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In vitro and ex vivo studies of other PADs have also shown Data availability statement
promise. Bcl-2 antagonists such as venetoclax caused Data sharing is not applicable to this article as no new data
disinhibition of MOMP and led to the depletion of latent HIV- were created or analysed in this study.
56
T from patients on cART in an ex vivo study. P13K/Akt
CM
inhibitors increase the expression of pro-apoptotic genes
downregulated by HIV and have shown promise in Disclaimer
predisposing latently infected macrophages and microglia to The views and opinions expressed in this article are those of
cell death. 57,58 RIG-1 inducers activate an innate immune the author and do not necessarily reflect the official policy or
response to viral RNA, triggering apoptosis. An ex vivo study position of any affiliated agency of the author.
demonstrated selective depletion of latent HIV-T using the
CM
RIG-1 inducer acitretin. These classes of PADs also merit References
59
further investigation and could be used in combination with
SMs in a future approach to clearing the latent reservoir to 1. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection.
Lancet. 2010;376(9734):49–62. https://doi.org/10.1016/s0140-6736(10)60676-9
induce apoptosis in a greater portion of latently infected cells. 2. Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persists for at least
7 years in patients onsuppressive antiretroviral therapy. Proc Natl Acad Sci U S A.
2008;105(10):3879–3884. https://doi.org/10.1073/pnas.0800050105
Conclusions 3. Fischer M, Hafner R, Schneider C, et al. HIV RNA in plasma rebounds within days
during structuredtreatment interruptions. AIDS. 2003;17(2):195–199. https://doi.
Recent ‘Shock and Kill’ research has failed to demonstrate org/10.1097/01.aids.0000042945.95433.4b
significant depletion of the viral reservoir, and it remains 4. Poggensee G, Kücherer C, Werning J, et al. Impact of transmission of drug-
resistant HIV on the course of infection and the treatment success. Data from the
unclear if the use of LRAs may cause HANDs. PADs may German HIV-1 seroconverter study. HIV Med. 2007;8(8):511–519. https://doi.
org/10.1111/j.1468-1293.2007.00504.x
represent a promising future approach to curing HIV given 5. Wittkop L, Günthard H, de Wolf F, et al. Effect of transmitted drug resistance on
their in vitro and ex vivo success in selectively causing apoptosis virological and immunological response to initial combination antiretroviral
in latently infected cells, with SMs appearing effective against therapy for HIV (EuroCoord-CHAIN joint project): A European multicohort study.
Lancet Infect Dis. 2011;11(5):363–371. https://doi.org/10.1016/S1473-3099(11)
the T reservoir and P13K/Akt inhibitors against myeloid 70032-9
CM
reservoirs. Several of these drugs have been used in clinical 6. Joos B, Fischer M, Kuster H, et al. HIV rebounds from latently infected cells, rather
than from continuing low-level replication. Proc Natl Acad Sci U S A.
trials for other conditions, and further investigation into their 2008;105(43):16725–16730. https://doi.org/10.1073/pnas.0804192105
potential for people living with HIV is merited. 7. Simonetti FR, Sobolewski M, Fyne E, et al. Clonally expanded CD4+ T cells can
produce infectious HIV-1 invivo. Proc Natl Acad Sci U S A. 2016;113(7):1883–1888.
https://doi.org/10.1073/pnas.1522675113
Acknowledgements 8. Collaboration A TC. Life expectancy of individuals on combination antiretroviral
therapy in high-income countries: A collaborative analysis of 14 cohort studies.
Lancet. 2008;372(9635):293–299. https://doi.org/10.1016/S0140-6736(08)61113-7
Grant Campbell provided theoretical assistance via email 9. UNAIDS website: https://www.unaids.org/en/regionscountries/countries/southafrica
correspondence for the limitations of the LRAs section, 10. Chun TW, Stuyver L, Mizell S, et al. Presence of an inducible HIV-1 latent reservoir
specifically about the potential neurological side effects LRAs during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997;
may have. 94(24):13193–13197. https://doi.org/10.1073/pnas.94.24.13193
11. Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1
in patients on highly active antiretroviral therapy. Science. 1997;278(5341):
Professor William James, Dunn School of Pathology, 1295–1300. https://doi.org/10.1126/science.278.5341.1295
University of Oxford, was my supervisor for the review, and 12. Chun TW, Engel D, Berrey M, et al. Early establishment of a pool of latently
infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci
so offered me advice and guidance on selecting a subject area U S A. 1998;95(15):8869–8873. https://doi.org/10.1073/pnas.95.15.8869
and how to go about writing the review. He has not read or 13. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the
stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med.
edited the review since I began writing it due to university 2003;9(1):727–728. https://doi.org/10.1038/nm880
examination regulations. 14. Abbas W, Tariq M, Iqbal M, Kumar A, Herbein G. Eradication of HIV-1 from the
macrophage reservoir: An uncertain goal? Viruses. 2015;7(4):1578–1598. https://
doi.org/10.3390/v7041578
Competing interests 15. Gama L, Abreu C, Shirk E, et al. SIV Latency in macrophages in the CNS. Curr Top
Microbiol Immunol. 2018;417:111–130. https://doi.org/10.1007/82_2018_89
I declare that no competing interests exists. 16. Honeycutt JB, Thayer W, Baker C, et al. HIV persistence in tissue macrophages of
humanized myeloidonly mice during antiretroviral therapy. Nat Med. 2017;23:
638–643. https://doi.org/10.1038/nm.4319
Author’s contributions 17. Churchill MJ, Gorry P, Cowley D, et al. Use of laser capture microdissection to detect
integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues.
J Neurovirol. 2006;12:146–152. https://doi.org/10.1080/13550280600748946
I am the sole author for this work. 18. Kramer-Hämmerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R. Cells of the
central nervous system as targets and reservoirs of the human immunodeficiency
virus. Virus Res. 2005;111(2):194–213. https://doi.org/10.1016/j.virusres.2005.
Ethical consideration 04.009
19. Kawamura T, Gulden F, Sugaya M, et al. R5 HIV productively infects Langerhans
This article followed all ethical standards for carrying cells, and infection levels are regulated by compound CCR5 polymorphisms. Proc
Natl Acad Sci U S A. 2003;100(14):8401–8406. https://doi.org/10.1073/pnas.
out research without direct contact with human or animal 1432450100
subjects. 20. Kandathil AJ, Sugawara S, Balagopal A. Are T cells the only HIV-1 reservoir?
Retrovirology. 2016;13:86. https://doi.org/10.1186/s12977-016-0323-4
21. Spiegel H, Herbst H, Niedobitek G, Foss HD, Stein H. Follicular dendritic cells are a
Funding information major reservoir for human immunodeficiency virus type 1 in lymphoid tissues
facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992;140:15–22.
This research received no specific grant from any funding 22. Xing S, Bullen C, Shroff N, et al. Disulfiram reactivates latent HIV-1 in a Bcl-2-
transduced primary CD4+ T cell model without inducing global T cell activation.
agency in the public, commercial or not-for-profit sectors. J Virol. 2011;85(12):6060–6064. https://doi.org/10.1128/JVI.02033-10

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