HIV Disease: Mechanisms of Neuropathy and Dementia - Essay Example

Introduction HIV is an abbreviation for human immunodeficiency virus which causes acquired immunodeficiency syndrome (AIDS). It is widely accepted that HIV is a zoonotic virus which involved transfer of a simian immunodeficiency virus from animal to human. The HIV type 2 is almost identical to a simian immunodeficiency virus which is found among sooty mangabey monkeys. The HIV virus is thus thought to have an origin in non human primates in sub Saharan Africa. It is believed to have been transferred to humans in either late 19th century or early 20th century [Cherry, et al, 20]. AIDS first received attention in 1981 when several deaths among young people were reported in New York City, San Francisco and Los Angeles. The young people were reported to die from pneumocystis jirovecii and Kaposi sarcoma. Prior to these pneumocystis was found to affect immunocompromised individuals. A report published by Morbidity and Mortality Weekly Report in 1982 summarizing these cases elicited publication of other reports in France, Central America and the Caribbean. The disease was first referred to as gay cancer and later called gay related immune deficiency in America because it was first exhibited among homosexual men. In Africa the disease was referred to as slim because it was associated with massive weight loss and diarrhea. Pediatric immunologists reported at almost the same time unexplained immune problems among young infants [Ferrarese, et al, 675]. According to Howard, et al 9, two separate research groups under the leadership of Luc Montagnier and Robert Gallo published findings that a retrovirus could have been infecting AIDS patients. The two publications appeared in journal Science in 1983. Gallo’s group named its newly isolated virus HTLV-III because it had similar characteristics to human T-lymphotropic viruses. Montagnier group named their isolate lymphadenopathy associated virus since it was isolated from individuals presenting with physical illness and lymphadenopathy of the neck. Due to controversies surrounding the naming of the virus which was later found to be similar, HIV was chosen avoid the controversies [Stone, Price and French, 585]. Since the recognition of HIV in 1981, it is estimated that over 25 million people have been killed by this virus. An estimated 2.8 million people were killed by AIDS in 2005 with a half a million being children. An estimated 36.1 million people were believed to be living with HIV in 2007 with 2.1 people succumbing to deaths from the disease in the same year. About 2.5 million new HIV infections occurred in the same year [McGuire and Marder, 255]. The worst affected region by the disease is sub Saharan Africa which has an estimated 27.4 million persons living with HIV currently accounting for more than 64% of all people infected with the virus world wide. Of this, about two million are believed to be children. About 15% of the people living with HIV are found in the South and East Asia. Currently South Africa tops the list of countries with highest number of HIV infected patients followed by Nigeria. Sudan has the lowest cases of HIV in sub Saharan Africa. Deaths resulting from HIV/AIDS have reduced as a result of use of highly active antiretroviral therapy (HAART) and at the same time increased rates of infection due to increased life expectancy of HIV infected patients. This paper describes the biology of HIV, its pathogenesis and diagnosis [Fiala, 90]. The biology of HIV HIV structure HIV has a rough spherical structure of about 120 nm in diameter. The virus has two copies of RNA which are positive single stranded. The RNA codes for nine genes. The RNA is enclosed in a capsid that is conical shaped. The capsid has 2000 of viral coded protein p24. The RNA strands are bound tightly to the nucleocapsid proteins, p7. The virus requires several enzymes for its development. These include reverse transcriptase, proteases, and integrase. For the purposes of the integrity of the capsid, the capsid is surrounded by a matrix made up of viral protein p17. The viral envelop surrounds this matrix [Cherry, et al, 18]. The envelop is composed of two layers of phospholipids which originate from the human cell membrane. The envelop has proteins taken from host cell embedded in it in addition to approximately 70 copies of HIV protein which transverses the envelop to its surface [Stone, Price and French, 579]. This HIV protein is referred to as Env and is made up of glycoprotein (gp) 41 which make up the stem of the protein and gp120 making up the cap of the Env protein. The two glycoproteins are usually in groups of three. The gp41 anchors the Env protein into the viral envelop while the gp120 protrudes through the envelop surface. The Env protein is essential for viral attachment and fusion with target cells for initiation of infectious cycle [Latov, et al, 258]. The diagram below illustrates the structure of HIV virus. Viral genome structure As noted from Melli 1338, HIV genome consists of various structural genes and non structural genes. The physical infrastructure of HIV virus is provided by gag (group specific antigen) gene while the basic mechanism of replication is provided by the pol gene. Other genes assist the HIV virus to enter the cell and are involved in enhancing replication. Transcription and translation of gag gene results in gag protein that is processed to yield capsid protein, p24; matrix protein, p17; nucleocapsid protein, p7; spacer peptide 1, p2 and spacer peptide 2, p1 in addition to p6. On the other hand pol gene is involved in the production of three enzymes involved in the replication process of the virus [McGuire and Marder, 268]. They include integrase, reverse transcriptase and HIV protease enzymes. Another HIV gene called env codes for glycoprotein (gp) 160. The gp160 is then processed to yield gp 120 and gp 41which are proteins which are embedded in the envelop of the HIV virus. The virus has other genes involved in transactivation [Brew, 5]. They include tat, rev and vpr. The vpr gene codes viral protein R. this protein regulates the nuclear importation of the HIV 1 pre-integration complex. In addition, the protein is essential for HIV viral replication in cells which are not undergoing cell division [Cherry, et al, 18]. The protein is also immunosuppressive. The rev (regulatory of virion) gene produces a protein enables HIV mRNA fragments containing Rev Response elements to be exported to the cytoplasm from the nucleus. The protein prevents host RNA splicing machinery to splice the viral mRNA fragments. The tat (trans-activator of transcription) gene produces a protein that increases transcription levels of dsRNA of the HIV virus [McGuire and Marder, 265]. From Cutler 628, the HIV virus has genes which produce proteins that are involved in regulatory purposes. They include vif, nef and vpu genes. Vif (viral infectivity factor) is a gene which produces a protein that disrupts the antiviral activity of the human enzyme called APOBEC. The protein targets the APOBEC for cellular degradation and ubiquitination. Thus vif protein is essential for the replication of HIV virus as it inhibits the APOBEC when the virus buds from the host cell. Nef (negative regulatory factor) gene produces nef protein that is involved in the manipulation of the cellular machinery of the host to allow infection to take place in addition to allowing replication or survival of the virus. Nef protein activates T cell and allows persistent state of infection. The protein also down modulates the expression of MHC I and MHC II thus enhancing the survival of HIV virus. Vpu (viral protein U) gene produces vpu protein which enhances the release of the virus via counteraction of BST2. Tev gene is a fusion of parts of rev, tat and env genes. It codes for a protein whose properties resemble those of tat but with no or little properties of rev. long terminal repeats (LTR) is a structural gene that flanks functional genes of HIV virus. It is made up of repeating sequences of RNA. They are essential during integration of the viral genome into the host genome. The diagram below shows the genome of HIV virus. Viral replication a) Virion attachment and entry The HIV virus target cells are macrophages and CD4+ T-cells. The virus adsorbs to the host cell receptors using its glycoprotein that are found on the surface of the viral envelope. This involves interaction of trimeric gp120 and gp41 complex with both CD4 and a chemokine receptor [Jacques, 90]. The chemokine receptor may be CXCR4 or CCR5. The chemokine receptors act as co-receptors of for viral glycoprotein. The Adsorption is followed by fusion between the host cell membrane and the viral envelope. The fusion is then followed by the release of the viral capsid into the host cell. The gp 160 complex has binding sites for both CD4 and chemokine receptors. b) Fusion and Penetration Fusion first involves attachment of gp 120 to CD4. This makes the viral envelope to undergo conformational changes that exposes the domains on the gp 120 where the chemokine binds. The exposure of the domain allows the active site to interact with chemokine receptors. Thus a two pronged attachment that is stable to be formed. This enables the N-terminal of the gp 41 fusion peptide to penetrate the host cell membrane. The repeat sequences in gp 41 interact to form a hair pin. This hair pin loop brings the cell membrane and the virus close to one another. This allows fusion of the envelope and the cell membrane leading to entry of the viral capsid into the host cell. Once the HIV virus is bound to the target cell the capsid which contains the HIV RNA and different enzymes are injected into the cell [McGuire and Marder, 256]. c) Reverse transcription Once the capsid has entered the host cell, the single stranded positive RNA genome is liberated by the reverse transcriptase enzyme from the attached proteins. The positive RNA strands are then copied into complementary DNA (cDNA) molecule. This copying of RNA into cDNA is called reverse transcription and is prone to many errors which can allow the virus to evade the immune system of the body in addition to becoming resistant to drugs. The RNA strand is degraded by reverse transcriptase as the cDNA is formed. The reverse transcriptase is also involved in synthesizing a sense DNA from the previously formed antisense cDNA. The sense DNA and antisense cDNA forms a double stranded viral DNA. This dsDNA is then transported to the cell nucleus [Victoria, et al, 2702]. d) Integration The integration of the viral dsDNA into the host genome is done by the integrase enzyme. The integrated HIV DNA is referred to as provirus. The provirus is involved in the production of new copies of HIV or it may remain dormant for some time [Fiala, 86]. e) HIV genome transcription The integrated DNA provirus is used for transcribing mRNA that are spliced and exported to cytoplasm from the nucleus. The mRNA are translated to produce tat and rev regulatory proteins. The rev proteins accumulate in the nucleus and binds to the mRNA preventing them from being spliced. This allows production of full length mRNA (virus genome) and structural proteins (gag and env). The virus genome then binds to gag protein. f) Capsid assembly The protease enzyme cuts the long protein chains of the HIV virus into individual proteins. The small HIV proteins come together with the RNA material of the virus to form a new virus particle containing the capsid and the nucleic acid in addition to proteins required for the next infection lifecycle of the virus [Kaufman, 66]. g) Budding (expression of gp120/gp41 on cell surface) The env poly protein moves via endoplasmic reticulum to the Golgi complex where it is processed by protease enzyme into gp 120 and gp 41 that are incorporated into the cell membrane of the infected cell. The gag poly proteins associate with inner part of the cell membrane and the capsid. The virion being formed begins to bud from the host cell [Sevigny, 2088]. h) Release The bud formed that contains the envelope consisting of glycoprotein and capsids enclosed in it are released from the cells by budding off. Pathogenesis of HIV a) Routes of transmission The blood, semen or vaginal fluid and breast milk of a person infected with HIV contain the HIV virus. Thus HIV can be transmitted through various routes. They include sex with a person infected with the virus or exposure to blood from an infected person such as through contaminated syringes and needles, sharing of unsterilized razors and tainted transfusions. The virus can also be transmitted to unborn baby from infected mother. The infected mother can also infect her child during child delivery or during breastfeeding [Fiala, 93]. b) Mechanisms of spread and target organs All CD4+ cells can be infected by HIV virus. The commonest target cell is the helper T cells and macrophages. In the CNS, the macrophages and microglial cells are target cells for HIV virus. The dentritic cells found in the lymphatic system are also target cells for HIV virus. The target cell is determined by a co receptor other than the CD4. The common co receptors for HIV include CCR5 and CXCR4. Thus the common target organs for HIV are lymphatic system organs and the CNS. Macrophages in the lymphoid organs are the major target and reservoir for HIV. They are essential in the spread of HIV in the host. After primary infection with HIV virus, the tissue macrophages pass the virus to T cells after the activation of lymphocytes [Melli, et al, 1336-1337]. c) Clinical features: (Stages of infection) The first stage called primary stage of infection occurs once body fluids from an infected person are transferred to uninfected individual. Once this happens there is a rapid replication of the virus. This results in abundance of the HIV virus in the peripheral blood and reducing number of CD4+ T cells. The CD8+ T cells are activated to kill the infected cells. There is also production of antibodies. The CD8 + T cell action decreases the progression of the disease. During this initial stage which lasts between 2 and 4 weeks, the individual usually develops influenza like illness referred to as acute HIV infection. The common symptoms at this stage include lymphadenopathy, fever, pharyngitis, myalgia, rash, malaise and sores on the mouth and esophageal. Other less common symptoms at this stage include nausea, headache, vomiting, enlarged spleen or liver, thrush, weight loss and neurological symptoms [Giorgia Melli, et al, 1331]. From Jack, et al, 95, the second stage is the latency stage. This stage is characterized by strong immune response which reduces the number of HIV viral particles in the peripheral blood. This stage lasts between 2 weeks and 20n years. During this stage the virus is active in the lymphoid organs. Thus many viral particles are trapped inn the network of the dentritic cells’ follicles. The viruses accumulate as free virus and in the infected cells. At this stage the individual is still infectious but rarely presents with any symptoms. The proviral load is carried by the CD4+ CD45RO+ T cells. Sanjay, et al, 10301, argues that the third stage is AIDS. At this stage the CD+ T cell count falls bellow 200 cells per µL. in addition cell mediated immunity declines and the individual becomes prone to opportunistic infections. Some of the common symptoms at this stage include moderate and unexplained weight loss, prostatis, recurring respiratory infections, oral ulcerations and skin rashes. The most common opportunistic infections include oral Candida species and Mycobacterium tuberculosis. The latent herpes viruses are reactivated causing eruption of herpes simplex, shingles, B cell lymphomas induced by Epstein Barr virus and Kaposi’s sarcoma. The patients are also commonly infected with Pneumocystis jirovecii fungi. During the final stages of AIDS the patient is likely to be infected by cytomegalovirus. d) HIV neuropathy mechanisms According to Anthony and Bell 15 17, Nucleoside neuropathy (NN) and distal sensory polyneuropathy (DSPN) are the commonest forms of peripheral neuropathy in HIV infections. Both NN and DSPN cause some disability. DSPN is a neuropathy of the axonal sensory that involves small fibers. It mainly occurs at advanced stages of AIDS. AIDS patients with APOE E4 allele are prone to DSPN since they have less repair mechanisms that are effective. The pathogenesis of HIV DSPN is unclear. However, local immune activation driven by HIV infection has been found to be related to peripheral neuropathy. The gp 120 of HIV virus has been shown to be capable of binding to sensory neurons leading tpo inflammation and pain induction. Thus this could explain the mechanism of DSPN [Melli, et al, 1337]. The axonal sensory neuropathy resulting from use of antiretroviral drugs such as nucleoside analogue reverse transcriptase inhibitor (NRTI) is referred to as NN. The common causes of NN are zalcitabine, didanosine, stavidine and lamivudinen [Giorgia Melli, et al, 1335]. The neurotoxicity of NRTI depends on the dose administered and can be potentiated by an underlying DSPN. The NN is believed to be due to mitochondrial toxicity that results from drug competition with DNA polymerase gamma. This is thought to result in impaired mitochondrial DNA replication. Patients with neuropathy have been found to have abnormal and reduced numbers of mitochondria due to ddC. NRTIs phosphorylation can be achieved selectively by specific thymidine kinase. This explains the selectivity of NRTI toxicity. There are four stages of DSPN and NN. The first stage involves damage of the peripheral nerves. This is mediated indirectly via chemokines by gp 120 in the case of DSPN and metabolic disyfunction in the case of NN. The nerve damage can either be necrosis in the case of NN or apoptosis in the case of DSPN. The second stage involves activation of the immune system following damage of peripheral nerves. The third stage involves persistent activation of the immune system resulting from the continuous replication of the HIV virus and deregulation of the immune system. The fourth stage is the impaired regeneration that results from factors released by persistent immune activation [Rowland and Pedley, 189]. e) HIV dementia mechanisms One of the most serious complications of HIV infection is dementia. Dementia is uncommon during the latency stage of HIV infection. However, as HIV progresses, there occurs neurocognitive deficits which results in frank dementia. Dementia presents in the form of cognitive, motor and behavioral dysfunction [Simpson and Tagliati, 779]. Lipton 87 99 130, argues that neuron dysfunction in HIV neuropathogenesis is attributed to indirect consequences of the infection of microglia or macrophages. The infected microglia or macrophages are involved in production of cytokines in addition to other soluble factors such as HIV proteins which are capable of intoxicating nearby neurons when they are produced for a prolonged period or when their concentration become high. HIV proteins that are neurotoxin include gp 120, nef and tat. The cytokines and other soluble factors that are elevated in the cerebrospinal fluid and brain during HIV infection include pro-inflammatory cytokines such as TNF-α and IL1-β; quinolinic acid; chemokines; arachidonic acid; platelet activating factor and nitric oxide. Increased quinolinic acid is associated with increased dementia. Increased numbers of TNF-α mRNA are associated with severe dementia [McGuire and Marder, 251]. f) Chemokines and cytokines involved in pathogenesis From Tan and Guiloff 25, HIV infection has been found to cause increased infiltration of monocytes across the blood brain barrier (BBB). Chemokines regulates movements of monocytes across the BBB into the CNS. Β-chemokines are prominent in the infection of the CNS by HIV. They attract monocytes and lymphocytes selectively. HIV infection up regulates expression of several chemokines which is correlated to dementia [Stone, Price and French, 590]. MIP-1 α and MIP-1 β are chemokines that have been found to be elevated in HIV patients with dementia. Other chemokines that are elevated in HIV infections include MCP-1 or RANTES which are related to the degree of encephalitis [Melli, et al, 1335]. The cytokines that are elevated in the cerebrospinal fluid and brain during HIV infection include pro-inflammatory cytokines such as TNF-α and IL1-β. Increased numbers of TNF-α mRNA are correlated to severe dementia. TNF-α is also capable of increasing white matter pallor that kills oligodentrocytes [Polydefkis, et al, 116]. g) Secondary infections such as: cytomegalovirus and toxoplasma Infection with HIV virus results in re-activation of cytomegalovirus (CMV) which is related to transition from AIDS related complex to AIDS. CMV activates the transcription of HIV and vice versa. The suppression of the immune system by the CMV is an additional co factor in AIDS. Patients with disseminated CMV and AIDS have a maximal activation of HIV p24 antigenaemia in addition to great CD8+ T cell deficiency. This implies that both CD4+ and CD8+ T cells are low and hence progression to terminal AIDS is faster [Ferrarese, et al, 674]. The co infection of CMV and HIV results in leucopenia, hypotension, pancytopenia and rapid encephalopathy. Thus CMV co infection with HIV accelerates progression of immune deficiency [Simpson and Tagliati, 780]. HIV positive patients are also susceptible to toxoplasmosis. HIV induces susceptibility to toxoplasmosis via depletion of the CD4 T cells, impaired cytotoxic T lymphocyte activity and impaired production of IFN gamma, IL-2 and IL-12. The decreased production of IL-12 and IFN and reduced CD154 expression in HIV patients potentiates development of toxoplasmosis associated with HIV infection. Diagnosis of HIV HIV diagnosis can be carried out using saliva, blood or cells from the inside of the cheek. The diagnosis for HIV/ AIDS can be done nucleic acid based tests such as RT-PCR for viral RNA and PCR for pro viral DNA, p24 antigen culture or testing. These can be used to demonstrate the HIV virus in primary infection. HIV antibody blood tests can detect HIV antibodies in blood within four weeks to six weeks of infection. Thus HIV infection can tested using the detection of antibodies to HIV, p24 HIV antigen, HIV nuclei acid and HIV virus in clinical samples. Serological tests are the most common test for diagnosis of HIV. They detect anti-HIV antibodies. ELIZA is the commonest technique for detecting antibodies to HIV. In young children aged below 18 months, diagnosis of HIV is done via detection of HIV nucleic acids, p24 antigen and viral culture [Anthony & Bell, 19]. Conclusion Infection with HIV virus exposes one to various complications. Of these complications, dementia is the one of the most serious complication. The dementia may result from either use of HAART or the virus pathogenesis which results in damage of the peripheral nerves. References: Anthony I, C, & Prof J, E, Bell. The Neuropathology of HIV/AIDS. International Review of Psychiatry: 2008 Feb 20 (1); 15-24. Bruce Brew. HIV Neurogy. Washington: University of Michagan Press; 2001. Cherry, C, L, et al. Age And Height Predict Neuropathy Risk In Patients With Hiv Prescribed Stavudine. Neurology. 2009 Jul; (73): 315 - 320. David M, Simpson and Michele Tagliati. Neurologic Manifestations of HIV Infection. Ann Intern Med. 1994 Nov; (121): 769 – 785. David Myland Kaufman. Clinical Neurology for Psychiatrists. Washington: Oxford Press; 2007. Dawn McGuire and Karen Marder. Pharmacological Frontiers In The Treatment Of Aids Dementia. J Psychopharmacol. 2000 May; (14): 251 - 257. Childs E, A, et al. Plasma Viral Load And Cd4 Lymphocytes Predict Hiv-Associated Dementia And Sensory Neuropathy. Neurology. 1999 Feb; (52): 607. Cutler R, G, et al. Dysregulation Of Sphingolipid And Sterol Metabolism By Apoe4 In Hiv Dementia. Neurology. 2004 Aug; (63): 626 – 630. Ferrarese, C, et al. Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology. 2001 Aug; (57): 671 - 675. Giorgia Melli, et al. Spatially Distinct And Functionally Independent Mechanisms Of Axonal Degeneration In A Model Of Hiv-Associated Sensory Neuropathy. Brain. 2006 May; (129): 1330 - 1338. Howard E, et al. The Neurology of AIDS. New York: Oxford University Press; 2005. Jack P, Antel, Gary Birnbaum and Hans-Peter Hartung. Clinical Neuroimmunology. London: Penguin Press; 2005. Jacques W, A, Reeders J, and Philip Charles Goodman. Radiology of AIDS. London: Springer Press; 2001 Judith C, Shlay, et al. Acupuncture and Amitriptyline for Pain Due to HIV-Related Peripheral Neuropathy: A Randomized Controlled Trial. JAMA. 1998 Nov; (280): 1590 - 1595. Karl Ng, Kishore Kumar, Bruce Brew, and David Burke. Axonal Excitability In Viral Polyneuropathy And Nucleoside Neuropathy In Hiv Patients. J Neurol Psychiatry. 2010 Jul; 10.1136/jnnp.2009.203091. Lewis P, Rowland and Timothy A, Pedley. Merritt’s Neurology. New York: Sage Press; 2009. Polydefkis M, et al. Reduced Intraepidermal Nerve Fiber Density In Hiv-Associated Sensory Neuropathy. Neurology. 2002 Jan; (58): 115 - 119. Sevigny J, J, et al. Evaluation of Hiv Rna And Markers Of Immune Activation As Predictors Of Hiv-Associated Dementia. Neurology. 2004 Dec; (63): 2084 - 2090. Sanjay C, Keswani, Christelene Jack, Chunhua Zhou, and Ahmet Höke. Establishment of a Rodent Model of HIV-Associated Sensory Neuropathy. J. Neurosci. 2006 Oct; (26): 10299 - 10304. Stone S, F, Price and French M, A. Cytomegalovirus (CMV)- specific CD8+ T Cells in Individuals with Hiv infection: Correlation with Protection From Cmv Disease. J. of Antimicobial Chemotherapy. 2006; (57); 585-588. Stuart A, Lipton. Neuronal Injury Associated With HIV-1: Approaches to Treatment. Annu. Rev. Pharmacol. Toxicol. 1998: (38); 77- 159. Tan S, V, and Guiloff R, J. Hypothesis On The Pathogenesis Of Vacuolar Myelopathy, Dementia, And Peripheral Neuropathy in AIDS. J. Neurol. Neurosurg. Psychiatry. 1998 Jul; (65): 23 - 28. Victoria C, J, et al. Characterization Of Rodent Models Of Hiv-Gp120 And Anti-Retroviral-Associated Neuropathic Pain. Brain. 2007 Oct; (130): 2688 - 2702. Fiala M. Multi-Step Pathogenesis of Aids- Role of Cytomegalovirus. Res. Immunol. 1991; (142): 87-95. Norman Latov, John H, J, Wokke and John Joseph Kelly. Immunological and Infections Diseases of the Peripheral Nerves. New York: Oxford University Press; 1998. Read More