Among the most newsworthy presentations at CROI 2018 earlier this year was Dan Barouch’s description of a study involving a toll-like receptor 7 (TLR7) agonist combined with a broadly neutralizing antibody (bNAb) in SHIV-infected macaques (see contemporary coverage by AIDSMap, i-Base and POZ Magazine). The results have now been published in the journal Nature.
The specific experimental candidates that were tested are vesatolimod (formerly known as GS-9620), a TLR7 agonist, and PGT121, a bNAb initially discovered by researchers supported by the International AIDS Vaccine Initiative but now licensed to Gilead Sciences for therapeutic development. Previous laboratory experiments using CD4 T cells isolated from people on ART found that the combination promoted the reversal of HIV latency and killing of virus-infected cells.
A key goal of Barouch’s study was to establish whether bNAbs are capable of mediating depletion of the viral reservoir in vivo, in addition to displaying the direct antiviral activities that have been documented in other experiments (such as the trials described in the previous blog post).
A total of 44 macaques were infected with SHIV-SF162P3, a hybrid virus that combines elements of SIV and HIV. ART was initiated seven days later—extremely early after infection—leading to rapid suppression of SHIV replication that was maintained for 96 weeks without any viral load blips.
For the subsequent intervention phase, animals were divided into four groups of 11 and received, respectively: sham administrations (control group), vesatolimod alone, PGT121 alone, or the combination of vesatolimod and PGT121. Vesatolimod was given orally every other week between weeks 96 and 114 of the study, while PGT121 was administered five times via infusion from weeks 106-114. ART was then interrupted in all macaques at week 130.
The most dramatic finding was a significantly reduced incidence of SHIV viral load rebound in the group that received the dual vesatolimod/PGT121 combination. Out of the 11 macaques, six (55%) rebounded, compared to all 11 of the sham controls, 10 out of 11 (91%) assigned to vesatolimod alone and nine of 11 (82%) given PGT121.
Among the animals in the combination group that did rebound, viral loads were 2.6 logs lower at the peak and 1.5 logs lower at the set point compared to the controls. Additional analyses showed that levels of SHIV DNA in lymph nodes were significantly lower in the combination group prior to the ART interruption.
The interventions appeared to be well tolerated. Vesatolimod caused transient activation of CD4 T cells and natural killer cells, as well as transient increases in proinflammatory cytokines, which were evident the day after administration.
In an effort to assess whether a reservoir of replication-competent SHIV was still present in the animals that failed to rebound, experiments were conducted in which large numbers of cells were transferred into uninfected macaques. SHIV infection was not transmitted in any case. In contrast, cells from animals that experienced viral load rebounds uniformly transmitted SHIV infection.
CD8 T cells were also depleted from some macaques, as a test of whether SHIV was being actively contained by the immune system in the group that did not experience viral load rebounds. The depletion did not lead to the reappearance of SHIV viral load in these animals.
A computer modeling study indicated that the activation of natural killer (NK) cells by vesatolimod was the strongest correlate of delayed viral load rebound. The researchers suggest that this is consistent with a mechanism of action in which stimulation of innate immunity and CD4 T cells by vesatolimod causes virus-infected cells to express viral antigens, which are then recognized and bound to by PGT121, triggering killing of the infected cells by NK cells and/or other effector cells such as monocytes. This antibody-mediated recruitment of immune cells capable of delivering the coup de grâce to virus-infected cells is known as antibody-mediated cellular cytotoxicity (ADCC) or antibody-mediated cellular phagocytosis (ADCP).
In the discussion section of the paper, the researchers emphasize that the study represented an idealized circumstance due to the very early ART initiation, and that the effects of the interventions were most evident in animals with the lowest pre-ART viral loads. The implications for the more typical circumstance of chronic infection are therefore unclear.
They also note that the failure to transmit SHIV infection is not definitive evidence that all replication-competent virus has been cleared. This has recently been demonstrated by Ron Desrosiers in a study in which replication-competent SHIV was eventually detected in a macaque that had failed to transmit the virus in several cell transfer experiments.
Additionally, there is limited experience with the SHIV-SF162P3 challenge virus in the context of cure research and prior studies have not documented an ability of this virus to develop resistance to PGT121. More information on HIV resistance to PGT121 should emerge from ongoing clinical trials.
Despite these caveats, the evidence that the dual combination promoted clearance—or at least significant depletion—of the viral reservoir in some cases is encouraging.
Gilead Sciences ultimately aims to study vesatolimod combined with a derivative of PGT121 dubbed GS-9722 in people with HIV. GS-9722 is a version of PGT121 that has been modified in an effort to further enhance ADCC/ADCP activity, and it is currently being tested in a phase I trial (the trial is listed on the subscription-only website Adis Insight so details are scarce; there is no clinicaltrials.gov entry yet).
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