Peripheral S‐Phase T Cells in HIV Disease Have a Central Memory Phenotype and Rarely Have Evidence of Recent T Cell Receptor Engagement

Abstract

Heightened proliferation and death of T lymphocytes may play a key role in human immunodeficiency virus (HIV) pathogenesis; however, the mechanism that mediates this effect and the phenotype of the proliferating T cells have not been clearly determined. We assessed S-phase cell frequencies and phenotype by ex vivo bromodeoxyuridine incorporation and flow-cytometric analysis in a group of 35 HIV-infected individuals. Frequencies of S-phase T cells were increased in HIV disease and were related to plasma HIV RNA levels but not to CD4 cell, total T cell, or total lymphocyte counts. S-phase cells were phenotypically defined as "central memory" cells (CD45RO+CD62L+CCR7+). Although activated (CD38+), S-phase cells lacked CD69 expression, rarely expressed CD25, and were not overrepresented among HIV-specific cells, as might have been expected if these cells had recently been activated by HIV antigens. Thus, in HIV infection, central memory T cells may be highly susceptible to bystander mechanisms of immune activation, leading to S-phase entry.

CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

“…Notably, IL-15 activated memory CD8 + T cells more efficiently than naive CD8 + T cells, which is consistent with the notion that activated and memory CD8 + T cells show increased turnover rates in HIV-1-infected patients compared with naive CD8 + T cells (54). These results support the idea that Agindependent cytokine-mediated activation contributes to the aberrant CD8 + T cell activation observed during HIV-1 infection (7) and is in line with a report showing that activated T cells in HIV-1-infected individuals rarely show signs of recent TCR stimulation (55). Furthermore, it has also been reported in mice that IL-15 regulates the homeostatic proliferation of memory CD8 + but not CD4 + T cells (56).…”

Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1

“…In this regard, it will be important to evaluate the relationships among HIV-1 replication and other potential drivers of immune activation in chronic HIV-1 infection, such as translocated microbial products on activation markers such as CD38 and Ki-67, and the frequencies of circulating central memory T cells in S phase of the cell cycle. 28,49 Plasma levels of HIV-1 RNA were not related to the immune activation as reflected by CD38 expression, nor were levels of HIV-1 expressed in the lymph node tissues related to CD38 expression. These data suggest that immune activation in lymphoid tissue is also not a consequence of HIV-1 antigenic load or other factors related to HIV-1 replication directly.…”

“…It is well recognized that T-cell depletion during the course of HIV-1 infection is not restricted to infected cells; [19][20][21][22][23][24] diminished thymic function, [25][26][27] peripheral naive T-cell expansion failure, 28 and distorted lymphoid architecture, 29 as well as heightened cellular turnover 4,30-32 have been implicated as underlying these depletions. In the current studies we examined cellular activation in lymphoid tissue, as heightened activation has been implicated as an underlying mediator of T-cell depletion in HIV-1 infection.…”

“…We propose that dysregulated activation underlies the profound expansion failure of circulating naive T cells in HIV-1 infection. 28 How immune activation promotes naive T-cell expansion failure remains to be determined. As we show here that these cells have evidence of in situ activation, we propose that this may underlie the functional impairment that we have observed ex vivo.…”

Antigen-Dependent and -Independent Mechanisms of T and B Cell Hyperactivation during Chronic HIV-1 Infection

“…Since immune responses are often associated with extensively proliferating T cells and precursor frequencies of T cells for specific antigens are low, it is conceivable that a proportion of proliferating T cells might be activated in a TCR-independent manner, at least during early time points of infection when antigen-specific T cells have not yet clonally expanded to their peak (146). Indeed, one study suggests that activated T cells in HIV-1 infection, albeit primarily of a memory phenotype, rarely show signs of recent TCR stimulation (130). However, this conclusion was based on the analysis of cell surface expression of CD69 and CD25, which are known to be very transiently expressed after TCR stimulation and hence might not provide direct evidence of whether or not cognate antigen stimulation is involved in the accumulation of activated T cells (as defined by CD38 and HLA-DR expression) during HIV infection (6,149).…”