Macrophages sustain HIV replication in vivo independently of T cells
Jenna B. Honeycutt, … , Joseph J. Eron, J. Victor Garcia
Jenna B. Honeycutt, … , Joseph J. Eron, J. Victor Garcia
Published March 7, 2016
Citation Information: J Clin Invest. 2016;126(4):1353-1366. https://doi.org/10.1172/JCI84456.
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Research Article AIDS/HIV

Macrophages sustain HIV replication in vivo independently of T cells

Abstract

Macrophages have long been considered to contribute to HIV infection of the CNS; however, a recent study has contradicted this early work and suggests that myeloid cells are not an in vivo source of virus production. Here, we addressed the role of macrophages in HIV infection by first analyzing monocytes isolated from viremic patients and patients undergoing antiretroviral treatment. We were unable to find viral DNA or viral outgrowth in monocytes isolated from peripheral blood. To determine whether tissue macrophages are productively infected, we used 3 different but complementary humanized mouse models. Two of these models (bone marrow/liver/thymus [BLT] mice and T cell–only mice [ToM]) have been previously described, and the third model was generated by reconstituting immunodeficient mice with human CD34+ hematopoietic stem cells that were devoid of human T cells (myeloid-only mice [MoM]) to specifically evaluate HIV replication in this population. Using MoM, we demonstrated that macrophages can sustain HIV replication in the absence of T cells; HIV-infected macrophages are distributed in various tissues including the brain; replication-competent virus can be rescued ex vivo from infected macrophages; and infected macrophages can establish de novo infection. Together, these results demonstrate that macrophages represent a genuine target for HIV infection in vivo that can sustain and transmit infection.

Authors

Jenna B. Honeycutt, Angela Wahl, Caroline Baker, Rae Ann Spagnuolo, John Foster, Oksana Zakharova, Stephen Wietgrefe, Carolina Caro-Vegas, Victoria Madden, Garrett Sharpe, Ashley T. Haase, Joseph J. Eron, J. Victor Garcia

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Figure 5

Human cells are present in the brains of MoM and increase in numbers during HIV infection.

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Human cells are present in the brains of MoM and increase in numbers dur...
(A) MNCs from the brains of infected (n = 25) and uninfected (n = 35) MoM were analyzed via flow cytometry, and the absolute numbers of human cells (hCD45+) and human macrophages (hCD33+/hCD11b+) were calculated per whole brain. There was a significant increase in the overall number of human cells (P = 0.0009) and human monocytes and macrophages (P = 0.0055) in the brains of infected mice compared with numbers detected in uninfected mice. P values were determined by Mann-Whitney U test. (B) Immunohistochemical analysis of the brain was used to confirm the presence of human macrophages (hCD68) in the brains of infected MoM. (C) Cell-associated vRNA copies per 100,000 total cells were measured in the brains of infected MoM. We were able to detect virus in the brains of 8 of 14 animals (lower limit of detection, 30 copies/105 cells). (D) Immunohistochemical analysis demonstrated the presence of HIV p24 in the brains of infected MoM. (B and D) Original magnification, ×10 and ×40 (insets). The location of CD68+ or p24+ cells is indicated by an abbreviation in each panel. BS, brain stem; CB, cerebellum; CC, cerebral cortex; CP, caudate putamen; CpC, corpus callosum; MB, midbrain; and VS, ventral striatum.