis. Here, our group demonstrates macrophage invasion into visceral tissues in patients with HIV encephalitis, with evidence of underlying renal disease. It is apparent that altered monocyte/macrophage homeostasis tissue invasion in HIV infection contribute to comorbid conditions in AIDS according to Fischer et al. [4]. As tissue invasion in patients with AIDS, but without encephalitis, also appears to be increased, altered macrophage trafficking may play an important role in immune dysfunction and comorbidities in patients with HIV infection and AIDS. It is likely that strategies directed to specific pathways dysregulated in HIV infection, or through utilization of strategies to normalize immune polarization, activation, and/or migration into tissues may be important, not only to address CNS associated manifestations of HIV infection, but also to treat comorbidities involving altered myeloid homeostasis and trafficking. In the coming years, studies in these directions should provide insights and novel therapeutic strategies, well beyond the context of HIV infection.

Keywords: HIV, immune polarization, macrophage, molecular pathways, monocyte, neurocognitive disorders, neurocognitive impairment, therapeutic strategies.

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