Abstract
Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution.
Highlights
The hallmark of HIV-1 infection, depletion of CD4+ T cells, has been largely attributed to direct mechanisms of infection and cell death from viral replication or killing by virus-specific cytotoxic Tlymphocytes (CTLs), and to indirect mechanisms such as increased apoptosis accompanying chronic immune activation associated with HIV-1 infections [1]
Chronic immune activation induces lymphoid tissues (LT) fibrosis to disrupt the fibroblastic reticular cell (FRC) network, the major source of the T cell survival factor interleukin 7 (IL-7). Fibrosis in this way interferes with the access of T cells to IL-7 ‘‘posted’’ on the FRC network
Without a source and access to IL-7, naıve cells are depleted prior to initiating Highly active antiretroviral therapy (HAART) because of increased apoptosis, and, even after initiating HAART, the losses continue by this mechanism because of preexisting LT damage
Summary
The hallmark of HIV-1 infection, depletion of CD4+ T cells, has been largely attributed to direct mechanisms of infection and cell death from viral replication or killing by virus-specific cytotoxic Tlymphocytes (CTLs), and to indirect mechanisms such as increased apoptosis accompanying chronic immune activation associated with HIV-1 infections [1]. It is puzzling that if these were the sole mechanisms responsible for CD4+ T cell depletion, why 20% of HIV-1 infected patients have no significant increase in their peripheral blood CD4 count after initiation of HAART, since treatment can suppress viral replication to undetectable levels and normalize much of the chronic immune activation associated with infection [2,3]. Cumulative observations suggest that there may be additional mechanisms that impair the survival of naıve T cells, thereby restricting immune reconstitution [1,3]
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