Restoration of the CD4 T Cell Compartment after Long-Term Highly Active Antiretroviral Therapy without Phenotypical Signs of Accelerated Immunological Aging

Abstract

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/μl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4–9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/μl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

IL-7–dependent STAT1 activation limits homeostatic CD4+ T cell expansion

“…Distinct reconstitution is observed in the CD8 + T cell pool in which cells undergo a profound proliferation accompanied by accumulation of cells with an activated memorylike phenotype (13-15, 17, 40). This reconstitution profile is also observed in patients with HIV infection in whom complete CD4 + T cell reconstitution following cART therapy is a slow process that typically requires many years and depends on the CD4 + T cell number prior to therapy and other factors (17)(18)(19). In the HIV infection, CD8 + T cell numbers are already expanded, and the CD8 + T cell pool does not seem to be influenced by the degree of CD4 + T cell depletion.…”

“…In contrast, such a correlation is not observed in the CD8 + T cell pool from patients and healthy volunteers. In patients with HIV infection, following combination antiretroviral therapy (cART), the CD4 + T cell reconstitution is slow and could take many years, depending on the CD4 + T cell number prior to initiation of therapy (17)(18)(19). Together, these observations suggest that CD4 + and CD8 + T cell pools are differentially regulated and these characteristics may be exploited by HIV, contributing to the dysregulation of the T cell pools observed in these patients (16,(20)(21)(22)(23)(24).…”

Quantifying the development of the peripheral naive CD4+ T-cell pool in humans

“…Identifying these rules requires a combination of experimental approaches and mathematical models, and will provide an essential background for understanding the dynamics of the T-cell pool when it is dysregulated-for example, during the reconstitution of the T-cell pools after medical interventions that induce lymphopenia, or after antiretroviral therapy in HIV infection. 3 As a step toward answering these questions, here we quantify the contributions of proliferation, loss, and thymic input to the development of the healthy naive T-cell compartment. We focus on naive CD4 ϩ T-cell dynamics in persons up to age 20.…”

CD4 and CD8 T Cell Immune Activation during Chronic HIV Infection: Roles of Homeostasis, HIV, Type I IFN, and IL-7

“…Together these forces contribute to increased proliferation in both CD4 and CD8 T cells (6). Complete CD4 T cell reconstitution after antiretroviral therapy (ART) is a slow process that typically requires many years and depends on the CD4 T cell number prior to therapy (9)(10)(11). In contrast, CD8 T cell numbers are already expanded, and the CD8 T cell pool does not seem to be influenced by the homeostatic forces associated with CD4 T cell depletion (6).…”