Substance abuse, HIV-1 and hepatitis

Abstract

During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.

Fig. (1)

Effects of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) on bone marrow (BM) biology. (A) The steady state within the BM compartment consists of hematopoietic stem cells (HSC), which can differentiate into hematopoietic progenitor cells (HPC). The HPCs can further differentiate into various committed progenitor populations such as committed lymphoid progenitors (CLP) and committed myeloid progenitors (CMP). CMPs can further differentiate into granuloctye-macrophage progenitors (GMPs), which develop into monocytes and erythrocytes. The CLPs can develop into B and T lymphocytes. In addition, dendritic cells, fibroblasts, and mesenchymal stem cells form the BM microenvironment. (B) HIV exerts a global effect on the BM, infecting HPCs, myeloid cells, and stromal cells, leading to an alteration in cytokine profiles within the BM, abnormal hematopoiesis, and growth patterns, and forming a latent reservoir in the HPCs. (C) HBV exerts a selective effect on BM hematopoiesis, wherein progenitor cells committed to the monocyte-macrophage lineage are induced into differentiation; the resultant monocytes and macrophages are induced into proliferating, while progenitors committed to differentiating into granulocytes are inhibited from proliferating. (D) HCV exerts an inhibitory effect on the monocyte-macrophage progenitors, thus hampering the proliferation of monocytes, macrophages, and erythrocytes, resulting in anemia in patients with chronic HCV, accompanied by a decrease in thrombopoietin and cytokine levels, responsible for platelet production.

Fig (2)

Migration of human immunodeficiency virus 1 (HIV-1)-infected cells from the bone marrow (BM) to the central nervous system (CNS). (1) Hematopoietic progenitor cells (HPCs) expressing CD4 and CXCR4/CCR5 can be infected in the BM of HIV-1-infected patients. (2) HIV-1-infected monocytes and macrophages from the bone marrow reseed the peripheral blood (PB). (3) HIV-1-infected cells from the BM that have reseeded the peripheral blood traverse the blood-brain barrier as well as (4) monocytic cells infected within the peripheral blood compartment. These cells have been shown to be more CD14⁺/16⁺ and associated with increased neurological disease. (5) Both monocytic cells that were infected in the BM and cells infected in the peripheral blood contribute to carrying HIV into the CNS, thereby spreading infection to cells found within the CNS such as perivascular macrophages, microglial cells, and astrocytes. Changes in cytokine profiles brought about by HIV-1 infection can also affect the migration of HIV-1-infected cells, thus helping to enhance the progression of HIV-1 infection. In addition, soluble CD163 found within the peripheral blood has been associated with HIV-1-associated neurological disease. BMEC, bone marrow microvascular endothelial cell; CLP, committed lymphoid progenitors; CMP, committed myeloid progenitors; DC, dendritic cells; GMP, granuloctye-macrophage progenitors; HSC, hematopoietic stem cells; MSC, mesenchymal stem cells.

Fig. (3). Effect of human immunodeficiency virus (HIV) on hepatitis pathogenesis

HIV can affect the natural history of hepatitis B virus (HBV) and hepatitis C virus (HCV) pathogenesis. HIV has been identified as a risk factor for increased probability of developing hepatocellular carcinoma (HCC). It leads to accelerated fibrosis and cirrhosis and also to increasing viral load (HBV) and RNA levels (HCV). It is still unclear whether HBV and HCV exert effects on HIV-1 pathogenesis. AIDS, acquired immunodeficiency syndrome.

Fig. (4). Impact of opioids and cocaine on human immunodeficiency virus (HIV) disease

Opioids such as morphine, an agonist for the μ-opioid receptor (MOR-1), have a variety of effects on HIV to exacerbate disease progression including increased replication of HIV-1 and altered cytokine profiles, which can prove to be detrimental to the central nervous system. Morphine can upregulate coreceptor expression levels, have a prosurvival effect on cells, and can act as an inducer of cell proliferation. Cocaine, a sigma₁ receptor agonist, can increase susceptibility of peripheral blood leukocytes to HIV-1, decrease proliferation of neural progenitor cells (NPCs), activate latent HIV-1 infection, and increase cytokine profiles. IL, interleukin; SDF, stromal cell-derived factor; TNF, tumor necrosis factor.