TY - JOUR
T1 - A quantitative approach for measuring the reservoir of latent HIV-1 proviruses
AU - Bruner, Katherine M.
AU - Wang, Zheng
AU - Simonetti, Francesco R.
AU - Bender, Alexandra M.
AU - Kwon, Kyungyoon J.
AU - Sengupta, Srona
AU - Fray, Emily J.
AU - Beg, Subul A.
AU - Antar, Annukka A.R.
AU - Jenike, Katharine M.
AU - Bertagnolli, Lynn N.
AU - Capoferri, Adam A.
AU - Kufera, Joshua T.
AU - Timmons, Andrew
AU - Nobles, Christopher
AU - Gregg, John
AU - Wada, Nikolas
AU - Ho, Ya-Chi
AU - Zhang, Hao
AU - Margolick, Joseph B.
AU - Blankson, Joel N.
AU - Deeks, Steven G.
AU - Bushman, Frederic D.
AU - Siliciano, Janet D.
AU - Laird, Gregory M.
AU - Siliciano, Robert F.
N1 - Funding Information:
Acknowledgements We thank D. Finzi of NIAID for discussions leading to this work. This work was supported by the NIH Martin Delaney I4C (UM1 AI126603), Beat-HIV (UM1 AI126620) and DARE (UM1 AI12661) Collaboratories, by NIH grant 43222, by the Howard Hughes Medical Institute and the Bill and Melinda Gates Foundation (OPP1115715), and by NIH SBIR grants R43AI124996 and R44AI124996 and NSF grants 1621633 and 1738428 to Accelevir Diagnostics. Samples for some study participants were obtained from the Baltimore-Washington DC Center of the Multicenter AIDS Cohort Study (MACS) supported by NIH grants U01-AI-35042 and UL1-RR025005 (ICTR).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1–3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7–9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.
AB - A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1–3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7–9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.
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U2 - 10.1038/s41586-019-0898-8
DO - 10.1038/s41586-019-0898-8
M3 - Article
C2 - 30700913
AN - SCOPUS:85061094564
SN - 0028-0836
VL - 566
SP - 120
EP - 125
JO - Nature
JF - Nature
IS - 7742
ER -