Austin J Clin Pathol. 2014;1(4): 1018.
Susanna L Lamers1* and Michael S Mc Grath2
1Bioinfoexperts LLC, USA
2Department of Pathology and Laboratory Medicine, University of California, USA
*Corresponding author: Susanna L Lamers, Bioinfoexperts, LLC, PO BOX 693, Thibodaux, LA 70301
Received: September 03, 2014; Accepted: September 22, 2014; Published: September 24, 2014
For almost 30 years, plasma viral load and CD4+ T-cell counts have been the primary indicators of human immunodeficiency virus type-1 (HIV-1) disease; however, with access to combined antiretroviral therapy (cART), HIV-infected individuals often maintain low plasma viral loads and adequate CD4+ T-cell counts and still yield to a variety of inflammatory diseases and cancers.HIV- 1 immune-cell cycle data show that in the absence of cART, when the T-cell population begins to fail, a persistently infected macrophage reservoir is important for disease progression. In patients on cART, a much slower process of macrophage infection and activation sustains HIV-1 disease and contributes to life-threatening pathologies. This has encouraged the development of drugs that target the replication of macrophage-tropic viruses and macrophages activated by HIV-1.
Keywords: Macrophages; HIV-1; HIV-related cancers; Vascular disease; Antiretroviral therapy
HIV-1: Human Immunodeficiency Virus; cART: Combined Antiretroviral Therapy; AIDS: Acquired Immune Deficiency Syndrome; ARL: AIDS-Related Lymphoma; KS: Kaposi's Sarcoma; EBV: Epstein Barr Virus; HHV8: Human Herpes Virus 8; HAD: HIV-Associated Dementia; HAND: HIV-Associated Neurological Disease
Acquired Immune Deficiency Syndrome (AIDS) occurs due to infection with HIV-1. Once an individual is infected, HIV-1 invades their immune system, infecting multiple cell types, including T-cells, monocytes, macrophages, Langerhans and dendritic cells . The virus evolves and adapts in multiple tissues, eventually crippling immune defenses and enabling the development of a number of debilitating and fatal diseases . The host's cells are damaged either directly by the virus or by immune responses to the virus. The antiviral immune response depends on the amount of virus present, the tissues infected, and the length of the infection [3,4]. Early in the HIV-1 epidemic, measurements of viral load and T-cell counts showed there were three well-defined stages of HIV-1 infection. The acute stage lasts 2-10 weeks at which time there is a decrease in circulating CD4+ T-cells and an increase in viral load. During the asymptomatic stage, which may last up to10 years, CD4+ T-cell populations return to near normal levels and viral load drops; however, viruses continue to multiply and infect new cells. Even though the virus may appear to be resting in this phase, there is a rapid turnover of infected cells and it is the cellular and humoral immune response that keeps viral loads to a constant level . Furthermore, during this chronic phase, the within-host viral diversity increases . Also, because CD4+ T-cells are a primary target of the virus, their number slowly decreases. During the last stage, AIDS, there is a final increase in viral load, complete collapse of the CD4+ T-cell reservoir and opportunistic infections are common [7,8].
The ability to monitor CD4+ T-cell levels and viral loads contributed immensely to the successful development of cART. However, because a patient's viral load and T-cell count are easily measured with simple laboratory tests; the perception that HIV- 1disease is primarily T-cell driven has been exaggerated. While cART has increased the HIV-infected patient's lifespan, cART does not cure disease or clear the virus permanently from the body. HIV-1-infected patients on so-called "effective cART", wherein viral loads and T-cell levels are controlled, can still succumb to a variety of diseases including cancers, neurological disease, and vascular diseases.
Much research has focused on HIV-1 latency, defined as a state of reversibly nonproductive infection of individual resting T-cells . The presence of the latent T-cell reservoir is said to be responsible for low-level viremia, lifelong persistence of HIV-1, and the "most worrisome" reservoir because of the inability of cART to clear HIV-1 from these cells . While latent T-cells indeed present a significant problem when designing drugs to control infection, other HIV-1 infected cell types are also present in compartments and reservoirs with unknown cART penetration.
Many HIV-1 anatomical reservoirs exist and their role in HIV- 1 persistence varies according to the microenvironment where the virus replicates . HIV has been isolated from genital foreskin , lung , liver , meninges , lymph nodes , spleen , thymus , stomach , brain , and many other tissue sites. Of these tissues, the brain is the most well known compartment. Due to the blood-brain barrier, the brain is not directly targeted by cART. HIV-1 that has entered the brain prior to therapy has the potential to expand and evolve independently from lymphoid tissues. While all tissues share several HIV-1 target immune cells, the brain is unique because it is void of T-cells and the primary immune target cell for HIV-1 is the macrophage.
Macrophages are long-lived reservoirs of HIV-1 in most tissues types [12,18,19]. Un-integrated viral HIV-1 DNA is unusually stable in macrophages and maintains biological activity along with persistent viral gene transcription . Studies show that HIV-1 can be found in macrophages from patients on extended cART therapy [21,22]. During late-stage disease, when CD4+ T cell counts drop to undetectable levels, HIV-1-infected macrophages continue to proliferate and are found at high levels in different tissue types . Circulating monocytes (macrophage precursors) also harbor HIV-1 and are permissive to viral replication after they differentiate into tissue macrophages [24,25]. Macrophages can disturb immune function and metabolism by altering cytokine immune-system signaling responses , increasing cholesterol efflux [27,28], blocking normal immune responses  and inducing tumor-promoting factors .
Abnormal macrophage function is associated with diseases that still concern the HIV-1 cART treated community. For example, a variety of cancers including B-cell lymphoma, Hodgkin's lymphoma, anal, head/neck/oral, liver, lung, testicular cancer and Kaposi's sarcoma (KS) are frequently diagnosed in patients on cART. Some of these cancers are associated with other viral infections, for example AIDS-related lymphoma (ARL) is associated with Epstein Barr Virus (EBV) infection and KS is associated with Human Herpes Virus 8 (HHV8) infection, but there are clearly inflammatory-mediated factors encouraging these cancers beyond EBV and HHV8 infection as nearly half of HIV-1 ARLs do not contain detectable EBV  and the development of KS usually depends upon HIV-induced immune dysfunction . One study found that during ARL, HIV- 1 migrates to metastatic sites within the lymphatic system where it becomes compartmentalized in tumors . Another study found that macrophages form specialize conduits that specifically transfer the HIV-1 nef protein into B-cells , which may underscore the macrophage-cancer association . The HIV-1 Nef protein is an accessory protein that is not required for HIV-1 replication in some cultures systems , but is necessary for HIV-1 replication in vivo and has been associated with a wide range of cellular interactions [35,36].
Compared to the uninfected populations, the HIV-1-infected population has up to twice the risk of developing cardiovascular disease, atherosclerosis, dyslipidemia or insulin resistance [37- 39]. Along with cART side effects, chronic immune activation and inflammation drive these diseases. In particular, macrophages are the primary cell-type associated with atherosclerotic plaque formation. Fitch et al. found that increased monocyte activation was associated with noncalcified coronary plaque in a young, asymptomatic HIV- 1 infected female cohort . Burdo et al. identified that sCD163, a marker for macrophage activation, is increased and associated with noncalcified coronary plaque in men with chronic HIV-1 infection and low or undetectable viremia .
Prior to cART, severe HIV-associated dementia (HAD) was frequently identified in HIV-1 infected individuals. At autopsy, the most strongly associated post-mortem finding associated with HAD was the number of activated macrophages present within affected areas of the brain . Since the introduction of cART, less severe HIV-associated neurological disease, termed HAND, is more prevalent. HAND is associated with a higher risk of developing other AIDS-associated illnesses . The best correlates of central nervous system disease are high viral loads, elevated CD16+ monocytes [44,45] and sCD14, a marker for macrophage activation . Increased numbers of CD16+ monocytes escalates their capacity to migrate across the blood-brain-barrier, infect brain macrophages, and establish a persistent infection . HIV-1 infection in the brain can begin early  and while cART likely reduces the viral burden outside and within the brain compartment, long-lived HIV-infected or activated macrophages in the brain likely cause damage over time through the production of neurotoxic inflammatory mediators [49,50], cytokines [51-53] and the alteration of normal signaling pathways .
The HIV-1 infected macrophage reservoir is emerging as the next major challenge in controlling HIV-1-related pathologies [54,55]. Macrophages possess three different macrophage activation states: 1) M1 is the IFN-γ classically activated macrophage that displays a pro-inflammatory response, 2) M2 is the macrophage activated by IL-4 and IL-13 that displays an anti-inflammatory response and, 3) dM represents a macrophage deactivated by IL-10 which leads to immune suppression . Some advances have been made to modulate macrophages that are alternatively activated due to a chronically pathogenic environment. C-reactive protein may inhibit macrophage transformation to the M2 phenotype . Thioredoxin-1 and adiponectin also promote anti-inflammatory macrophages of the M2 phenotype [57,58]. Macrophage activation inhibitors could include drugs that alter macrophage-signaling pathways and directly treat diseases where infiltrating macrophages contribute to their progression [59,60]. Peroxisome proliferator-activated receptors(PPAR) are ligand-activated factors that that play a role in oxidative stress , control lipid and glucose metabolism , as well as the inflammatory response [63,64]. Targeted inhibition of the enzyme MLK3 has been presented as a strategy to reverse HAND and rebuild synaptic architecture . A novel candidate drug called PA300 was recently described that decreases the number of activated macrophages in the hearts of macaques with cardiac disease . These approaches are being considered because it is clear that even when T-cell levels and viral loads are controlled, many people infected with HIV-1 may develop potentially deadly pathologies that are less common in those uninfected with HIV-1. The ability to modify macrophage activation states has great potential to alter the course of HIV-1 disease in those on cART.
SLL and MSM are funded by The National Institutes of Health #R01MH100984.
- Levy JA. HIV and the Pathogenesis of AIDS. 3rd edn: ASM Press. 2007.
- Levy JA. Mysteries of HIV: challenges for therapy and prevention. Nature. 1988; 333: 519-522.
- Trkola A, Kuster H, Leemann C, Oxenius A, Fagard C, Furrer H, et al. Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection reflects capacity of immune system to improve viral set point. Blood. 2004; 104: 1784-1792.
- Hadjiandreou M, Conejeros R, Vassiliadis VS. Towards a long-term model construction for the dynamic simulation of HIV infection. Math Biosci Eng. 2007; 4: 489-504.
- Ding L, Yang CY, Xu WJ. [Effect of removable partial denture(RDP) generated occlusal interference on masticatory efficiency-A preliminary study] Shanghai Kou Qiang Yi Xue. 1999; 8: 86-88.
- Brashear A, Mulholland GK, Zheng QH, Farlow MR, Siemers ER, Hutchins GD, et al. PET imaging of the pre-synaptic dopamine uptake sites in rapid-onset dystonia-parkinsonism (RDP). Mov Disord. 1999; 14: 132-137.
- Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Annu Rev Pathol. 2011; 6: 223-248.
- Buggert M, Norström MM, Czarnecki C, Tupin E, Luo M, Gyllensten K, et al. Characterization of HIV-specific CD4+ T cell responses against peptides selected with broad population and pathogen coverage. PLoS One. 2012; 7: e39874.
- Siliciano JD, Siliciano RF. HIV-1 eradication strategies: design and assessment. Curr Opin HIV AIDS. 2013; 8: 318-325.
- Pierson T, McArthur J, Siliciano RF. Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy. Annu Rev Immunol. 2000; 18: 665-708.
- Svicher V, Ceccherini-Silberstein F, Antinori A, Aquaro S, Perno CF. Understanding HIV compartments and reservoirs. Curr HIV/AIDS Rep. 2014; 11: 186-194.
- Galiwango RM, Lamers SL, Redd AD, Manucci J, Tobian AA, Sewankambo N, et al. HIV type 1 genetic variation in foreskin and blood from subjects in Rakai, Uganda. AIDS Res Hum Retroviruses. 2012; 28: 729-733.
- Costiniuk CT, Jenabian MA. The lungs as anatomical reservoirs of HIV infection. Rev Med Virol. 2014; 24: 35-54.
- Salemi M, Lamers SL, Huysentruyt LC, Galligan D, Gray RR, Morris A, et al. Distinct patterns of HIV-1 evolution within metastatic tissues in patients with non-Hodgkins lymphoma. PLoS One. 2009; 4: e8153.
- Lamers SL, Gray RR, Salemi M, Huysentruyt LC, McGrath MS. HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues. Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2011; 11: 31-37.
- Salemi M, Burkhardt BR, Gray RR, Ghaffari G, Sleasman JW, Goodenow MM, et al. Phylodynamics of HIV-1 in lymphoid and non-lymphoid tissues reveals a central role for the thymus in emergence of CXCR4-using quasispecies. PLoS One. 2007; 2: e950.
- Salemi M, Lamers SL, Yu S, de Oliveira T, Fitch WM, McGrath MS, et al. Phylodynamic analysis of human immunodeficiency virus type 1 in distinct brain compartments provides a model for the neuropathogenesis of AIDS. J Virol. 2005; 79: 11343-11352.
- Churchill M, Nath A. Where does HIV hide? A focus on the central nervous system. Current opinion in HIV and AIDS. 2013; 8: 165-169.
- Wu L. The role of monocyte-lineage cells in human immunodeficiency virus persistence: mechanisms and progress. Wei Sheng Wu Yu Gan Ran. 2011; 6: 129-132.
- Kelly J, Beddall MH, Yu D, Iyer SR, Marsh JW, Wu Y. Human macrophages support persistent transcription from unintegrated HIV-1 DNA. Virology. 2008; 372: 300-312.
- Lambotte O, Taoufik Y, de Goër MG, Wallon C, Goujard C, Delfraissy JF, et al. Detection of infectious HIV in circulating monocytes from patients on prolonged highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2000; 23: 114-119.
- Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S. Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. J Virol. 2002; 76: 707-716.
- Lamers SL, Salemi M, Galligan DC, de Oliveira T, Fogel GB, Granier SC, et al. Extensive HIV-1 intra-host recombination is common in tissues with abnormal histopathology. PLoS One. 2009; 4: e5065.
- Almodóvar S, Del C Colón M, Maldonado IM, Villafañe R, Abreu S, Meléndez I, et al. HIV-1 infection of monocytes is directly related to the success of HAART. Virology. 2007; 369: 35-46.
- Valcour VG, Shiramizu BT, Shikuma CM. HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications. J Leukoc Biol. 2010; 87: 621-626.
- Herbein G, Varin A. The macrophage in HIV-1 infection: from activation to deactivation? Retrovirology. 2010; 7: 33.
- Mujawar Z, Rose H, Morrow MP, Pushkarsky T, Dubrovsky L, Mukhamedova N, et al. Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol. 2006; 4: e365.
- Crowe SM, Westhorpe CL, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M, et al. The macrophage: the intersection between HIV infection and atherosclerosis. J Leukoc Biol. 2010; 87: 589-598.
- Tsang J, Chain BM, Miller RF, Webb BL, Barclay W, Towers GJ. HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation. AIDS. 2009; 23: 2255-2263.
- Huysentruyt LC, McGrath MS. The role of macrophages in the development and progression of AIDS-related non-Hodgkin lymphoma. J Leukoc Biol. 2010; 87: 627-632.
- Jessop S. HIV-associated Kaposi's sarcoma. Dermatol Clin. 2006; 24: 509-520, vii.
- Xu W, Santini PA, Sullivan JS, He B, Shan M, Ball SC, et al. HIV-1 evades virus-specific IgG2 and IgA responses by targeting systemic and intestinal B cells via long-range intercellular conduits. Nat Immunol. 2009; 10: 1008-1017.
- Lamers SL, Fogel GB, Huysentruyt LC, McGrath MS. HIV-1 nef protein visits B-cells via macrophage nanotubes: a mechanism for AIDS-related lymphoma pathogenesis? Curr HIV Res. 2010; 8: 638-640.
- Ryan-Graham MA, Peden KW. Both virus and host components are important for the manifestation of a Nef- phenotype in HIV-1 and HIV-2. Virology. 1995; 213: 158-168.
- Lamers SL, Fogel GB, Singer EJ, Salemi M, Nolan DJ, Huysentruyt LC. HIV-1 Nef in macrophage-mediated disease pathogenesis. Int Rev Immunol. 2012; 31: 432-450.
- Azad AA. Could Nef and Vpr proteins contribute to disease progression by promoting depletion of bystander cells and prolonged survival of HIV-infected cells? Biochem Biophys Res Commun. 2000; 267: 677-685.
- Klein D, Hurley LB, Quesenberry CP Jr, Sidney S. Do protease inhibitors increase the risk for coronary heart disease in patients with HIV-1 infection? J Acquir Immune Defic Syndr. 2002; 30: 471-477.
- Currier JS, Lundgren JD, Carr A, Klein D, Sabin CA, Sax PE. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation. 2008; 118: e29-35.
- Hsue PY, Hunt PW, Schnell A, Kalapus SC, Hoh R, Ganz P, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS. 2009; 23: 1059-1067.
- Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013; 208: 1737-1746.
- Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011; 204: 1227-1236.
- Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995; 38: 755-762.
- Vivithanaporn P, Heo G, Gamble J, Krentz HB, Hoke A, Gill MJ. Neurologic disease burden in treated HIV/AIDS predicts survival: a population-based study. Neurology. 2010; 75: 1150-1158.
- Pulliam L, Gascon R, Stubblebine M, McGuire D, McGrath MS. Unique monocyte subset in patients with AIDS dementia. Lancet. 1997; 349: 692-695.
- Williams K, Westmoreland S, Greco J, Ratai E, Lentz M, Kim WK, et al. Magnetic resonance spectroscopy reveals that activated monocytes contribute to neuronal injury in SIV neuroAIDS. J Clin Invest. 2005; 115: 2534-2545.
- Lyons JL, Uno H, Ancuta P, Kamat A, Moore DJ, Singer EJ. Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr. 2011; 57: 371-379.
- Williams DW, Eugenin EA, Calderon TM, Berman JW. Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol. 2012; 91: 401-415.
- Strickland SL, Rife BD, Lamers SL, Nolan DJ, Veras NM, Prosperi MC, et al. Spatiotemporal Dynamics of SIV Brain Infection in CD8+ Lymphocyte-Depleted Rhesus Macaques with NeuroAIDS. J Gen Virol. 2014; .
- Xiong H, Zeng YC, Zheng J, Thylin M, Gendelman HE. Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: a mechanism for cognitive dysfunction in HIV-1-associated dementia. Journal of neurovirology. 1999; 5: 519-528.
- Meisner F, Neuen-Jacob E, Sopper S, Schmidt M, Schlammes S, Scheller C, et al. Disruption of excitatory amino acid transporters in brains of SIV-infected rhesus macaques is associated with microglia activation. J Neurochem. 2008; 104: 202-209.
- Yao H, Bethel-Brown C, Li CZ, Buch SJ. HIV neuropathogenesis: a tight rope walk of innate immunity. J Neuroimmune Pharmacol. 2010; 5: 489-495.
- Sui Y, Stehno-Bittel L, Li S, Loganathan R, Dhillon NK, Pinson D, et al. CXCL10-induced cell death in neurons: role of calcium dysregulation. Eur J Neurosci. 2006; 23: 957-964.
- Rostasy K, Monti L, Yiannoutsos C, Kneissl M, Bell J, Kemper TL. Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol. 1999; 46: 207-216.
- Rappaport J. Editorial: The Monocyte/Macrophage in the Pathogenesis of AIDS: The Next Frontier for Therapeutic Intervention in the CNS and Beyond: Part I. Current HIV research. 2014; 12: 75-76.
- Lamers SL, Fogel GB, Nolan DJ, McGrath MS, Salemi M. HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy. Biosystems. 2014; 119: 53-61.
- Devaraj S, Jialal I. C-reactive protein polarizes human macrophages to an M1 phenotype and inhibits transformation to the M2 phenotype. Arteriosclerosis, thrombosis, and vascular biology. 2011; 31: 1397-1402.
- El Hadri K, Mahmood DF, Couchie D, Jguirim-Souissi I, Genze F, Diderot V, et al. Thioredoxin-1 promotes anti-inflammatory macrophages of the M2 phenotype and antagonizes atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2012; 32: 1445-1452.
- Lovren F, Pan Y, Quan A, Szmitko PE, Singh KK, Shukla PC, et al. Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages. Am J Physiol Heart Circ Physiol. 2010; 299: H656-663.
- Pixley FJ. Macrophage Migration and Its Regulation by CSF-1. Int J Cell Biol. 2012; 2012: 501962.
- Mouchemore KA, Pixley FJ. CSF-1 signaling in macrophages: pleiotrophy through phosphotyrosine-based signaling pathways. Critical reviews in clinical laboratory sciences. 2012; 49: 49-61.
- Huang W, Andras IE, Rha GB, Hennig B, Toborek M. PPARalpha and PPARgamma protect against HIV-1-induced MMP-9 overexpression via caveolae-associated ERK and Akt signaling. FASEB J. 2011; 25: 3979-3988.
- Raulin J. Human immunodeficiency virus and host cell lipids. Interesting pathways in research for a new HIV therapy. Prog Lipid Res. 2002; 41: 27-65.
- Bouhlel MA, Staels B, Chinetti-Gbaguidi G. Peroxisome proliferator-activated receptors--from active regulators of macrophage biology to pharmacological targets in the treatment of cardiovascular disease. J Intern Med. 2008; 263: 28-42.
- Kamin D, Hadigan C, Lehrke M, Mazza S, Lazar MA, Grinspoon S, et al. Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone. J Clin Endocrinol Metab. 2005; 90: 3423-3426.
- Gelbard HA, Dewhurst S, Maggirwar SB, Kiebala M, Polesskaya O, Gendelman HE. Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: a therapeutic strategy based on modulation of mixed lineage kinase. Neurotherapeutics. 2010; 7: 392-398.
- Walker J, Burdo T, Miller A, Misgin K, Sulciner M, McGrath M, et al. Macrophages in Hearts of SIV+ Rhesus Macaques with Cardiac Disease Are Decreased Using PA300. Conference on Retroviruses and Opportunistic Infection, Atlanta, GA. 2013.