A quantitative approach for measuring the reservoir of latent HIV-1 proviruses

Katherine M. Bruner, Zheng Wang, Francesco R. Simonetti, Alexandra M. Bender, Kyungyoon J. Kwon, Srona Sengupta, Emily J. Fray, Subul A. Beg, Annukka Antar, Katharine M. Jenike, Lynn N. Bertagnolli, Adam A. Capoferri, Joshua T. Kufera, Andrew Timmons, Christopher Nobles, John Gregg, Nikolas Wada, Ya Chi Ho, Hao Zhang, Joseph Bernard MargolickJoel N Blankson, Steven G. Deeks, Frederic D. Bushman, Janet M Siliciano, Gregory Laird, Robert F Siliciano

Research output: Contribution to journalLetter

Abstract

A stable latent reservoir for HIV-1 in resting CD4 + T cells is the principal barrier to a cure 1–3 . Curative strategies that target the reservoir are being tested 4,5 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 activation 1 . However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation 6 may underestimate the reservoir size because one round of activation does not induce all proviruses 7 . 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 defective 7–9 . 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.

Original languageEnglish (US)
Pages (from-to)120-125
Number of pages6
JournalNature
Volume566
Issue number7742
DOIs
StatePublished - Feb 7 2019

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Proviruses
HIV-1
Virus Release
T-Lymphocytes
Viral RNA
HIV Infections
Polymerase Chain Reaction
DNA

ASJC Scopus subject areas

  • General

Cite this

Bruner, K. M., Wang, Z., Simonetti, F. R., Bender, A. M., Kwon, K. J., Sengupta, S., ... Siliciano, R. F. (2019). A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature, 566(7742), 120-125. https://doi.org/10.1038/s41586-019-0898-8

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. / Bruner, Katherine M.; Wang, Zheng; Simonetti, Francesco R.; Bender, Alexandra M.; Kwon, Kyungyoon J.; Sengupta, Srona; Fray, Emily J.; Beg, Subul A.; Antar, Annukka; Jenike, Katharine M.; Bertagnolli, Lynn N.; Capoferri, Adam A.; Kufera, Joshua T.; Timmons, Andrew; Nobles, Christopher; Gregg, John; Wada, Nikolas; Ho, Ya Chi; Zhang, Hao; Margolick, Joseph Bernard; Blankson, Joel N; Deeks, Steven G.; Bushman, Frederic D.; Siliciano, Janet M; Laird, Gregory; Siliciano, Robert F.

In: Nature, Vol. 566, No. 7742, 07.02.2019, p. 120-125.

Research output: Contribution to journalLetter

Bruner, KM, Wang, Z, Simonetti, FR, Bender, AM, Kwon, KJ, Sengupta, S, Fray, EJ, Beg, SA, Antar, A, Jenike, KM, Bertagnolli, LN, Capoferri, AA, Kufera, JT, Timmons, A, Nobles, C, Gregg, J, Wada, N, Ho, YC, Zhang, H, Margolick, JB, Blankson, JN, Deeks, SG, Bushman, FD, Siliciano, JM, Laird, G & Siliciano, RF 2019, 'A quantitative approach for measuring the reservoir of latent HIV-1 proviruses', Nature, vol. 566, no. 7742, pp. 120-125. https://doi.org/10.1038/s41586-019-0898-8
Bruner KM, Wang Z, Simonetti FR, Bender AM, Kwon KJ, Sengupta S et al. A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. Nature. 2019 Feb 7;566(7742):120-125. https://doi.org/10.1038/s41586-019-0898-8
Bruner, Katherine M. ; Wang, Zheng ; Simonetti, Francesco R. ; Bender, Alexandra M. ; Kwon, Kyungyoon J. ; Sengupta, Srona ; Fray, Emily J. ; Beg, Subul A. ; Antar, Annukka ; Jenike, Katharine M. ; Bertagnolli, Lynn N. ; Capoferri, Adam A. ; Kufera, Joshua T. ; Timmons, Andrew ; Nobles, Christopher ; Gregg, John ; Wada, Nikolas ; Ho, Ya Chi ; Zhang, Hao ; Margolick, Joseph Bernard ; Blankson, Joel N ; Deeks, Steven G. ; Bushman, Frederic D. ; Siliciano, Janet M ; Laird, Gregory ; Siliciano, Robert F. / A quantitative approach for measuring the reservoir of latent HIV-1 proviruses. In: Nature. 2019 ; Vol. 566, No. 7742. pp. 120-125.
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AU - Deeks, Steven G.

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N2 - A stable latent reservoir for HIV-1 in resting CD4 + T cells is the principal barrier to a cure 1–3 . Curative strategies that target the reservoir are being tested 4,5 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 activation 1 . However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation 6 may underestimate the reservoir size because one round of activation does not induce all proviruses 7 . 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 defective 7–9 . 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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