Lymphoid Tissue Damage in HIV-1 Infection Depletes Naïve T Cells and Limits T Cell Reconstitution after Antiretroviral Therapy

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.

Author Summary

The hallmark of HIV-1 infection is depletion of CD4 T cells, whose loss leads to the opportunistic infections and cancers characteristic of AIDS. Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but reconstitution particularly of naïve T cells is often incomplete and slow. We show here that fibrosis damages lymphoid tissues (LT), thereby contributing to depletion and incomplete reconstitution. Prior to treatment, chronic immune activation induces 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, naïve cells are depleted prior to initiating HAART because of increased apoptosis, and, even after initiating HAART, the losses continue by this mechanism because of pre-existing LT damage. Thus, LT fibrosis impairs immune reconstitution despite the beneficial effects of HAART in suppressing viral replication. Because less LT damage has accumulated in earlier stages of infection, early initiation of HAART also improves immune reconstitution. This LT damage mechanism also suggests that anti-fibrotic treatment in addition to HAART could further improve immune reconstitution.