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ART in Acute Infection Limits Viral Reservoirs in Three-Group Monkey Comparison
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CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Delaying antiretroviral therapy (ART) for as few as 3 days during the "hyperacute" phase of simian immunodeficiency virus (SIV) infection in macaque monkeys resulted in 10- to 100-fold higher viral reservoir sizes, according to results of a 22-monkey study at the Oregon National Primate Research Center [1]. Afam Okoye and colleagues concluded that ART begun before peak viral replication "limits systemic virus dissemination and seeding of the reservoir in peripheral and extralymphoid mucosal compartments."
Reports of the Mississippi baby [2], the Long Beach baby [3], and the adult VISCONTI cohort [4] suggest that ART very early in the course of infection can block HIV from long-lived reservoirs or greatly limit reservoir size. In light of this and other research, the Oregon team asked if HIV reservoirs established before peak viral replication differ in size or quality from those established later. To address that question they assessed HIV RNA in plasma, cells, and tissue and SIV DNA in cells and tissue of macaques infected intravenously with a highly virulent SIV strain, SIVmac239.
ART involved four antiretrovirals, tenofovir, emtricitabine, dolutegravir, and ritonavir-boosted darunavir. Two monkeys (group A) began treatment 7 days after SIV infection, before peak viral replication; 2 (group B) began treatment 10 days after infection, at or near peak viral replication; and 18 (group C) began treatment 42 days after infection, early in chronic infection.
In group A macaques plasma viral load continued rising after ART began, peaked at day 12 at an average 71,000 copies/mL, then dropped below the 30-copy detection limit after 6 weeks of therapy. In group B plasma viral load peaked at day 12 at an average 1.8 million copies/mL and did not become undetectable until 18 weeks after treatment began. Group C macaques, the 18 chronically infected animals, reached peak plasma viral load at an average 14 million copies/mL 12 to 14 days after infection. Twenty weeks after ART began, 7 of these monkeys still had detectable SIV RNA in plasma.
Group A animals had no detectable SIV RNA in peripheral blood mononuclear cells (PBMCs) 20 weeks after infection, while 1 of the 2 group B animals still had detectable SIV RNA in PBMCs 32 weeks after infection, and all 18 group C animals still had detectable SIV RNA in PBMCs at that point. Thirty-two weeks after infection, SIV RNA became undetectable in small intestine of the 2 group A macaques, undetectable in 1 of 2 group B macaques, and detectable in all group C macaques. One of 2 group A macaques had no detectable SIV RNA in lymph nodes 32 weeks after infection, whereas all animals in groups B and C had detectable SIV RNA in lymph nodes at that point. SIV RNA was detectable at low levels in PBMCs and bone marrow of group A animals and detectable at higher levels in group B and C animals.
Thirty-two weeks after infection, SIV DNA in PBMCs averaged 2.5 log (about 300 copies) per 100 million cells in the group A macaques (treated 7 days after infection), 3.5 log (about 3000 copies) in the group B macaques (treated 10 days after infection), and 4.4 log (about 25,000 copies) in group C animals (treated 42 days after infection). SIV DNA was also lower in group A animals than in groups B or C in lymph nodes, bone marrow, and small intestine. Peak plasma viral load correlated positively with SIV DNA in PBMCs 32 weeks after SIV infection (r = 0.44, P = 0.03).
Coculture could not detect replication-competent SIV in the 4 macaques treated 7 or 10 days after infection but remained detectable in macaques treated 42 days after infection. However, adoptive transfer of lymphocytes from animals treated 7 days after infection to 2 antiretroviral-naive macaques induced productive infection. And when ART stopped in the 4 macaques treated 7 to 10 days after infection, SIV RNA promptly rebounded in plasma.
Okoye and colleagues proposed several conclusions:
-- SIV reservoirs become established early during acute infection in CD4 memory cells.
-- SIV DNA increases exponentially in PBMCs and tissues 7 to 10 days after infection.
-- Delaying ART for as few as 3 days in the "hyperacute" phase of infection results in 10- to 100-fold higher SIV levels in tissue reservoirs after treatment begins.
-- ART begun before peak SIV replication limits seeding of reservoirs in various compartments.
-- But virus from reservoirs established during acute SIV infection can induce rapid viremia in untreated animals and in treated animals after treatment stops.
The Oregon team proposed that "aggressive monitoring for acute [HIV] infection with immediate introduction of ART could profoundly influence treatment outcomes and enhance viral eradication strategies."
It is worth remembering that 10 years ago Bruce Walker and colleagues reported failure of off-treatment HIV control in 14 people who began ART between 9 and 33 days after the onset of acute infection symptoms [5].
From Jules: Of note during the Q&A John Mellors said: "outstanding study, I'm struck by a couple of things, that you had rebound viremia and you could adoptively infect animals despite not being able to detect any replication competent virus from blood in any of the assays that were used, and that really strongly suggests that our assays are incapable of detecting replication competent virus that can fuel rebound or in your instance result in adoptive infections, so the entire field has to reconcile that". And Deborah Persuad said "the data suggests 7 days is too late, we need to figure out what is that window of opportunity for early therapy to prevent reservoir establishment rather than just diminishing it to a point that I couldn't tell f she said we can or can't detect it but once therapy is stopped there is rebound viremia, so do you have plans to narrow that window, this is relevant to perinatal infection, in terms of how early should we treat to accomplish not minimal reservoir but complete blockage of reservoir formation. The presenter responded...they have done some studies...probably within 24-48 hours you probably would not get rebound but after that its probably too late"
CROI webcast:
http://www.croiwebcasts.org/console/player/22273?mediaType=slideVideo&
References
1. Okoye AA, Rohankhedkar M, Reyes M, et al. Early treatment in acute SIV infection limits the size and distribution of the viral reservoir. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 136LB.
2. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013;369:1828-1835. http://www.nejm.org/doi/full/10.1056/NEJMoa1302976
3. Persaud D, Deveikis A, Gay H, et al. Very early combination antiretroviral therapy in perinatal HIV infection: two case studies. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 75LB. http://www.natap.org/2014/CROI/croi_34.htm
4. Saez-Cirion A, Bacchus C, Hocqueloux L, et al; ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211. http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003211
5. Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control followed treated acute HIV infection. PLoS Med. 2014;1:e36. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0010036
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