A study published last Thursday in the journal Science has hit the headlines, reporting that sustained post-treatment control of SIV has been achieved in macaques using an antibody therapy developed for the treatment of inflammatory gastrointestinal (GI) disorders. The antibody targets α4β7, a receptor expressed on CD4 T cells (and other immune system cells) that is involved in promoting trafficking to the GI tract. Some, but not all, studies have suggested that α4β7 also plays a role in mediating HIV infection of target CD4 T cells.
The rationale for the study came from previous experiments which found that infusions of the antibody prior to an SIVmac239 challenge reduced post-infection viral loads in macaques and, in low-dose challenge studies, lessened the risk of SIV acquisition. The mechanism remains unknown but the researchers hypothesize that it relates to inhibition of trafficking of CD4 T cells, natural killer cells and plasmacytoid dendritic cells to the gut, limiting the availability of target cells for SIV and also dampening the inflammatory immune response that promotes and disseminates virus replication.
In the latest work, 18 macaques were challenged with the same dose of SIVmac239 used in previous experiments (200 TCID 50) and all became infected. Five weeks post-challenge, combination antiretroviral therapy (ART) was initiated in all animals and maintained for 90 days. Around three weeks prior to ART cessation, 11 macaques were administered the anti-α4β7 antibody by infusion while the remaining seven received a control antibody. The antibody administrations were then continued every three weeks (after ART withdrawal) until a total of eight infusions had been given, at which point all treatments were stopped. Three macaques developed antibodies against the anti-α4β7 antibody and were excluded from further study, so analyses were limited to eight animals in the anti-α4β7 group and seven controls.
After ART cessation, control macaques all experienced a rebound of SIV viral load within two weeks; levels averaged around a million copies/ml and persisted throughout follow up. Outcomes in recipients of the anti-α4β7 antibody were very different: two animals never rebounded, and the remaining six were able to exert control of SIV viral load within four weeks, for the most part to undetectable levels but with some intermittent blips. This suppression of SIV has been maintained out to 81 weeks of follow up (the last anti-α4β7 antibody infusion occurred at week 32). Levels of proviral SIV DNA in GI tissues followed a similar pattern, persisting at detectable levels in the control animals but declining to undetectable levels in the anti-α4β7 antibody group from week 30 onwards.
Measurements of CD4 T cell numbers in blood and gut showed an ongoing repopulation in the anti-α4β7 antibody group compared to declines in controls. Notably, this recovery included Th17 and Th22 CD4 T cell subsets, which are known to contribute to the maintenance of GI barrier integrity. In terms of possible mechanisms of viral load containment, increases in cytokine-producing natural killer cells and innate lymphoid cells were seen in the gut post-ART in the anti-α4β7 antibody recipients but not controls. Some evidence of preferential induction of antibodies against the V2 region of the SIV envelope was also reported. SIV-specific CD4 and CD8 T cell responses were assessed based on expression of CD107a, IFN-γ, MIP-1β or TNF-α but did not show significant differences between groups
The results of the study appear very encouraging, and the researchers are hoping to rapidly evaluate whether they have any relevance to humans. A small clinical trial of the anti-α4β7 antibody vedolizumab, which is FDA-approved for the treatment of ulcerative colitis and Crohn's disease, is now recruiting at the National Institutes of Health Clinical Center. The target population is HIV-positive people who have been on suppressive ART for at least two years and the primary goal is assess safety (the antibody has been reported to have a favorable side effect profile for approved indications). An ART interruption is planned to evaluate any effects on viral load rebound.
Media coverage of the paper has generally been accurate, but has had to wrestle with the uncertainty that exists among scientists regarding how ART-free control of viral load should be described. The press release issued by the researchers uses the term “sustained SIV remission” in the headline but adds: “also known as a ‘functional cure’” in the body text. The problem, as TAG has highlighted in the past, is that it cannot be assumed that ART-free control of viral load automatically equates to a state of health that can be considered as “remission” or a “functional cure” – i.e. a state of health equivalent to an HIV-positive person on suppressive ART or a comparable HIV-negative person. It is known from studies of elite controllers and individuals with HIV-2 infection that low or even undetectable viral loads do not necessarily completely eliminate the risk of disease progression. Thus, if an intervention leads to a state of ART-free control of viral load, it will be necessary to carefully evaluate immunological and health outcomes over a long period before concluding that HIV remission or a functional cure has been achieved.
One possible technical issue that has been noted about the study is that after the SIVmac239 challenge, peak viral loads averaged around three million copies/ml, which, as Louis Picker points out in an accompany Science news article by Jon Cohen, is unusually low for SIVmac239 – in one of the prior studies by the same researchers, peak viral loads in controls averaged >32 million copies/ml. The study authors do not address this apparent discrepancy. Although it would not explain the differences between the the anti-α4β7 antibody recipients and controls, the generalizability of the findings could be limited if the SIVmac239 challenge stock was unusually attenuated.
Update 10/19/16: Anthony Fauci discussed the study during a plenary presentation at the HIV Research for Prevention (HIVR4P) conference in Chicago on October 17th, and a webcast is available online. Fauci noted that some of the recipients of the anti-α4β7 antibody have now been followed for two years and continue to maintain low SIV viral loads.