Since the advent of antiretroviral drugs, perinatally HIV-1-infected children have grown up into the adolescent age with lower rates of AIDS related mortality and morbidity 
. Despite combination antiretroviral therapy (cART), perinatally HIV-1 infected subjects have striking differences in HIV-1 disease progression compared to adults and adolescents and have higher viral load (VL) and lower virological responses rates than adults 
. This is primarily as a consequence of poor adherence to drugs over a lifetime, underdosing, treatment fatigue, altered pharmacokinetics, novel toxicities, caregiver-related problems and high rates of psychiatric illness including the complications of long-standing infection and the deleterious effects of cART 
. In horizontally infected adults with chronic treated HIV-1 infection, it is evident that mortality due to non-AIDS events is more common than mortality due to AIDS-related events 
and this could potentially occur in perinatally infected children earlier. As perinatally HIV-1-infected children age with HIV-1, deleterious consequences to protective T cell immunity may persist or develop despite cART 
. The exact nature of these immunological events and the association with disease progression in vertically infected patients remain unclear.
On encountering antigen, CD8+
T cells differentiate from the least differentiated (naive or early memory) stage to the most mature (memory/effector) stage. In this process, cell surface receptors are progressively downregulated (CD45RA, CCR7, CD28, CD27, CD127) or upregulated (CD57 and CD45RA) as CD8+
T cells differentiate 
. In adults with HIV-1 infection, T cells fail to fully mature into effector T cells 
. We have previously shown that the differentiation status of HIV-1 specific T cells in adults were not readily altered by cART despite declines in T cell activation suggesting that cART does not reverse T cell effector defects 
. We further showed that in perinatally infected children, T cell effector maturation induced by HIV-1 infection was markedly weaker compared to adults, even in those on cART 
. As HIV-1 specific T cells develop increased CD57 expression, they have replicative senescence 
, and remain senescent despite suppressive cART.
During many chronic viral infections a distinct terminal state of T cell differentiation, or T cell exhaustion arises 
. Such functionally impaired T cells are characterized by abnormally low cytokine production, poor proliferative capacity with the upregulation of several inhibitory receptors including Programmed Death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3) among others 
. These receptors not only mark but also induce inhibitory signals to dampen T cell immune responses. In HIV-1 infection, PD-1, a CD28 family member, is increased on CD8+
T cells in progressive HIV-1 disease 
. Tim-3, an immunoglobulin (Ig) superfamily member, initially identified as a negative regulator of Th1 response through the Tim-3/Galectin-9 pathway in several inflammatory disease states 
, is also elevated in HIV-1 disease 
and associated with disease progression. cART can reduce PD-1 levels in T cells in HIV-1 infected adults, and in some subjects Tim-3 expression is also reduced 
. Several combinations of markers are therefore used to discriminate differentiated and senescent T cells. However, whether there are common mechanisms regulating them remain unclear 
In the setting of treated HIV-1 disease in adults, T cell function remains perturbed with CD8+
T cell activation, defined by CD38+
coexpression, at higher levels than in uninfected subjects 
. Immune activation occurs in perinatally infected children and the degree of immune activation present as early as 1–2 months of age can be used to predict which children will become long-term non-progressors 
. In children, the relationship between HIV-1 viral load and immune activation appears to be less clear-cut than in adults, in whom a higher level of viremia is predictably associated with higher levels of activation 
As adults with HIV-1 infection age, it appears that alterations in immune profile or immunosenescence begin to resemble those of much older uninfected subjects, and is now referred to as “premature aging” 
. Phenotypic and functional T cell alterations observed during advancing human age lead to poor responses to and efficacy of vaccines, and increased susceptibility to new infections and tumors in the elderly 
. With an acceleration of aging and T cell decline induced by HIV-1 infection, a similar impact on T cell immunity could occur in perinatal HIV-1 infected children as they age into adolescenthood.
In this study we sought to assess the effects of HIV-1 infection on T cell differentiation, senescence and exhaustion in two age groups of perinatally HIV-1-infected subjects with shorter and longer durations of infection that present with persistently high HIV viremia despite access to cART, and determine the associations with markers for disease progression (viral load, immune activation) to improve our understanding of how these parameters may modulate the ability of protective T cell immunity to control HIV infection in children.