AV-HALT

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AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) are an investigational class of antiretroviral drugs used to treat Human Immunodeficiency Virus (HIV) infection. Unlike other antiretroviral agents given to reduce viral replication, AV-HALTs are single or combination drugs designed to reduce the rate of viral replication while, at the same time, also directly reducing the state of immune system hyperactivation now believed to drive the loss of CD4+ T helper cells leading to disease progression and Acquired Immunodeficiency Syndrome (AIDS).

Contents

Mechanism

Chronic immune stimulation due to persistent HIV replication and microbial translocation across impaired gut-associated lymphoid tissues (GALT) induces continuous T-cell activation and proliferation of both HIV-infected and bystander cells, ultimately resulting in the exhaustion of the immune system. [1] [2] [3] [4] [5] [6]

There is a growing recognition that successful long-term therapy for the treatment of HIV infection should not only reduce viral replication, but also limit the hyper-activation of the immune system now proposed as the cause of the eventual progression to AIDS. [7] [8] [9] [10] AV-HALTs are designed to accomplish two goals – the reduction of viral load (decreased viral load) and the reduction of immune system hyperactivation (decreased markers of cellular activation and proliferation). First generation AV-HALTs accomplish this by combining an antiviral drug (e.g. didanosine) with a cytostatic agent (e.g. hydroxyurea). [11]

Examples

Synonyms

Related Research Articles

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The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

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<i>Simian immunodeficiency virus</i> Species of retrovirus

Simian immunodeficiency virus (SIV) is a species of retrovirus that cause persistent infections in at least 45 species of non-human primates. Based on analysis of strains found in four species of monkeys from Bioko Island, which was isolated from the mainland by rising sea levels about 11,000 years ago, it has been concluded that SIV has been present in monkeys and apes for at least 32,000 years, and probably much longer.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to the point of needing to take medication in order not to develop AIDS.

HIV-associated neurocognitive disorders (HAND) are neurological disorders associated with HIV infection and AIDS. It is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe. HAND may include neurological disorders of various severity. HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia. These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. The essential features of HIV-associated dementia (HAD) are disabling cognitive impairment accompanied by motor dysfunction, speech problems and behavioral change. Cognitive impairment is characterised by mental slowness, trouble with memory and poor concentration. Motor symptoms include a loss of fine motor control leading to clumsiness, poor balance and tremors. Behavioral changes may include apathy, lethargy and diminished emotional responses and spontaneity. Histopathologically, it is identified by the infiltration of monocytes and macrophages into the central nervous system (CNS), gliosis, pallor of myelin sheaths, abnormalities of dendritic processes and neuronal loss.

<span class="mw-page-title-main">HIV/AIDS</span> Spectrum of conditions caused by HIV infection

Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual may not notice any symptoms, or may experience a brief period of influenza-like illness. Typically, this is followed by a prolonged incubation period with no symptoms. If the infection progresses, it interferes more with the immune system, increasing the risk of developing common infections such as tuberculosis, as well as other opportunistic infections, and tumors which are rare in people who have normal immune function. These late symptoms of infection are referred to as acquired immunodeficiency syndrome (AIDS). This stage is often also associated with unintended weight loss.

HIV superinfection is a condition in which a person with an established human immunodeficiency virus infection acquires a second strain of HIV, often of a different subtype. These can form a recombinant strain that co-exists with the strain from the initial infection, as well from reinfection with a new virus strain, and may cause more rapid disease progression or carry multiple resistances to certain HIV medications.

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Long-term nonprogressors (LTNPs), sometimes also called elite controllers, are individuals infected with HIV, who maintain a CD4 count greater than 500 without antiretroviral therapy with a detectable viral load. Many of these patients have been HIV positive for 30 years without progressing to the point of needing to take medication in order not to develop AIDS. They have been the subject of a great deal of research, since an understanding of their ability to control HIV infection may lead to the development of immune therapies or a therapeutic vaccine. The classification "Long-term non-progressor" is not permanent, because some patients in this category have gone on to develop AIDS.

<span class="mw-page-title-main">HIV disease–related drug reaction</span>

HIV disease–related drug reaction is an adverse drug reaction caused by drugs used for the treatment of HIV/AIDS.

Stuart C. Ray is an American physician. He is Vice Chair of Medicine for Data Integrity and Analytics, Associate Director of the Infectious Diseases Fellowship Training Program at the Johns Hopkins School of Medicine, and a Professor in the Department of Medicine, Division of Infectious Diseases. Ray also holds appointments in Viral Oncology and the Division of Health Sciences Informatics. He is affiliated with the Institute for Computational Medicine at Johns Hopkins and is licensed to practice medicine in Maryland.

<span class="mw-page-title-main">Pathophysiology of HIV/AIDS</span>

HIV is commonly transmitted via unprotected sexual activity, blood transfusions, hypodermic needles, and from mother to child. Upon acquisition of the virus, the virus replicates inside and kills T helper cells, which are required for almost all adaptive immune responses. There is an initial period of influenza-like illness, and then a latent, asymptomatic phase. When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS, a condition characterized by deficiency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer.

<span class="mw-page-title-main">Signs and symptoms of HIV/AIDS</span>

The stages of HIV infection are acute infection, latency, and AIDS. Acute infection lasts for several weeks and may include symptoms such as fever, swollen lymph nodes, inflammation of the throat, rash, muscle pain, malaise, and mouth and esophageal sores. The latency stage involves few or no symptoms and can last anywhere from two weeks to twenty years or more, depending on the individual. AIDS, the final stage of HIV infection, is defined by low CD4+ T cell counts, various opportunistic infections, cancers, and other conditions.

The Berlin patient is an anonymous person from Berlin, Germany, who was described in 1998 as exhibiting prolonged "post-treatment control" of HIV viral load after HIV treatments were interrupted.

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<span class="mw-page-title-main">Sharon Lewin</span>

Sharon Ruth Lewin, FRACP, FAHMS is the inaugural Director of The Peter Doherty Institute for Infection and Immunity. She is also a Professor of Medicine at The University of Melbourne, a National Health and Medical Research Council (NHMRC) Practitioner Fellow, Director of the Cumming Global Centre for Pandemic Therapeutics, and President of the International AIDS Society (IAS).

References

  1. ↑ Ameisen, J. C.; Capron, A (1991). "Cell dysfunction and depletion in AIDS: The programmed cell death hypothesis". Immunology Today. 12 (4): 102–5. doi:10.1016/0167-5699(91)90092-8. PMID   1676268.
  2. ↑ McCune, J. M. (2001). "The dynamics of CD4+ T-cell depletion in HIV disease". Nature. 410 (6831): 974–9. Bibcode:2001Natur.410..974M. doi:10.1038/35073648. PMID   11309627. S2CID   4419786.
  3. ↑ Meyaard, L.; Otto, S. A.; Keet, I. P.; Roos, M. T.; Miedema, F. (1994). "Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease". Journal of Clinical Investigation. 93 (3): 982–988. doi:10.1172/JCI117105. PMC   294014 . PMID   8132784.
  4. ↑ Grossman, Z; Paul, W. E. (2000). "The impact of HIV on naïve T-cell homeostasis". Nature Medicine. 6 (9): 976–7. doi:10.1038/79667. PMID   10973313. S2CID   21350300.
  5. ↑ Hellerstein, M. K.; Hoh, R. A.; Hanley, M. B.; Cesar, D; Lee, D; Neese, R. A.; McCune, J. M. (2003). "Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection". Journal of Clinical Investigation. 112 (6): 956–66. doi:10.1172/JCI17533. PMC   193663 . PMID   12975480.
  6. ↑ Finkel, T. H.; Tudor-Williams, G; Banda, N. K.; Cotton, M. F.; Curiel, T; Monks, C; Baba, T. W.; Ruprecht, R. M.; Kupfer, A (1995). "Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes". Nature Medicine. 1 (2): 129–34. doi:10.1038/nm0295-129. PMID   7585008. S2CID   37444589.
  7. ↑ Brenchley, J. M.; Price, D. A.; Schacker, T. W.; Asher, T. E.; Silvestri, G; Rao, S; Kazzaz, Z; Bornstein, E; Lambotte, O; Altmann, D; Blazar, B. R.; Rodriguez, B; Teixeira-Johnson, L; Landay, A; Martin, J. N.; Hecht, F. M.; Picker, L. J.; Lederman, M. M.; Deeks, S. G.; Douek, D. C. (2006). "Microbial translocation is a cause of systemic immune activation in chronic HIV infection". Nature Medicine. 12 (12): 1365–71. doi:10.1038/nm1511. PMC   1717013 . PMID   17115046.
  8. ↑ Douek, D. C. (2003). "Disrupting T-cell homeostasis: How HIV-1 infection causes disease". AIDS Reviews. 5 (3): 172–7. PMID   14598566.
  9. ↑ Hunt, P. W.; Martin, J. N.; Sinclair, E; Bredt, B; Hagos, E; Lampiris, H; Deeks, S. G. (2003). "T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy". The Journal of Infectious Diseases. 187 (10): 1534–43. doi: 10.1086/374786 . PMID   12721933.
  10. ↑ Kaufmann, G. R.; Perrin, L; Pantaleo, G; Opravil, M; Furrer, H; Telenti, A; Hirschel, B; Ledergerber, B; Vernazza, P; Bernasconi, E; Rickenbach, M; Egger, M; Battegay, M; Swiss HIV Cohort Study Group (2003). "CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: The Swiss HIV Cohort Study". Archives of Internal Medicine. 163 (18): 2187–95. doi:10.1001/archinte.163.18.2187. PMID   14557216.
  11. ↑ Lori, F.; Foli, A.; Groff, A.; Lova, L.; Whitman, L.; Bakare, N.; Pollard, R.; Lisziewicz, J. (2005). "Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms". AIDS. 19 (11): 1173–1181. doi: 10.1097/01.aids.0000176217.02743.d1 . PMID   15990570. S2CID   25239001.
  12. 1 2 "Research and Development". ViroStatics. Archived from the original on 2011-07-17. Retrieved 2011-09-22.
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