Sustained virologic control in SIV ⁺ macaques after antiretroviral and α ₄ β ₇ antibody therapy

Abstract

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of both the immunodeficiency viruses, human (HIV) and simian (SIV); however, virus rebounds soon after ART is withdrawn.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normal CD4+ T cell counts in plasma and gastrointestinal tissues for more than 9 months, even after all treatment was withdrawn.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.

Progress in HIV vaccine development

“…90 More recently, infusion of a4b7 integrin mAb, in RM SIV models, was associated with sustained control of plasma viremia even months after ART and a4b7 integrin mAb were discontinued. 91 The mechanism for persistent virologic control remains to be defined, but was not associated with nAb or classical cell mediated immune responses. This major breakthrough show that antibody administration has the potential to modulate anti-HIV immune responses and has implications for both HIV-1 prevention and cure.…”

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…GALT-infiltrating CD4 + T cells represent optimal HIV targets, likely due to their high expression of CCR5 (4,5,8), a major coreceptor for HIV entry (9)(10)(11), and integrin α4β7, a gut-homing molecule (12) identified as an HIV-binding molecule (13). Very recently, integrin α4β7-blocking Abs proved efficacy in controlling viral replication upon ART interruption in an SIV infection model (14), indicative that interfering with HIV replication in gut-homing α4β7…”

Targeting the Latent Reservoir for HIV-1

“…While not a marker of the reservoir per se, the integrin α4β7 expressed on CD4 + T cells has become an interesting antigenic target from a different standpoint. This integrin directs CD4 + T homing to MAdCAM-expressing mucosal and gut-associated lymphoid tissue (GALT) (Byrareddy et al 2016). SIV preferentially infects CD4 + T cells with α4β7 (Kader et al 2009), and administration of primatized antibodies against α4β7 integrin (ACT-1) protects macaques against vaginal challenge with SIV (Byrareddy et al 2014).…”

“…SIV preferentially infects CD4 + T cells with α4β7 (Kader et al 2009), and administration of primatized antibodies against α4β7 integrin (ACT-1) protects macaques against vaginal challenge with SIV (Byrareddy et al 2014). In addition, one recent study found that administration of cART with ACT-1 after 5 weeks of SIV infection led to virologic control for up to 9 months after cART interuption in several macaques (Byrareddy et al 2016). While these results are intriguing, the macaques may have had small reservoirs due to early treatment (5 weeks), and there is naturally a higher rate of spontaneous control of SIV compared to HIV-1 (Asquith et al 2009; Shedlock et al 2009; Bruel et al 2015).…”

“…Recently, α4β7 was shown to be incorporated in virions, providing another potential mechanism for control: anti-α4β7 antibodies may both help prevent viral entry and block new infections, contributing to decreased spreading of viral infection in the gut (Guzzo et al 2017). An antibody to α4β7 (vedolizumab) is already approved for use in Crohn’s disease, and provided that it does not induce anti-drug antibodies (as seen with 3 out of 11 tested macaques) (Byrareddy et al 2016), it may be an important addition to the HIV-1 cure regimen in humans. The efficacy of vedolizumab with ART is being tested in a phase I clinical trial (https://clinicaltrials.gov/ct2/show/NCT02788175).…”