No recovery of replication-competent HIV-1 from human liver macrophages
Abraham J. Kandathil, … , Alan S. Perelson, Ashwin Balagopal
Abraham J. Kandathil, … , Alan S. Perelson, Ashwin Balagopal
Published October 1, 2018; First published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4501-4509. https://doi.org/10.1172/JCI121678.
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Research Article AIDS/HIV Infectious disease

No recovery of replication-competent HIV-1 from human liver macrophages

Abstract

Long-lived HIV-1 reservoirs that persist despite antiretroviral therapy (ART) are a major impediment to a cure for HIV-1. We examined whether human liver macrophages (LMs), the largest tissue macrophage population, comprise an HIV-1 reservoir. We purified LMs from liver explants and included treatment with a T cell immunotoxin to reduce T cells to 1% or less. LMs were purified from 9 HIV-1–infected persons, 8 of whom were on ART (range 8–140 months). Purified LMs were stimulated ex vivo and supernatants from 6 of 8 LMs from persons on ART transmitted infection. However, HIV-1 propagation from LMs was not sustained except in LMs from 1 person taking ART for less than 1 year. Bulk liver sequences matched LM-derived HIV-1 in 5 individuals. Additional in vitro experiments undertaken to quantify the decay of HIV-1–infected LMs from 3 healthy controls showed evidence of infection and viral release for prolonged durations (>170 days). Released HIV-1 propagated robustly in target cells, demonstrating that viral outgrowth was observable using our methods. The t1/2 of HIV-1–infected LMs ranged from 3.8–55 days. These findings suggest that while HIV-1 persists in LMs during ART, it does so in forms that are inert, suggesting that they are defective or restricted with regard to propagation.

Authors

Abraham J. Kandathil, Sho Sugawara, Ashish Goyal, Christine M. Durand, Jeffrey Quinn, Jaiprasath Sachithanandham, Andrew M. Cameron, Justin R. Bailey, Alan S. Perelson, Ashwin Balagopal

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Figure 5

HIV-1–infected LMs persist and decay with inconstant dynamics in vitro.

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HIV-1–infected LMs persist and decay with inconstant dynamics in vitro. ...
LMs from 3 donors were infected with GFP–HIV-1 and maintained in culture for 100–200 days. HIV-1 RNA was quantified in supernatants during 2 phases: pre-ART and during ART. ART comprised tenofovir disoproxil fumarate (10 μM), emtricitabine (1 μM), and raltegravir (1 μM), all administered at concentrations at least 4-fold higher than their published IC50. In parallel, decay in HIV-1 RNA was quantified in HIV-1–infected CD4+ T cells using the same concentrations of ART over the same time course as the second phase of LM infection. Shown are 4 representative panels of decay rates in HIV-1 RNA in supernatants from LMs (A–C) and CD4+ T cells (D). Individual points are plotted before (red) and during (green) ART. The vertical dashed lines indicate when ART was added. Trend lines (green dashes) are indicated, computed using scaling to account for differing intervals between media changes (see Supplemental Material). Moderate declines in HIV-1 RNA were observed in all LM donors pre-ART. Decay of HIV-1–infected LMs can be inferred from supernatant HIV-1 RNA levels during treatment with ART: (A) fast; (B) intermediate; and (C) slow/indefinite decay were all observed in vitro. The t1/2 was unable to be calculated for wells in which slow/indefinite decay was noted. GFP+ cells were evident in all wells for which HIV-1 RNA was detectable in supernatants.