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Southern African Journal of HIV Medicine
ISSN: (Online) 2078-6751, (Print) 1608-9693
Page 1 of 6 Review Article

Future approaches to clearing the latent

human immunodeficiency virus reservoir:

Beyond latency reversal

Author: Background: While combined antiretroviral therapy (cART) allows near-normal life expectancy
Alexander M.L. Hayes 1 for people living with human immunodeficiency virus (HIV), it is unable to cure the infection

Affiliation: and so life long treatment is required.
1 Medical Sciences Division,
Faculty of Clinical Medicine, Objectives: The main barrier to curing HIV is the latent reservoir of cells, which is stable and
University of Oxford, resistant to cART.
Oxford, United Kingdom
Method: Current approaches under investigation for clearing this reservoir propose a
Corresponding author: ‘Shock and Kill’ mechanism, in which active replication is induced in latent cells by latency
Alexander Hayes, reversal agents, theoretically allowing killing of the newly active cells.
[email protected].
ac.uk Results: However, previous studies have failed to achieve depletion of the T central memory
cell reservoir, are unable to target other latent reservoirs and may be causing neurological
Dates:
Received: 25 Mar. 2020 damage to participants.
Accepted: 12 May 2020 Conclusion: Future approaches to clearing the latent reservoir may bypass latency reversal
Published: 12 Aug. 2020
through the use of drugs that selectively induce apoptosis in infected cells. Several classes of
How to cite this article: these pro-apoptotic drugs have shown promise in in vitro and ex vivo studies, and may
Hayes AML. Future represent the basis of a future functional cure for HIV.
approaches to clearing
the latent human Keywords: HIV; latency reversal; viral reservoir; pro-apoptotic drugs; cART.
immunodeficiency virus
reservoir: Beyond latency
reversal. S Afr J HIV Med. Introduction
2020;21(1), a1089. https://
doi.org/10.4102/sajhivmed. The global HIV/AIDS pandemic has caused over 25 million deaths since its origins in the
v21i1.1089
20th century and remains without a cure. Combined antiretroviral therapy (cART) is the current
1
Copyright: treatment of choice for human immunodeficiency virus (HIV) infection and suppresses viral load
© 2020. The Authors. below detectable levels with correct administration. However, lifelong treatment is required,
1,2
Licensee: AOSIS. This work at considerable expense to healthcare systems, as the cessation of therapy causes a rapid
1
is licensed under the
3
Creative Commons rebound of viraemia within days and eventual progression of the disease to AIDS. Furthermore,
Attribution License. escape mutations of the virus are common and reduce efficacy, necessitating expensive
4,5
combination therapy with multiple drugs. Viral rebound occurs due to the presence of latent viral
reservoirs, rather than continuing low-level replication during cART, as shown by clonal
evolutionary studies. On therapy cessation these latently infected cells clonally expand, seeding
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a population of infected cells containing intact provirus. Whilst cART has been successful in
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extending life expectancy of people living with HIV in high-income countries, this remains
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impaired compared to healthy adults. As cART is limited by mutations, is an expensive lifelong
treatment and may not be available to those in countries with poorly developed healthcare
systems, development of a cure for HIV is desirable. Cure research would be of considerable
impact in South Africa, which has the highest number of people living with HIV in the world, at
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7.7 m as of 2018, a prevalence of 20.4% in adults (UNAIDS 2019) . In that year 77 000 deaths were
recorded due to AIDS-related illnesses (UNAIDS 2019), although this number is coming down
and life expectancy is rising as the cART programme continues to grow.
Reservoirs of latently infected cells are the main barrier to cART curing HIV. The first latently
infected cells to be identified were CD4 central memory T cells (T ) containing replication-
+
CM
Read online: competent, integrated provirus. These were found to be present in patients on cART, with no
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Read online:
Scan this QR change in reservoir size with continuous therapy as the quiescent cells do not contain
Scan this QR
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code with your
code with your
smart phone or
smart phone or actively replicating virus, and so are unaffected by cART. The T CM reservoir is present even if
mobile device cART is initiated within the first week post exposure, so is established early in infection. It is
mobile device
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to read online.
to read online.
also extremely stable, as the latent cells have a half-life of around 44 months, so is unlikely to
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http://www.sajhivmed.org.za 174 Open Access