Premature Aging of T cells Is Associated With Faster HIV-1 Disease Progression

Abstract

Objective To determine if untreated HIV-1 infection and progression is associated with premature aging of memory CD8+ and CD4+ T cells and naive CD4+ T cells. Methods Twenty HIV-1–infected fast progressors and 40 slow progressors were included in our study, using risk set sampling. The expression of cell surface markers reflecting the differentiation stages of lymphocytes was measured using flow cytometry analyses performed on cryopreserved peripheral blood mononuclear cells. Results We found that HIV-1 disease progression is associated with a decreased CD28 median florescence intensity on CD4+ and CD8+ T cells; an increased proportion of intermediate- and late-differentiated CD8+ T cells and a decreased CD31 median florescence intensity on naive CD4+ T cells of recent thymic origin. A selective depletion of peripherally expanded naive CD4+ T cells was found to be associated with HIV-1 infection but not with HIV-1 disease progression. Conclusions The overall change during HIV-1 infection and progression is associated with a shift in the T-cell population toward an aged conformation, which may be further compromised by impaired renewal of the less-differentiated CD4+ T-cell population. Our results suggest that HIV-1 infection induces an accelerated aging of T lymphocytes, which is associated with the clinical progression to AIDS and death.

Elite Controllers with Low to Absent Effector CD8 + T Cell Responses Maintain Highly Functional, Broadly Directed Central Memory Responses

“…Interestingly, as is the case with strong responders, the levels of inhibition correlated with the frequencies of expanded HIV-specific cells, suggesting that traditional virus inhibition assays are not sensitive to measure the inhibitory capacity of lowfrequency central memory cells and instead characterize mainly high-frequency cells, which are maintained by continuous antigenic stimulation and are therefore more differentiated (8). Not surprisingly, no differences in virus inhibition activity between cells from different differentiation stages have been found in studies combining phenotypic cell sorts and functional antiviral assays (17).…”

“…CD8 ϩ T cells exist in a continuum of differentiation states ranging from naïve to the terminally differentiated stage (12,24). The fate of the differentiation pathways is predisposed by the sequence of the infecting virus, immunological escape due to viral mutations, and antigen load (8,22,44,49). In situations in which plasma viremia is successfully and durably controlled to exceedingly low levels, central memory T cell populations might be expected to undergo less stimulation to effector memory cells, which would result in a lower frequency of effector memory responses.…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…These 2 factors make more difficult to achieve HIV diagnosis and consequently they cause a delay that can lead to a severe immune deficiency. The progression to AIDS is faster in older people [5][6] mainly because of the immunosenescence due both to age and to HIV infection itself. Moreover, progression to AIDS or occurrence of non-AIDS related comorbidities can be only partially prevented with HAART.…”

Shelterin Dysfunction and p16 INK4a -Mediated Growth Inhibition in HIV-1-Specific CD8 T Cells

“…Interestingly, due to alternative mechanisms of immune regulation (15)(16)(17), persistent HIV-1 replication and ensuing immune activation seem to affect CD4 and CD8 T cells differently. While CD4 T cells seem to undergo apoptosis and physical elimination, as evidenced by progressively declining cell numbers during chronic infection, CD8 T cells are numerically expanded but acquire a distinct functional and phenotypic profile that closely resembles the aging and senescent cells typically encountered in elderly individuals (6,13,38). Functionally, these cells remain metabolically active and are capable of executing specific lymphocellular effector functions, such as gamma interferon secretion, but lose their ability for antigen-specific proliferation and may develop immunosuppressive properties (14).…”