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Review
. 2015 Mar 31;7(4):1578-98.
doi: 10.3390/v7041578.

Eradication of HIV-1 from the macrophage reservoir: an uncertain goal?

Wasim Abbas  1 , Muhammad Tariq  2 , Mazhar Iqbal  3 , Amit Kumar  4 , Georges Herbein  5
Affiliations
Review

Eradication of HIV-1 from the macrophage reservoir: an uncertain goal?

Wasim Abbas et al. Viruses. .

Abstract

Human immunodeficiency virus type 1 (HIV-1) establishes latency in resting memory CD4+ T cells and cells of myeloid lineage. In contrast to the T cells, cells of myeloid lineage are resistant to the HIV-1 induced cytopathic effect. Cells of myeloid lineage including macrophages are present in anatomical sanctuaries making them a difficult drug target. In addition, the long life span of macrophages as compared to the CD4+ T cells make them important viral reservoirs in infected individuals especially in the late stage of viral infection where CD4+ T cells are largely depleted. In the past decade, HIV-1 persistence in resting CD4+ T cells has gained considerable attention. It is currently believed that rebound viremia following cessation of combination anti-retroviral therapy (cART) originates from this source. However, the clinical relevance of this reservoir has been questioned. It is suggested that the resting CD4+ T cells are only one source of residual viremia and other viral reservoirs such as tissue macrophages should be seriously considered. In the present review we will discuss how macrophages contribute to the development of long-lived latent reservoirs and how macrophages can be used as a therapeutic target in eradicating latent reservoir.

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Figures

Figure 1
Figure 1
Modulation of macrophage activity by cytokines. Classical activation of macrophages by IFN-γ which display pro-inflammatory characteristics while the alternative activation is mediated by IL-4 and IL-13 and express anti-inflammatory or tissue repairing properties. Macrophages can be deactivated by IL-10.
Figure 2
Figure 2
Macrophages fuel HIV-1 pathogenesis. HIV-1 infected macrophages secrete pro-inflammatory cytokines and chemokines that attract T cells in their vicinity, thereby transmitting virus to uninfected CD4+ T cells. Infected CD4+ T cells die soon (due to viral cytopathic effects or antiviral immune response) or return into memory CD4+ T cells as latent viral reservoirs. HIV-1 infected macrophages secrete soluble CD23 and ICAM that results in CD4+ T cell activation favoring the viral infection to CD4+ T cells. Viral gp120 increases the expression of TNF-α and TNFR2 in macrophages and T cells, resulting in CD8+ T cell apoptosis. Bystander CD4+ T cell apoptosis is triggered by FasL ligation to Fas receptor. HIV-1 infection of macrophages enhances its telomerase activity. HIV-1 expands macrophage survival by upregulating antiapoptotic genes. The P-glycoprotein transporter present on macrophages pumps out the antiretroviral drugs and limits the distribution of antiretroviral drugs to macrophages. Furthermore, macrophages spread the virus to CD4+ T cells through virological synapses. HIV-1 infected macrophages store virus into the intracellular cytoplasmic compartments providing the protection against antiviral immune response. HIV-1 infection of macrophages results in the secretion of pro-inflammatory cytokines and chemokines that ultimately accounts for the perturbation of immune trafficking.
Figure 3
Figure 3
Therapeutic approaches could favor the clearance of HIV-1 from macrophage reservoirs. Macrophages harbor integrated as well as unintegrated proviral DNA. Antiretroviral therapy interferes with several steps of HIV-1 life cycle including entry, reverse transcription, proviral DNA integration, polyprotein processing and release of viral progeny. HIV-1 infection also results in the establishment of latency in less studied reservoirs (macrophages). Macrophages harboring latent HIV-1 [157,158] can be activated by variety of approaches including chemokines, cytokines and HDACi. In addition several apoptotic reagents have been also employed which can specifically induce apoptosis in infected macrophages in vitro [44].
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