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 April 1, 2016; First 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 1

Absence of HIV DNA in monocytes but not in T cells isolated from peripheral blood of infected patients.

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Absence of HIV DNA in monocytes but not in T cells isolated from periphe...
(A) Schematic of monocyte and T cell purification strategy. Total MNCs were isolated from the peripheral blood of 8 HIV-infected patients (from Table 1). T cells were depleted using positive magnetic selection, and monocytes were enriched using negative magnetic selection. (B) Flow cytometric analysis of total MNCs, T cells, non–T cells, non-monocytes, and monocytes revealed very pure populations of both T cells and monocytes isolated using this protocol (data from patient 04 are shown). (C) One million purified T cells or monocytes (Mono) were analyzed for the presence or absence of HIV-gag DNA using nested PCR analysis of untreated and treated patients. The lower limit of detection for these analyses was 2 copies of HIV DNA. Purified T cells or monocytes from untreated patients 01, 02, and 03 were injected into BLT mice. (D) vDNA analysis demonstrated systemic infection of BLT mice injected with patients’ purified T cells but not monocytes. LN, lymph node; Org, human thymic organoid; Pt, patient.