In a promising experiment in rhesus macaque monkeys, scientists from Emory University in Atlanta have used a monkey-adapted version of vedolizumab (Entyvio), a drug used to treat gut inflammation, to produce persistent viral load control and T-cell restoration in monkeys taken off antiretroviral therapy (ART).
The viral control and immune recovery persisted for 30 weeks: 14 weeks after monkeys were taken off ART but kept on the vedolizumab analogue, and for 16 more weeks after this was withdrawn. In fact, viral load control appeared to continue to improve throughout the period when the monkeys were off all therapy.
The researchers are uncertain why the drug works, but saw increases in a particular kind of Natural Killer (NK) cell that appears to be enabled by the drug to deal with HIV infection better, and an immune response to the HIV envelope protein that resembles one of the responses seen in the trial of the RV144 HIV vaccine.
A small human trial of vedolizumab is already underway.
Vedolizumab or α4β7mAb is a monoclonal antibody that binds to a cell-surface molecule called α4β7. This molecule makes cells more susceptible to HIV infection and also binds them to another protein in the lining of small blood vessels that permeate gastro-intestinal tissues. One of the hallmarks of HIV infection is an early, massive and never-completely restored destruction of immune cells in the gut: even early ART treatment does not stop this happening. This immune damage may in turn be one of the primary mechanisms of the progressive immune exhaustion seen in untreated HIV infection.
The drug’s mechanism of action dampens down the gut inflammation seen in Crohn’s disease and ulcerative colitis; it was licensed as a medicine for these conditions in 2013 in the US and 2014 in Europe. It was hoped it might do the same for HIV. The researchers hypothesised that the α4β7mAb might prevent HIV-infected cells reaching the gut and causing the immune damage there.
Experiments in monkeys had already shown that α4β7mAb had promise as a drug preventing HIV infection: in some animals it prevented infection while others were still infected but developed low viral loads.
In the current experiment, 18 rhesus macaques were infected with SIV, the monkey equivalent of HIV. Five weeks after infection, they were all started on ART. Four weeks after that, eleven of them were started on a course of eight three-weekly infusions of monkey-adapted α4β7mAb. The ART was stopped after 13 weeks (18 weeks after infection). The α4β7mAb infusions were continued off ART till 32 weeks after infection (14 weeks off ART). Then all therapy was withdrawn and the experiment continued till 50 weeks after infection (16 weeks off all therapy).
The other eight monkeys got control infusions of non-specific immunoglobulin G protein (IgG), one of the proteins that provides the basic structure of antibodies, but immunologically inactive.
Initially all animals developed SIV viral loads of about a million copies/ml, but were fully virally suppressed on ART. After ART was withdrawn, viral loads quickly rebounded to previous values in the eight control monkeys.
In the eleven monkeys given α4β7mAb, three developed an anti-antibody response – in other words their bodies rejected the α4β7mAb and they became resistant to its effects. In the other eight, three monkeys stayed virally suppressed (viral load below 50 copies/ml) for the whole 30 weeks off ART. In the other five, transient viral rebounds were initially seen. Viral load in the eight monkeys averaged 6300 copies/ml in the first four weeks after ART withdrawal, between weeks 18 and 22, and varied between undetectable and 200 copies/ml thereafter till week 42 of the experiment. However in the last three samples taken, at weeks 44, 46 and 50, none of the eight monkeys had a viral load over 50 copies/ml. No intracellular SIV DNA was detectable within cells in any animal in the period off all treatment.
CD4 cell counts in the α4β7mAb-treated monkeys increased from a trough level of about 500 cells/mm3 to nearly 2000, the level before infection. There was a particularly strong relative increase in the types of cells called T-effector memory cells.
A PET scan of the monkeys showed that something unexpected was happening. It had been assumed that, as happens in treatment for Crohn’s disease, the α4β7mAb would stop T-cells from trafficking to the gut. Instead what they saw was a general repopulation of largely non-infected T-cells in all immune tissue including the gut. The researchers comment that they do not know if the viral load was being controlled by a more effective T-cell response, or whether the controlled viral load allowed T-cells to repopulate the gut.
However, there were hints that α4β7mAb might have produced an interesting series of immune changes that protected gut T-cells from further infection. These changes included a particular increase in a type of natural killer (NK) cell called cytokine-secreting cells: these also express α4β7 and might have been potentiated to produce a more efficient immune response by having α4β7 blocked. Certain protective cytokines (circulating immune-mediating chemicals) increased, including retinoic acid and interleukin-10, while a whole panel of inflammatory cytokines including D-dimer, interleukin 1β, a protein induced by interferon-γ, and two chemicals associated with ‘leaky gut’, all decreased.
Tests of immune reactivity showed that treated animals all had immune responses to a part of the HIV surface protein called the V2 loop, whereas only three of the control animals did, and they were weak ones. Interestingly, one specific immune response seen was similar to a protective response seen in the trial of the RV144 HIV vaccine.
The researchers say they are still puzzled by the immune responses seen and their effect, and will conduct further experiments. Nonetheless, a small human trial of vedolizumab in 20 people has already begun at the National Institue of Allergies and Infectious Diseases (NIAID) at Bethesda, Maryland.
It is important to emphasise that results of immune-modulating drugs in monkeys have not always been replicated in humans. The monkeys were treated in early infection, whereas the human study is happening in chronically infected people, who may present more of a challenge. The anti-HIV immune responses seen were striking, but not particularly strong. And there is the problem that three of the monkeys mounted an immune response to the vedolizumab analogue itself, rendering it ineffective.
This is also not a complete cure: the viral load ‘blips’ seen off ART suggest that the α4β7mAb was suppressing SIV but had not necessarily cleared it from the monkeys altogether, and how long the effect would last beyond 16 weeks off the therapy is unknown.
Nonetheless, this is a striking result. In a commentary, reactions from other scientists have ranged from “Fascinating” and “A complete first” to “Too amazing to be real.”
NIAID chief Anthony Fauci said that “the results knocked us out, they were so stunning.”
HIV cure researchers were all intrigued; Rafick-Paul Sékaly of Case Western University in Cleveland commented: “That paper is going to orient the research in a completely new direction.” But Sharon Lewin of Melbourne University issued the caution that “It may just be a quirk of the monkey model.”
In a separate article, HIV pioneer Robert Gallo speaks of the need for HIV cure approaches that dampen down, rather than stimulate, the body’s response to HIV, calling them “Sooth and Snooze” approaches rather than “Kick and Kill”. He cites the trial of the tat inhibitor didehydro-cortistatin A as an example. The vedolizumab trial may turn out to be an example of the same thing.
Fauci’s verdict? ““We’re going to find out very soon whether this is all a bunch of nonsense or actually works.”
Antiretroviral drug therapy (ART) effectively suppresses replication of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn. SIV-infected monkeys were treated with a 90-day course of ART initiated at 5 weeks post infection followed at 9 weeks post infection by infusions of a primatized monoclonal antibody against the α4β7 integrin administered every 3 weeks until week 32. These animals subsequently maintained low to undetectable viral loads and normal CD4+ T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy.
Siddappa N Byrareddy, James Arthos, Claudia Cicala, Francois Villinger, Kristina T Ortiz, Dawn Little, Neil Sidell, Maureen A Kane, Jianshi Yu, Jace W Jones, Philip J Santangelo, Chiara Zurlq, Lyle R McKinnon, Kelly B Arnold, Caroline E Woody, Lutz Walter, Christian Roos, Angela Noll, Donald Van Ryk, Katija Jelicic, Raffaello Cimbro, Sanjeev Gumber, Michelle D Reid, Volkan Adsay, Praveen K Amancha, Ann E Mayne, Tristram G Parslow, Anthony S Fauci, Aftab A Ansari