Title:Editorial (Thematic Issue: The Monocyte/Macrophage in the Pathogenesis of AIDS: The Next Frontier for Therapeutic Intervention in the CNS and Beyond: Part I)
VOLUME: 12 ISSUE: 2
Author(s):Jay Rappaport
Affiliation:Department of Neuroscience Temple University School of Medicine MERB, Rm. 746 Philadelphia PA 19140 USA.
Keywords:HIV, immune polarization, macrophage, molecular pathways, monocyte, neurocognitive disorders, neurocognitive
impairment, therapeutic strategies.
Abstract: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 [6].
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. [2]. 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. [3] 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 [1] 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. [4]. 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. [5].
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.