Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection

Abstract

The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIVmac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIVmac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIVmac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4+ T cell proliferation.

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

“…1C), the latter suggesting that vaccination controlled viral infection in the local mucosal tissues. Even in the adjuvant-only group 5, one animal (O) was protected and another (J) showed some decline in VL over time, in contrast to all (30/30) naive historical controls (7,(22)(23)(24)(25) and animals in groups 1, 2, and 4. This finding motivated a search for possible correlates of protection in both innate and adaptive immunity.…”

“…A fifth group, given TLR agonists and IL-15 without vaccine, was included during immunization as an adjuvant-only control. Seven weeks after the last boost (3 weeks after surgical biopsy to allow recovery), all animals were intrarectally challenged with 10 infectious doses of SIVmac251, a batch and dose that has infected 100% (30/30) of naive animals in previous studies of our collaborators (22)(23)(24)(25) and others (7). Indeed, even a 5-fold lower dose infected 11 of 11 animals (26).…”

“…Macaques were primed at week 0, 3, and 6 with peptides or adjuvants and boosted at week 12 and 15 with MVA-SIV and adjuvants (22). At week 22, all animals received an intrarectal inoculation of 10 ID 50 of SIVmac251 [provided by Nancy Miller, National Institute of Allergy and Infectious Diseases (NIAID), National Insitutes of Health], sufficient to infect 100% (30/30) of naive controls in previous studies (7,(22)(23)(24)(25). After challenge, SIV RNA levels were monitored by NASBA assays for 6 months by Advanced BioScience Laboratories, Inc with a cutoff value of 50 copies.…”

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

“…In support of immune activation as an important factor for AIDS progression, Cecchinato et al utilized antibody to block CTLA-4 function in SIVmac251 infection both in acute and chronic stages of disease. This treatment led to increased viral load in plasma and tissue, correlating with increased T-cell activation, and exacerbation of MALT CD4 + T cell loss, but it surprisingly had no effect on HIV-specific T-cell responses [90]. A clear understanding of immune balance and the alteration of immune-homeostasis in HIV infection is required to elucidate mechanisms contributing to HIV pathogenenis.…”

Immune Checkpoint Drug Goes Viral: Developing New Treatment Paradigm for Chronic Viral Infection

“…Finally, it also prolonged the survival of infected macaques [13]. These results are highly significant considering that the related co-inhibitory molecule CTLA4 failed to either expand virus-specific CD8+ T cells or reduce viremia in SIV macaque model [14]. Similarly, inhibition of PD-1 signaling by anti-PD-1 antibody also achieved a reduction in viral load in a humanized mouse model with chronic HIV-1 infection [15].…”