title: Short communication: CD4 T cell declines occurring during suppressive antiretroviral therapy reflect continued production of Casp8p41.
abstract: Most patients on suppressive antiretroviral therapy (ART) experience improvements in CD4 T cell count. However, some patients with undetectable viral load continue to lose CD4 T cells for unknown reasons. Casp8p41 is a host-derived protein fragment that is present only in productively infected cells and that causes the death of HIV-infected cells. We questioned whether ongoing CD4(+) T cell losses while on suppressive ART were associated with subclinical HIV replication causing production of Casp8p41. We analyzed the association of Casp8p41 content with subsequent CD4 losses in patients on continuous suppressive ART and in patients who discontinued ART after Casp8p41 content was determined, adjusting for age, baseline CD4(+) T cell count, and baseline HIV RNA level. Casp8p41 expression in memory CD4(+) T cells was measured by intracellular flow cytometry and was correlated with viral load and CD4(+) T cell change over time. In patients who stopped therapy after Casp8p41 content was determined, baseline Casp8p41 content did not predict CD4(+) T cell change. However, in patients on continuous ART, higher baseline Casp8p41 content was associated with a greater odds of a CD4(+) T cell decline at 6 months (p=0.01). Therefore, patients on suppressive ART, who have ongoing production of Casp8p41, have an increased risk of CD4 T cell losses, suggesting that subclinical HIV replication is driving both Casp8p41, which in turn causes a CD4(+) T cell decline.
authors.affiliation: 1 Division of Infectious Diseases, Mayo Clinic , Rochester, Minnesota.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Cummins
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Neuhaus
authors.forename: Amy M
authors.initials: AM
authors.lastname: Sainski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Strausbauch
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wettstein
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Rizza
authors.forename: Zelalem
authors.initials: Z
authors.lastname: Temesgen
authors.forename: Giota
authors.initials: G
authors.lastname: Touloumi
authors.forename: Matthew
authors.initials: M
authors.lastname: Freiberg
authors.forename: James
authors.initials: J
authors.lastname: Neaton
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D053181:Caspase 8 / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; C505530:CASP8 protein, human; D053181:Caspase 8