CommentPurging latent HIV with reactivating drugs is one of themost promising approaches to curing HIV infection.
In The Lancet HIV, Thomas Rasmussen and colleagues
report results of a phase 1/2 trial1 of panobinostat, ahistone deacetylase inhibitor, to reactivate latent HIV.
They show that the drug was well tolerated in the shortterm and the treatment increased both the amountof cell-associated HIV RNA and low-level transient
HIV viraemia. There was, however, no overall change
in measurements of the HIV reservoir after 8 weeksof panobinostat treatment. A subset of patients had
a planned interruption in antiretroviral therapy, all ofwhom had rapid rebound of viraemia, although there
was a post-hoc correlation between changes in HIV
DNA on panobinostat and the time to re-emergence ofviraemia. Although this study shows the most robust
reactivation of HIV reported to date, it also shows thediﬃculty of aﬀecting a well established HIV reservoir.
Why was there no eﬀect on the HIV reservoir despite
clear evidence of reactivating HIV? Unfortunately, thetotal number of cells reactivated during panobinostat
treatment was probably extremely low. Plasma HIV
RNA was barely detectable. Although cell-associatedunspliced HIV RNA increased (presumably fromreactivated latently infected cells), it was only a twofold to three-fold increase from the baseline level. If
reactivation contributes to the normal rate of decay ofthe latent reservoir, then the increase in reactivation
caused by panobinostat might only be two to threetimes faster than normal decay of the reservoir. The
half-life of the reservoir in patients taking antiretroviraltreatment is roughly 4 years.2 Speeding up this halflife by several-fold during the short period of theintervention is likely to have a negligible eﬀect onreservoir size, as Rasmussen and colleagues noted.
A second diﬃculty with reactivation strategies suchas panobinostat treatment is that the drug might
not truly purge the reservoir because the cells fromwhich HIV is reactivated might return to a latentstate. Immune responses might be needed to kill thereactivated cells. HIV-speciﬁc immune responses thatcan recognise virus-expressing cells, such as cytotoxic
T cells and antibodies that mediate antibodydependent cellular cytotoxicity, decrease during longterm combination antiretroviral therapy.3,4 Anti-HIV
www.thelancet.com/hiv Vol 1 October 2014

immune responses might need to be boosted withtherapeutic vaccines to assist in the killing of virusexpressing cells.5 In this context, it will be interesting
to assess whether the low-level reactivation reportedby Rasmussen and colleagues stimulated HIV-speciﬁc
immunity itself.
A third issue with attempting to reactivate HIV after
long-term antiretroviral therapy initiated during chronic
HIV infection is that this might not be the optimum
timing of the intervention. Studies of SIV-infected
macaques6–8 suggest that the reservoir might be more
susceptible to reactivation and purging at the initiationof antiretroviral therapy than after long-term treatment.
Such a strategy also leaves little time for virus-speciﬁc
immunity to fall. Studies of very early initiation of
antiretroviral therapy during acute infection show thatthe residual reservoir is much smaller, and purging
studies might be more successful in that setting.9
Indeed, antiretroviral therapy was initiated within a
day of diagnosis for two of the four participants whose
HIV DNA decreased during panobinostat treatment.
One of these patients also had an antiretroviral therapy
interruption and this patient also had the longest time
until HIV rebound (around 40 days). Purging strategies
might, therefore, be more successful in some subsets ofpatients than in others.
The results of this study conﬁrm that the latent
reservoir can be stimulated into low-level virus
replication, an important step. A concern with thesafety of histone deacetylase inhibitors is their ability toinduce long-term changes in gene expression proﬁles.10
Long-term safety should be carefully monitored. Morespeciﬁc and eﬀective drugs to reactivate the latent
reservoir are in development.11 Modelling studies12
suggest that the reservoir would need to be reduced bymore than 1000-fold to enable a durable interruptionof antiretroviral therapy. Although Rasmussen andcolleagues’ results are promising, much work is leftto do.

Russell Kightley/Science Photo Library

Tentative ﬁrst steps to eradicate latent HIV

Published Online
September 16, 2014
http://dx.doi.org/10.1016/
S2352-3018(14)70015-3
See Articles page e13*Stephen J Kent, Miles P Davenport
Department of Microbiology and Immunology, The University ofMelbourne, Peter Doherty Institute for Infection and Immunity,
VIC 3010, Australia (SJK); Centre for Vascular Research, UNSW
Australia, Sydney, NSW, Australia (MPD)e2Comment

We declare no competing interests.
123

456

e3

Rasmussen TA, Tolstrup M, Brinkmann CR, et al. Panobinostat, a histone
deacetylase inhibitor, for latent-virus reactivation in HIV-infected patientson suppressive antiretroviral therapy: a phase 1/2, single group, clinical
trial. Lancet HIV 2014; published online Sept 16. http://dx.doi.org/10.1016/
S2352-3018(14)70014-1.
Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies conﬁrm thestability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med
2003; 9: 727–28.
Shan L, Deng K, Shroﬀ NS, et al. Stimulation of HIV-1-speciﬁc cytolytic
T lymphocytes facilitates elimination of latent viral reservoir after virus
reactivation. Immunity 2012; 36: 491–501.
Madhavi V, Ana-Sosa-Batiz FE, Jegaskanda S, et al. Antibody-dependenteﬀector functions against HIV decline in subjects on antiretroviral therapy.
J Infect Dis 2014; published online Aug 28. 10.1093/infdis/jiu486.
Deeks SG. HIV: shock and kill. Nature 2012; 487: 439–40.
Reece JC, Martyushev A, Petravic J, et al. Measuring turnover of SIV DNA inresting CD4+ T cells using pyrosequencing: implications for the timing ofHIV eradication therapies. PLoS One 2014; 9: e93330.

789101112Kent SJ, Reece JC, Petravic J, et al. The search for an HIV cure: tackling latent
infection. Lancet Infect Dis 2013; 13: 614–21.
Reece J, Petravic J, Balamurali M, et al. An “escape clock” for estimating
the turnover of SIV DNA in resting CD4(+) T cells. PLoS Pathog 2012;
8: e1002615.
Ananworanich J, Puthanakit T, Suntarattiwong P, et al. Reduced markers ofHIV persistence and restricted HIV-speciﬁc immune responses after early
antiretroviral therapy in children. AIDS 2014; 28: 1015–20.
Ellis L, Pan Y, Smyth GK, et al. Histone deacetylase inhibitor panobinostat
induces clinical responses with associated alterations in gene expression
proﬁles in cutaneous T-cell lymphoma. Clin Cancer Res 2008; 14: 4500–10.
Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo
approaches distinguish eﬀective and ineﬀective single agents for reversing
HIV-1 latency in vivo. Nat Med 2014; 20: 425–29.
Hill AL, Rosenbloom DI, Fu F, Nowak MA, Siliciano RF. Predicting the outcomesof treatment to eradicate the latent reservoir for HIV-1. Proc Natl Acad Sci USA
2014; published online Aug 5. DOI:10.1073/pnas.1406663111.

www.thelancet.com/hiv Vol 1 October 2014