HIV-1 Infection of Bone Marrow Hematopoietic Progenitor Cells and Their Role in Trafficking and Viral Dissemination

Patients with HIV-1 often present with a wide range of hematopoietic abnormalities, some of which may be due to the presence of opportunistic infections and to therapeutic drug treatments. However, many of these abnormalities are directly related to HIV-1 replication in the bone marrow (BM). Although the most primitive hematopoietic progenitor cells (HPCs) are resistant to HIV-1 infection, once these cells begin to differentiate and become committed HPCs they become increasingly susceptible to HIV-1 infection and permissive to viral gene expression and infectious virus production. Trafficking of BM-derived HIV-1-infected monocytes has been shown to be involved in the dissemination of HIV-1 into the central nervous system (CNS), and it is possible that HIV-1 replication in the BM and infection of BM HPCs may be involved in the early steps leading to the development of HIV-1-associated dementia (HAD) as an end result of this cellular trafficking process. In addition, the growth and development of HPCs in the BM of patients with HIV-1 has also been shown to be impaired due to the presence of HIV-1 proteins and changes in the cytokine milieu, potentially leading to an altered maturation process and to increased cell death within one or more BM cell lineages. Changes in the growth and differentiation process of HPCs may be involved in the generation of monocyte populations that are more susceptible and/or permissive to HIV-1, and have potentially altered trafficking profiles to several organs, including the CNS. A monocyte subpopulation with these features has been shown to expand during the course of HIV-1 disease, particularly in HAD patients, and is characterized by low CD14 expression and the presence of cell surface CD16

Functional Studies of CCAAT/Enhancer Binding Protein Site Located Downstream of the Transcriptional Start Site.

Previous studies have identified a CCAAT/enhancer binding protein (C/EBP) site located downstream of the transcriptional start site (DS3). The role of the DS3 element with respect to HIV-1 transactivation by Tat and viral replication has not been characterized. We have demonstrated that DS3 was a functional C/EBPβ binding site and mutation of this site to the C/EBP knockout DS3-9C variant showed lower HIV-1 long terminal repeat (LTR) transactivation by C/EBPβ. However, it was able to exhibit similar or even higher transcription levels by Tat compared to the parental LTR. C/EBPβ and Tat together further enhanced the transcription level of the parental LAI-LTR and DS3-9C LTR, with higher levels in the DS3-9C LTR. HIV molecular clone viruses carrying the DS3-9C variant LTR demonstrated a decreased replication capacity and delayed rate of replication. These results suggest that DS3 plays a role in virus transcriptional initiation and provides new insight into C/EBP regulation of HIV-1

Trafficking of HIV-1-Infected Cells from the BM to the CNS.

<p>Monocytes infected in the BM with HIV-1 either as HPCs or as commited monocyte progenitors emigrate from the BM into the blood, and through the blood circulation reach the capillary vessels of the brain, where they may cross the blood–brain barrier and migrate into the CNS. Following entry into the CNS, monocytes differentiate into perivascular macrophages, which has been shown to typically lead to upregulation of viral protein production, release of virions, and infection of resident cells of the CNS.</p

Cells of the BM Susceptible to HIV-1 Infection.

<p>The cellular components of the BM include HPCs at all stages of differentiation, megakaryocytes, fibroblasts, endothelial cells, adipocytes, macrophages, osteoblasts, osteoclasts, and MSCs, while DCs, T cells, and B cells may also migrate from the blood into the BM. A black arrow indicates the differentiation process from one cell type to another. A dashed black line indicates that one or more intermediate cell types have been omitted from the respective differentiation process. A red line points to cells that are known to be infected by HIV-1. A dashed red line points to cells that have been shown to be infected by HIV-1, but the extent of their infection and their role in HIV-1 pathogenesis is questionable.</p

Mechanism of HIV-1-Induced Myelosuppression.

<p>Several mechanisms may be involved in HIV-1-induced impairment of hematopoiesis. (A) HPCs may be infected by HIV-1. (B) The interaction of HIV-1 proteins with HPCs may have a direct effect on hematopoiesis. (C) HIV-1 may indirectly affect HPCs by interacting and/or infecting BM stromal cell populations, making them unable to support normal HPC functions. (D) HIV-1 replication in the BM may lead to changes in the cytokine milieu, which may in turn profoundly impact HPC function.</p