title: Age-related expansion of Tim-3 expressing T cells in vertically HIV-1 infected children.
abstract: As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an "immune exhaustion", with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28(-)CD57(+)CD8(+) T cells between the groups. However, the frequency of Tim-3(+)CD8(+) and Tim-3(+)CD4(+) exhausted T cells, but not PD-1(+) T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1(+)CD8(+) T cells were directly associated with T cell immune activation in children. The frequency of Tim-3(+)CD8(+) T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion.
authors.affiliation: Hawaii Center for AIDS, Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA. rtandon@hawaii.edu
authors.forename: Ravi
authors.initials: R
authors.lastname: Tandon
authors.forename: Maria T M
authors.initials: MT
authors.lastname: Giret
authors.forename: Devi
authors.initials: D
authors.lastname: Sengupta
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: York
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wiznia
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenberg
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallas
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
mesh_terms: D000375:Aging / Q000378:metabolism*; D002648:Child; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism* / Q000635:transmission; D015497:HIV-1; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D008565:Membrane Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D019562:Viral Load
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins