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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 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

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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 3

HIV-1 transmission from LMs of HIV-1–infected individuals.

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HIV-1 transmission from LMs of HIV-1–infected individuals.
(A) LM VOA re...
(A) LM VOA results for all HIV-1–infected individuals. Using qPCR, HIV-1 proviral DNA was measured in lysed target cells that were incubated with LM supernatants from each donor (red diamonds). Error bars represent mean ± SEM for some with multiple positive values. Grey triangles indicate negative control target cells that were inoculated with media alone before lysis. N7 is not included in this figure because HIV-1 RNA was detectable in LM supernatants before initiation of the LM VOA. (B) LM VOA yields HIV-1 RNA only in people with ART exposure less than 1 year. HIV-1 RNA was measured in target cell supernatants in LM VOA from all people, and in N7 LM supernatants directly. HIV-1 RNA was only detectable from LMs in 2 people who were also those who had the least amount of exposure to ART before liver explantation. N9 is not included in this figure because the duration of ART prior to liver explantation was not available. LOD, limit of detection; ND, not done.
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