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

cAMP Signaling Enhances HIV-1 Long Terminal Repeat (LTR)-directed Transcription and Viral Replication in Bone Marrow Progenitor Cells.

CD34+ hematopoietic progenitor cells have been shown to be susceptible to HIV-1 infection, possibly due to a low-level expression of CXCR4, a coreceptor for HIV-1 entry. Given these observations, we have explored the impact of forskolin on cell surface expression of CXCR4 in a cell line model (TF-1). The elevation of intracellular cyclic adenosine monophosphate (cAMP) by forskolin through adenylyl cyclase (AC) resulted in transcriptional upregulation of CXCR4 with a concomitant increase in replication of the CXCR4-utilizing HIV-1 strain IIIB. Transient expression analyses also demonstrated an increase in CXCR4-, CCR5-, and CXCR4-/CCR5-utilizing HIV-1 (LAI, YU2, and 89.6, respectively) promoter activity. Studies also implicated the protein kinase A (PKA) pathway and the downstream transcription factor CREB-1 in interfacing with cAMP response elements located in the CXCR4 and viral promoter. These observations suggest that the cAMP signaling pathway may serve as a regulator of CXCR4 levels and concomitantly of HIV-1 replication in bone marrow (BM) progenitor cells. © 2017, © The Author(s) 2017

Leukemia and Retroviral Disease

Two human retroviruses, identified as the human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1), have been shown to affect millions of people worldwide. In the context of coinfection, the impact of their interactions with respect to HTLV-1-induced adult T-cell leukemia and neurologic disease as well as HIV-1 disease progression has been an understudied area of investigation. HTLV-1/HIV-1 coinfections occur frequently, particularly in large metropolitan areas of the Americas, Africa, Europe, and Japan. The retroviruses HTLV-1 and HIV-1 share some similarities with regard to their genetic structure, general mechanisms of replication, modes of transmission, and cellular tropism; however, there are also significant differences in the details of these properties as well, and they also differ significantly with respect to the etiology of their pathogenic and disease outcomes. Both viruses impair the host immune system with HIV-1 demonstrated to cause the hallmark lethal disease known as the acquired immune deficiency syndrome (AIDS), while HTLV-1 infection has been shown to cause several different forms of T-cell leukemia. In addition, both viruses have also been shown to cause a spectrum of neurologic disorders with HIV-1 shown to cause an array of neurologic syndromes referred to as HIV-1-associated neurologic disorders or HAND, while HTLV-1 has been shown to be the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis or HAM/TSP. The natural history of the coinfection, however, is different from that observed in monoinfections. Several studies have demonstrated utilizing a number of in vitro models of HTLV-1/HIV-1 coinfection that the two viruses interact in a manner that results in enhanced expression of both viral genomes. Nevertheless, there remains unresolved controversy regarding the overall impact of each virus on progression of disease caused by both viruses during the course of coinfection. Although combination antiretroviral therapy has been shown to work very effectively with respect to maintaining HIV-1 viral loads in the undetectable range, these therapeutic strategies exhibit no benefit for HTLV-1-infected individuals, unless administered immediately after exposure. Furthermore, the treatment options for HTLV-1/HIV-1-coinfected patients are very limited. In recent years, allogeneic stem cell transplantation (alloSCT) has been used for the treatment of leukemia. In this regard, the case of a leukemic patient positive for HIV-1 who was cured of their HIV-1 infection while treated with alloSCT for acute myeloid leukemia has also been examined with regard to impact on HIV-1 disease

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

Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage

Human immunodeficiency virus type 1 (HIV-1) has been shown to replicate productively in cells of the monocyte-macrophage lineage, although replication occurs to a lesser extent than in infected T cells. As cells of the monocyte-macrophage lineage become differentiated and activated and subsequently travel to a variety of end organs, they become a source of infectious virus and secreted viral proteins and cellular products that likely initiate pathological consequences in a number of organ systems. During this process, alterations in a number of signaling pathways, including the level and functional properties of many cellular transcription factors, alter the course of HIV-1 long terminal repeat (LTR)-directed gene expression. This process ultimately results in events that contribute to the pathogenesis of HIV-1 infection. First, increased transcription leads to the upregulation of infectious virus production, and the increased production of viral proteins (gp120, Tat, Nef, and Vpr), which have additional activities as extracellular proteins. Increased viral production and the presence of toxic proteins lead to enhanced deregulation of cellular functions increasing the production of toxic cellular proteins and metabolites and the resulting organ-specific pathologic consequences such as neuroAIDS. This article reviews the structural and functional features of the cis-acting elements upstream and downstream of the transcriptional start site in the retroviral LTR. It also includes a discussion of the regulation of the retroviral LTR in the monocyte-macrophage lineage during virus infection of the bone marrow, the peripheral blood, the lymphoid tissues, and end organs such as the brain. The impact of genetic variation on LTR-directed transcription during the course of retrovirus disease is also reviewed

Human Immunodeficiency Virus (HIV) Infection and Cancer

Human immunodeficiency virus type 1 (HIV-1) infection confers an increased risk for the development of many cancers. Although the incidences of acquired immunodeficiency syndrome (AIDS)-defining malignancies have declined since the advent of antiretroviral therapy (ART), a number of non-AIDS–defining cancers appear more common in HIV-1–infected individuals relative to the general population. ART-treated HIV-1–infected subjects are also aging, leading to an increased cancer burden in these populations. However, longevity alone is not sufficient to explain these epidemiologic trends. A causative link between HIV-1–induced immune suppression and elevated cancer risk is well defined in certain malignancies; however, the direct role of HIV-1 replication products in oncogenesis remains unclear. Nevertheless, it is evident that cooperation between HIV-1 and co-infecting viruses in targeting immune compartments as well as nonimmune microenvironments can regulate both the development and progression of cancer. Treating cancer in HIV-1–infected patients remains challenging due to drug interactions, compounded side effects and intensified immunosuppression from chemotherapy and/or radiation. While survival of HIV-1–infected patients with certain cancers now rivals that of their uninfected counterparts, a better understanding of HIV-1–induced oncogenesis, viral mechanisms of immune perturbation, nonimmune microenvironmental abnormalities and outcomes of therapy will provide the basis for better diagnosis and management of cancer