title: In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice.
abstract: The programmed death-1 (PD-1) pathway limits the function of virus-specific T cells during chronic infection. We previously showed that blockade of the PD-1 pathway increases HIV-1-associated T cell function in vitro. However, the effect of PD-1 blockade on HIV-1 disease progression in vivo has not been examined. As in humans, HIV-1-infected humanized BALB/c-Rag2(-/-)γc(-/-) (Rag-hu) mice express elevated levels of PD-1 on T cells during chronic infection. To examine the effect of PD-1 blockade on disease progression, Rag-hu mice with chronic HIV-1 infection were treated with a blocking mAb directed against programmed cell death-1 ligand-1, the ligand for PD-1. Programmed cell death-1 ligand-1-treated Rag-hu mice exhibited a progressive decrease in the HIV-1 plasma viral load, with a 7-fold decrease by day 7, a 20-fold decrease by day 14, a 178-fold decrease by day 21, and a 269-fold decrease by day 28 postinitiation of treatment. By day 7, the percentage of CD4(+) T cells was statistically higher in the treated compared with the untreated group, and this trend was sustained throughout the 28-d treatment period. Moreover, there was a strong inverse correlation between plasma viral load and the percentage of both CD4(+) (r = -0.66; p < 0.0001) and CD8(+) (r = -0.64; p < 0.0001) T cells in the treated mice but not the untreated mice. This study provides "proof of concept" that humanized mice can be used to examine the effects of immunotherapeutic interventions on HIV-1 infection. Furthermore, to our knowledge, these data demonstrate for the first time that blockade of the PD-1 pathway reduces HIV-1 viral loads.
authors.affiliation: Division of Allergy and Clinical Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. brent.palmer@ucdenver.edu
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lecureux
authors.forename: Angelica
authors.initials: A
authors.lastname: Ehler
authors.forename: Michelle
authors.initials: M
authors.lastname: Dsouza
authors.forename: Leila
authors.initials: L
authors.lastname: Remling-Mulder
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fontenot
authors.forename: Ramesh
authors.initials: R
authors.lastname: Akkina
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D015536:Down-Regulation / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000254:growth & development / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D019562:Viral Load / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor