Achieving Sustained HIV remission with Alpha-4-beta-7 Monoclonal Antibodies

Highly active antiretroviral therapy (HAART) is a very successful treatment of HIV in those individuals who are infected. However, when treatment ceases, the virus comes back in full force. Different hypotheses try to explain this by either claiming virus dormancy, reservoirs in which concentrations are high in the places where HAART has low penetration, or both.¹

An integrin is a receptor protein attached to cells that facilitate the cell to react to the extracellular matrix. The α₄β₇ integrin on CD4, CD8, and natural killer cells has shown to mediate binding with the very conservative gp120 on HIV.² Results on an in vitro study concludes that because of integrin α₄β₇, cells with this particular integrin have higher susceptibility to HIV-1.³

In a research article published in October in Science, 15 macaque monkeys with SIV were subject to ART + α₄β₇ mAb (monoclonal antibody) or ART + immunoglobulin G (IgG) as the control. The study was split into 5 phases:

· Phase 1 (Weeks 1-5): Animals were infected with SIV (no treatment)

· Phase 2 (Weeks 6-8): 90 day ART treatment to suppress the virus

· Phase 3 (Weeks 9-18): Add-on therapy. Eleven animals received α₄β₇ mAb, and 7 animals received IgG

· Phase 4 (Weeks 18-32): ART withdrawn and other treatments continued

· Phase 5: (Weeks 32-50): All treatment discontinued at week 32. At time of discontinuation, 3/11 α₄β₇ mAb treated animals developed antibodies against the α₄β₇ mAb and were excluded.

In phase 4, all 7 IgG treated monkeys rebounded to high viremia levels (~10⁶) within 2 weeks of stopping ART and maintained high levels until week 50 (end of phase 5). Throughout phase 4 and 5, 6/8 animals in the α₄β₇ mAb treated group rebounded, but regained control within 4 weeks. The remaining 2 α₄β₇ mAb treated animals never rebounded throughout the study. The difference in viremia after discontinuation of ART was significant (P<.0001). All animals treated with α₄β₇ mAb showed virologic control until week 81.⁴

This study has further supported the need to treat gut-associated lymphoid tissue (GALT) in the quest to a functional or sterilizing cure to HIV. ART affect the GALT and some other tissues as well it does in the bloodstream to remove the virus from the body.

That is great news, but now the whole process from developing an α₄β₇ mAb and progression to phase 3 has to start now, right? Enter vedolizumab (Entyvio®). Currently approved for adult ulcerative colitis and adult Crohn’s disease, vedolizumab is a α₄β₇mAb that is currently recruiting for phase 1 testing (ClinicalTrials.gov Identifier: NCT02788175).⁵ This trial will be set up with similar timelines as far as treatment with vedolizumab (every 4 weeks for 30 weeks) and halting ART (after week 22 infusion). Patients will be monitored every 4 weeks for 24 weeks thereafter. It is currently recruiting participants.

References

1. Archin NM, Sung JM, Garrido C, Soriano-sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12(11):750-64.

2. Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol. 2008;9(3):301-9.

3. Cicala C, Martinelli E, Mcnally JP, et al. The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci USA. 2009;106(49):20877-82.

4. Byrareddy SN, Arthos J, Cicala C, et al. Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy. Science. 2016;354(6309):197-202.

5. Entyvio® [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2014.