HIV-1 Replication and Pathogenesis in the Human Thymus

Abstract

How HIV replicates and causes destruction of the thymus, and how to restore thymic function, are among the most important questions of HIV-1 pathogenesis and therapy in adult as well as pediatric patients. The thymus appears to function, albeit at reduced levels, throughout the life of adults, to respond to T cell depletion induced by HIV and to be suppressed by HIV. In this review, we summarize recent findings concerning HIV replication and pathogenesis in the human thymus, focusing on mechanistic insights gleaned from studies in the SCID-hu Thy/Liv mouse and human fetal-thymus organ culture (HF-TOC) models. First, we discuss HIV viral determinants and host factors involved in the replication of HIV in the thymus. Second, we consider evidence that both viral factors and host factors contribute to HIV-induced thymocyte depletion. We thus propose that multiple mechanisms, including depletion and suppression of progenitor cells, paracrine and direct lytic depletion of thymocytes, and altered thymocyte selection are involved in HIV-induced pathology in the thymus. With the SCID-hu Thy/Liv mouse and HF-TOC models, it will be important in the coming years to further clarify the virological, cell biological, and immunological mechanisms of HIV replication and pathogenesis in human thymus, and to correlate their significance in HIV disease progression.

Fusion-Induced Apoptosis Contributes to Thymocyte Depletion by a Pathogenic Human Immunodeficiency Virus Type 1 Envelope in the Human Thymus

“…From previous studies it is still unclear whether HIV-1 infection in lymphoid organs depletes only infected cells or both infected and uninfected bystander cells (6,30,39,48). Our data suggest that direct depletion of infected thymocytes is clearly involved, as inhibition of HIV-1 infection during its peak levels of replication and depletion halts further thymocyte depletion (Fig.…”

Disseminated and sustained HIV infection in CD34+cord blood cell-transplanted Rag2−/−γc−/−mice

“…2B). Thus, these findings suggest a causative rather than secondary role of CXCR4 virus in accelerated immunodeficiency, possibly in part by destruction of emerging thymocytes (35,37).…”

Acute Thymic Involution and Mechanisms for Recovery

“…Two articles have reviewed the similar morphological events in HIV-induced ATI (Jaïdane et al 2012;Nunes-Alves et al 2013). Several different mechanisms are involved in the HIV-induced ATI, which may cause severe damage to the thymic architecture (including stromal disruption, thymocyte depletion and abnormal maturation or apoptosis of thymocytes) due to host factors or viral load/HIV replication within thymocytes (Meissner et al 2003). Because conducting research investigations on the thymuses of HIV-infected humans (Verinaud et al 2004) is difficult, many animal model systems have been developed.…”