Date Published: May 13, 2019
Publisher: Public Library of Science
Author(s): Giulia Calenda, Ines Frank, Géraldine Arrode-Brusés, Amarendra Pegu, Keyun Wang, James Arthos, Claudia Cicala, Kenneth A. Rogers, Lisa Shirreff, Brooke Grasperge, James L. Blanchard, Stephanie Maldonado, Kevin Roberts, Agegnehu Gettie, Francois Villinger, Anthony S. Fauci, John R. Mascola, Elena Martinelli, Guido Silvestri.
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
Integrin α4β7 (α4β7) is expressed at high levels by CD4+ T cells trafficking to the gut associated lymphoid tissues (GALT) [1–3], a critical site for HIV-1 replication and dissemination after transmission [4–7]. α4β7high CD4+ T cells are highly susceptible to HIV-1 infection and are preferentially depleted during acute HIV-1 and SIV infection [8–10]. Higher frequencies of α4β7high CD4+ T cells have been correlated with increased susceptibility to HIV-1 infection in humans and SIV infection in macaques and with disease progression in both humans and macaques [11, 12]. The higher risk of HIV-1 acquisition due to prevalent HSV-2 infection has also been associated with increased levels of α4β7 expression [13–15]. Targeting α4β7 with a simianized anti-α4β7 monoclonal antibody (Rh-α4β7; mAb) prior to and during a vaginal repeated low-dose challenge (RLDC) study in rhesus macaques prevented SIV acquisition in half of the animals and delayed disease progression in those animals that did become infected . Reportedly, simultaneous treatment with Rh-α4β7 and cART led to sustained viral control after cessation of all forms of therapy in at least one model of SIV infection . The mechanism(s) underlying the anti-HIV-1 activity of the Rh-α4β7 mAb are poorly understood. Rh-α4β7 does not block viral entry into CD4+ T cells and has weak anti-HIV-1 activity in vitro [8, 18, 19]. We have recently shown that signaling through α4β7 can promote HIV-1 replication  and, in this regard, we previously demonstrated that Rh-α4β7 blocks α4β7 from adopting an active conformation that is critical for this signaling .
bNAbs are being tested in the clinic for the prevention and therapy of HIV-1 infection. VRC01 is the first to reach efficacy testing and other bNAbs will soon follow [44, 45]. However, it is clear that individual bNAbs cannot be used alone as a single intervention. Combinations of more bNAbs or bi- or tri-specific molecules need to be employed to achieve better and more durable protection from HIV-1 acquisition [33, 46–48]. Moreover, recent data suggest that bNAbs treatment may impact immune responses to infection [49–51]. This feature represents a potential new therapeutic approach toward an HIV-1 cure. Rh-α4β7 has also demonstrated the ability to partially prevent SIV infection in macaques  and treatment of SIV infected macaques with Rh-α4β7 in combination with cART has shown its potential utility in inducing long-term control of SIV replication without eradicating the virus . Nonetheless, much more needs to be understood about the ability of bNAbs and α4β7-blockage to impact immune responses against SIV/HIV.