Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells with Stem Cell-Like Properties

Abstract

HIV-1-specific CD8 T cells can influence HIV-1 disease progression during untreated HIV-1 infection, but the functional and phenotypic properties of HIV-1-specific CD8 T cells in individuals treated with suppressive antiretroviral therapy remain less well understood. Here we show that a subgroup of HIV-1-specific CD8 T cells with stem cell-like properties, termed T memory stem cells (T SCM cells), is enriched in patients receiving suppressive antiretroviral therapy compared with their levels in untreated progressors or controllers. In addition, a prolonged duration of antiretroviral therapy was associated with a progressive increase in the relative proportions of these stem cell-like HIV-1-specific CD8 T cells. Interestingly, the proportions of HIV-1-specific CD8 T SCM cells and total HIV-1-specific CD8 T SCM cells were associated with the CD4 T cell counts during treatment with antiretroviral therapy but not with CD4 T cell counts, viral loads, or immune activation parameters in untreated patients, including controllers. HIV-1-specific CD8 T SCM cells had increased abilities to secrete interleukin-2 in response to viral antigen, while secretion of gamma interferon (IFN-␥) was more limited in comparison to alternative HIV-1-specific CD8 T cell subsets; however, only proportions of IFN-␥-secreting HIV-1-specific CD8 T SCM cells were associated with CD4 T cell counts during antiretroviral therapy. Together, these data suggest that HIV-1-specific CD8 T SCM cells represent a long-lasting component of the cellular immune response to HIV-1 that persists in an antigen-independent fashion during antiretroviral therapy but seems unable to survive and expand under conditions of ongoing viral replication during untreated infection. IMPORTANCE Memory CD8 T cells that imitate the functional properties of stem cells to maintain lifelong cellular immunity have been hypothesized for many years, but only recently have such cells, termed T memory stem cells (T SCM cells), been physically identified Cytotoxic T cell responses against HIV-1 are mounted early in the disease process and can be readily detected in the vast majority of untreated HIV-1-infected patients (1, 2). Evidence from a number of investigations, including animal models (3), immunogenetic associations (4, 5), human cohort studies (6, 7), and phylogenetic explorations of viral sequence evolution (8, 9), suggests that these cells can importantly modulate clinical HIV-1 disease progression, particularly in rare groups of patients who spontaneously control HIV-1 infection in the absence of treatment. In these patients, HIV-1-specific CD8 T cells typically exhibit a polyfunctional profile characterized by strong abilities to proliferate, secrete antiviral cytokines, and execute major histocompatibility complex (MHC) class I-restricted cytolysis through perforin and granzyme B (6, 10, 11). In contrast, HIV-1-specific CD8 T cells in persons with progressive untreated disease seem to have markedly weaker cytotoxic activities, upregulate markers of immune senescen...

Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux

“…Similarly, vaccine-induced T SCM cells can persist for decades with a naive-like profile (Fuertes Marraco et al., 2015). The T SCM compartment is also preserved in HIV-infected individuals on long-term anti-retroviral therapy (Vigano et al., 2015), despite the presence of a latent viral reservoir in the CD4 + lineage (Jaafoura et al., 2014, Buzon et al., 2014). Further evidence attests to the proliferative capacity of T SCM cells.…”

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

“…Notably, an optimal balance between immature precursor cells and more committed effector cells has previously also been found to be critical for regulating CD8 + T cell immunity (53). In addition, a higher proportion of total immature memory CD8 + and CD4 + T cells are associated with improved prognosis in chronic HIV-1 infection (54) and can be enriched in the absence of viremia and immune activation in treated HIV-1-positive individuals (55). Interestingly, we found evidence that Notch signaling, previously mostly shown to regulate hematopoietic and thymic precursor cell differentiation (37,38), is also involved in regulating the transition of long-lasting PD-1 lo into short-lived PD-1 hi Tfh-like cells.…”

Initiation of Antiretroviral Therapy Restores CD4 + T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques

“…Additional properties of T SCM include a long in vivo life span, greater proliferative potential than other T cell memory subsets, and preferential homing to secondary lymphoid tissues (8,10). In the context of HIV and SIV infection, CD8 ϩ T SCM are thought to be involved in the long-term maintenance of virus-specific cellular immune responses (11)(12)(13), while CD4 ϩ T SCM were shown to be important targets of HIV infection both in untreated and in ART-treated individuals (14,15). The observation of high levels of HIV DNA in CD4 ϩ T SCM from HIV-infected individuals under ART, together with particular biological properties of these cells, such as high in vivo longevity, relative quiescence, and marked proliferative potential, led to the hypothesis that these cells represent a crucial contributor to virus persistence despite their relative low frequency (15).…”