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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 4

HIV-1 pol sequence analysis reveals that liver macrophages and bulk liver contain genetically similar viruses.

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HIV-1 pol sequence analysis reveals that liver macrophages and bulk live...
p distances between HIV-1 pol amplicons (160 bp) from purified LMs after culture or from bulk liver tissue were calculated. All comparisons were of 160 nucleotide amplicons, except comparisons including subject LT01, which used 44 nucleotide amplicons as that was the largest obtainable sequence. The LT02 LM sequence included in the analysis was amplified from RNA. (A) Pairwise p distances. Dark red indicates lower values (i.e., more genetically similar), and dark blue indicates higher values (i.e., more genetically distinct). (B) Comparison of inter- and intraindividual p distances between LMs and bulk liver amplicons from the same donor to p distances between LMs and bulk liver amplicons from different individuals. Error bars represent mean ± SD. P value was calculated by 2-tailed Mann Whitney U test, **P < 0.005.
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