The Immunology of Aids Introduction Although HIV was first identified in 1983,studies of previously stored blood samples indicate that the virus entered theU.
S. population sometime in the late 1970s. Worldwide, an estimated 27. 9 millionpeople had become HIV-infected through mid-1996, and 7.
7 million had developedAIDS, according to the World Health Organization (WHO). AIDS is a disease of theimmune system, and is caused by Human Immuno deficiency Virus (HIV). HIV targetsand infects T-helper cells and macrophages. After infection, replication of thevirus occurs within the T-helper cells. The cells are lysed and the new virusesare released to infect more T-helper cells.
The course of the disease results inthe production of massive numbers of virus (1 billion/day) over the full courseof the disease. The T- helper cells are infected, and rapidly destroyed both byvirus and by cytotoxic T cells. T-helper cells are replaced with nearly abillion produced per day. Over many years (average may be 10), the T-helper cellpopulation is depleted and the body loses its ability to mount an immuneresponse against infections.
Thus, we mount a very strong immune responseagainst the virus for a long time, but the virus is produced at a very high rateand ultimately overcomes the ability of the immune system to respond. Since HIVbelongs to a class of viruses called retroviruses, it has genes composed ofribonucleic acid (RNA) molecules. Like all viruses, HIV can replicate onlyinside host cells, commandeering the cell’s machinery to reproduce. However,only HIV and other retroviruses, once inside a cell, use an enzyme calledreverse transcriptase to convert their RNA into DNA, which can be incorporatedinto the host cell’s genes. HIV belongs to a subgroup of retroviruses known aslenti-viruses, or “slow” viruses. The course of infection with theseviruses is characterized by a long interval, up to 12 years or more, betweeninitial infection and the onset of serious symptoms.
Like HIV in humans, thereare animal viruses that primarily infect the immune system cells, often causingimmuno-deficiency and AIDS-like symptoms. Scientists use these and other virusesand their animal hosts as models of HIV disease. The CDC currently defines AIDSwhen one of 25 conditions indicative of severe immuno-suppression associatedwith HIV infection, such as Pneumocystis carinii pneumonia (PCP) is present, orHIV infection in an individual with a CD4+ T cell count less than 200 cells percubic millimeter (mm3) of blood. However, the question that now remains to beanswered is ‘How does HIV effectively overcome the human immune system?’ In thispaper I will try to answer this question. In the first chapter I will explainhow HIV is transmitted and what its life cycle looks like.
This in order toincrease the understanding of how the virus operates. It can be seen as anintroductory chapter to the main body of the paper, chapter 2. In the secondchapter the specific interactions between the virus and the human immune systemwill be discussed and shown why its is so threatening. In the last chapter Iwill deal with certain promising treatments against AIDS. Chapter 1 TheTransmission of HIV Among adults, HIV is spread most commonly during sexualintercourse with an infected partner.
During sex, the virus can enter the bodythrough the mucosal linings of the vagina, vulva, penis, rectum or, very rarely,via the mouth. The likelihood of transmission is increased by factors that maydamage these linings, especially other sexually transmitted diseases that causeulcers or inflammation. Research suggests that immune system cells calleddendritic cells, which reside in the mucosa, may begin the infection processafter sexual exposure by binding to and carrying the virus from the site ofinfection to the lymph nodes where other cells of the immune system becomeinfected. HIV also can be transmitted by contact with infected blood, most oftenby the sharing of drug needles or syringes contaminated with minute quantitiesof blood containing the virus. The risk of acquiring HIV from blood transfusionsis now extremely small in Western countries, as all blood products in thesecountries are screened routinely for evidence of the virus. Almost allHIV-infected children acquire the virus from their mothers before or duringbirth.
The anatomy of HIV HIV has a diameter of 1/10,000 of a millimeter and isspherical in shape. The outer coat of the virus, known as the viral envelope, iscomposed of lipid bi-layer, taken from the membrane of a human cell when a newlyformed virus particle buds from the cell. Embedded in the viral envelope areproteins from the host cell, as well as 72 copies (on average) of a complex HIVprotein that protrudes from the envelope surface. This protein, known as Env,consists of a cap made of three or four molecules called glycoprotein (gp) 120,and a stem consisting of three or four gp41 molecules that anchor the structurein the viral envelope.
Within the envelope of a mature HIV particle is abullet-shaped core or capsid, made of 2000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV RNA, each of which has a copy ofthe virus’s nine genes. Three of these, gag, pol and env, contain informationneeded to make structural proteins for new virus particles. The env gene, forexample, codes for a protein called gp160 that is broken down by a viral enzymeto form gp120 and gp41, the components of Env. Three regulatory genes, tat, revand nef, and three auxiliary genes, vif, vpr and vpu, that contain theinformation necessary for the production of proteins that control the ability ofHIV to infect a cell, produce new copies of virus or cause disease.
The proteinencoded by nef, for instance, appears necessary for the virus to replicateefficiently, and the vpu-encoded protein influences the release of new virusparticles from infected cells. The Life Cycle of HIV When HIV encounters itstarget cell, the external glycoprotein portion of the viral envelope (GP120)binds with high affinity to the extra cellular component of the receptor proteinCD 4, present on helper lymphocytes(Helper T cells). The membrane portion of theviral envelope fuses to the lymphocyte membrane and the virus is expelled intothe cell. Then the reverse transcriptase of the virus copies the RNA into DNA. Once the DNA is integrated into the host cell genome, the presence of HIV hasbecome a permanent part of the lymphocyte (Helper T).
The viral productionproceeds through a complex set of highly regulated steps. First, messenger RNAof the virus and viral proteins are produced. Proteins are then modified by aviral protease to become mature viral proteins. Current efforts at anti-viraltherapy involve the use of reverse transcriptase inhibitors (notably AZT) andnewly developed inhibitors of the viral protease. AZT Chapter 2 The ImmuneSystem and HIV The body’s health is defended by the immune system.
Lymphocytes(B cells and T cells) protect the body from “germs” such as viruses,bacteria, parasites, and fungi. When germs are detected, B cells and T cells areactivated to defend the body. This process is hindered in the case of theacquired immuno-deficiency syndrome (AIDS). AIDS is a disease in which thebody’s immune system breaks down. AIDS is caused by the human immuno-deficiencyvirus (HIV).
When HIV enters the body, it infects the CD4+ T cells, where thevirus grows. The virus kills these cells slowly. As more and more of the T cellsdie, the body’s ability to fight infection weakens. A person with HIV infectionmay remain healthy for many years. People with HIV infection are said to haveAIDS when they are sick with serious illnesses and infections that can occurwith HIV.
The illnesses tend to occur late in HIV infection, when only 200 Tcells per cubic millimeter remain. One reason HIV is unique is that despite thebody’s aggressive immune responses, which are sufficient to clear most viralinfections, some HIV invariably escapes. One explanation is that the immunesystem’s best soldiers in the fight against HIV-certain subsets of killer Tcells- multiply rapidly following initial HIV infection and kill manyHIV-infected cells, but then appear to exhaust themselves and disappear,allowing HIV to escape and continue replication. Additionally, in the few weeksthat they are detectable, these specific cells appear to accumulate in thebloodstream rather than in the lymph nodes, where most HIV is sequestered.
ViralVariation Another reason for the uniqueness of HIV are the dynamics of HIVreplication. They also have profound implications for the generation of geneticdiversity of HIV quasispecies in individual patients. Virus isolates obtainedfrom patients at the time of initial infection show little geneticheterogeneity. Over time, however, the population of viruses circulating in anindividual patient becomes increasingly diverse. The rapid replication kineticsand high mutation rate of HIV reverse transcriptase drive the diversification ofthe HIV quasispecies in response to selective pressure from the host immuneresponse. The rapid turnover of HIV also provides the ideal mechanism forproducing variants with mutations that confer drug resistance, or permit escapefrom immunological control of HIV infection.
When drugs that inhibit HIV-1replication are partially or inappropriately administered, the resultingevolutionary pressure selects for the emergence of resistant strains. In thecase of lamivudine (3TC) or nevirapine, a single nucleotide change in the HIV-1RT gene is sufficient to produce high-level resistance. The entire viruspopulation evolves from wild-type to resistant in a matter of weeks when thesedrugs are given as single agents. Little or no viral variation emerges inpatients with complete suppression of plasma HIV-1 RNA in response to potentcombination therapy. The Role of Immune Activation in HIV Disease During HIVinfection, however, the immune system may be chronically activated, withnegative consequences.
For HIV replication and spread are much more efficient inactivated CD4+ cells. Chronic immune system activation during HIV disease mayalso result in a massive stimulation of a person’s B cells, impairing theability of these cells to make antibodies against other pathogens. Chronicimmune activation also can result in apoptosis, and an increased production ofcytokines that may not only increase HIV replication but also have otherdeleterious effects. Increased levels of TNF-alpha , for example, may be atleast partly responsible for the severe weight loss or wasting syndrome seen inmany HIV-infected individuals. The persistence of HIV and HIV replicationprobably plays an important role in the chronic state of immune activation seenin HIV-infected people.
In addition, researchers have shown that infections withother organisms activate immune system cells and increase production of thevirus in HIV-infected people. Chronic immune activation due to persistentinfections, or the cumulative effects of multiple episodes of immune activationand bursts of virus production, likely contribute to the progression of HIVdisease. The Role of CD8+ T Cells CD8+ T cells are important in the immuneresponse to HIV during the acute infection and the clinically latent stage ofdisease. These cells attack and kill infected cells that are producing virus. CD8+ T cells also appear to secrete soluble factors that suppress HIVreplication.
Three of these molecules-RANTES, MIP-1alpha andMIP-1beta-apparently block HIV replication by occupying receptors necessary forthe entry of certain strains of HIV into their target cells. Researchers havehypothesized that an abundance of RANTES, MIP-1alpha or MIP-1beta, or a relativelack of receptors, notably CCR-5, for these molecules, block the entry of HIV. This may help explain why some individuals have not become infected with HIV,despite repeated exposure to the virus. A possible explanation for that is thatsome people have a mutation in the allele coding for that receptor.
Figure 2. New Co-receptors for HIV-1. T-cell-tropic strains of HIV-1, which are usuallysyncytium-inducing, require CXCR-4 as co-receptor. This receptor is found on Tlymphocytes, but not monocytes. Mono-cytotropic strains, which are usually non-syncytium-inducing,require the CCR-5 receptor, which is found on both monocytes and T lymphocytes. This illustrates why these isolates can infect monocytes and primarylymphocytes, both of which express CCR-5, but not T-cell lines, which lack thisco-receptor.
By contrast, T-cell-tropic strains cannot infect monocytes becausethey lack the CXCR-4 co-receptor. CD8+ T cells are thought to also secrete othersoluble factors-as yet unidentified-that suppress HIV replication. The Loss ofCells of the Immune System Researchers around the world are studying how HIVdestroys or disables CD4+ T cells, and it is thought that a number of mechanismsmay occur simultaneously in an HIV-infected individual. Recent data suggest thatbillions of CD4+ T cells may be destroyed every day, eventually overwhelming theimmune system’s regenerative capacity. Infected CD4+ T cells may be killeddirectly when large amounts of virus are produced and bud off from the cellsurface, disrupting the cell membrane, or when viral proteins and nucleic acidscollect inside the cell, interfering with cellular machinery. Infected CD4+ Tcells may be killed when cellular regulation is distorted by HIV proteins,probably leading to their suicide by a process known as programmed cell death orapoptosis.
Recent reports indicate that apoptosis occurs to a greater extent inHIV-infected individuals, both in the bloodstream and lymph nodes. Normally,when CD4+ T cells mature in the thymus gland, a small proportion of these cellsis unable to distinguish self from non-self. Because these cells would otherwiseattack the body’s own tissues, they receive a biochemical signal from othercells that results in apoptosis. Investigators have shown in cell cultures thatgp120 alone or bound to gp120 antibodies sends a similar but inappropriatesignal to CD4+ T cells causing them to die even if not infected by HIV.
Uninfected cells may die in an innocent bystander scenario: HIV particles maybind to the cell surface, giving them the appearance of an infected cell andmarking them for destruction by killer T cells. Killer T cells also maymistakenly destroy uninfected CD4+ T cells that have consumed HIV particles andthat display HIV fragments on their surfaces. Alternatively, because HIVenvelope proteins bear some resemblance to certain molecules that may appear onCD4+ T cells, the body’s immune responses may mistakenly damage such cells aswell. Studies suggest that HIV also destroys precursor cells that mature to havespecial immune functions, as well as the parts of the bone marrow and the thymusneeded for the development of such cells. These organs probably lose the abilityto regenerate, further compounding the suppression of the immune system. HIV isActive in the Lymph Nodes Although HIV-infected individuals often exhibit anextended period of clinical latency with little evidence of disease, the virusis never truly latent.
NIAID researchers have shown that even early in disease,HIV actively replicates within the lymph nodes and related organs, where largeamounts of virus become trapped in networks of specialized cells with long,tentacle-like extensions. These cells are called follicular dendritic cells (FDCs). FDCs are located in hot spots of immune activity called germinal centers. Theyact like flypaper, trapping invading pathogens (including HIV) and holding themuntil B cells come along to initiate an immune response. Close on the heels of Bcells are CD4+ T cells, which rush into the germinal centers to help B cellsfight the invaders.
CD4+ T cells, the primary targets of HIV, probably becomeinfected in large numbers as they encounter HIV trapped on FDCs. Researchsuggests that HIV trapped on FDCs remains infectious, even when coated withantibodies. Once infected, CD4+ T cells may leave the germinal center and infectother CD4+ cells that congregate in the region of the lymph node surrounding thegerminal center. However, over a period of years, even when little virus isreadily detectable in the blood, significant amounts of virus accumulate in thegerminal centers, both within infected cells and bound to FDCs. In and aroundthe germinal centers, numerous CD4+ T cells are probably activated by theincreased production of cytokines such as TNF-alpha and IL-6, possibly secretedby B cells. Activation allows uninfected cells to be more easily infected andincreases replication of HIV in already infected cells.
While greater quantitiesof certain cytokines such as TNF-alpha and IL-6 are secreted during HIVinfection, others with key roles in the regulation of normal immune function maybe secreted in decreased amounts. For example, CD4+ T cells may lose theircapacity to produce interleukin 2 (IL-2), a cytokine that enhances the growth ofother T cells and helps to stimulate other cells’ response to invaders. Infectedcells also have low levels of receptors for IL-2, which may reduce their abilityto respond to signals from other cells. Ultimately, accumulated HIV overwhelmsthe FDC networks. As these networks break down, their trapping capacity isimpaired, and large quantities of virus enter the bloodstream.
The destructionof the lymph node structure seen late in HIV disease may prevent a successfulimmune response against not only HIV but other pathogens as well. Thisdevastation heralds the onset of the opportunistic infections and cancers thatcharacterize AIDS. HIV’s Strategy Researchers have discovered a devious strategyused by the human immuno-deficiency virus (HIV) to undermine the immune system. They found that even when HIV does not enter a cell, proteins in the outerenvelope of the virus can bind to CCR5 receptor on the cell’s surface andinitiate a biochemical cascade that sends a signal to the cell’s interior.
Thissignaling process may activate the cell, making it more vulnerable to HIVinfection. It also may cause cells to migrate to sites of HIV replication,thereby increasing their vulnerability to infection. If the cell is alreadyinfected with HIV, activation may boost the production of the virus. HIVgenerally requires two receptors (as discussed in ‘The Role of CD8+ T Cells’) toenter a target cell: CD4, and either CCR5 or CXCR4, depending on the strain ofvirus. The strains of HIV most commonly seen early in HIV disease, known asmacrophage-tropic (M-tropic) viruses, use CD4 and CCR5 for cell entry. Manystrains of the simian immuno-deficiency virus (SIV), a cousin of HIV thatinfects non-human primates such as monkeys, also use these receptors forcellular entry.
Researchers found that envelope proteins from four differentM-tropic HIV strains and one M-tropic SIV strain induced a signal through CCR5that caused cells to migrate in culture. In contrast, envelope proteins fromother strains of the viruses, known as T-cell tropic (T-tropic) strains, did notcause signaling. Chapter 3 Immunological Treatments for HIV/AIDS HRG 214: Ajoint effort between scientists and industry has resulted in the development ofa new drug to treat patients in the advanced stages of AIDS. Dr. Frank Gelder,director of Immuno-diagnostic Testing Laboratories, Department of Surgery atLouisiana State University Medical Center in Shreveport, Louisiana, invented thedrug, HRG214. HRG214 is formulated as an immuno-chemically-engineered group ofantibodies that neutralize and inactivate essential steps in the life cycle ofHIV.
HRG214 is the first immunology based pharmaceutical to show successfultreatment of HIV infection. When HRG214 is used in conjunction with twoadditional drugs, one to initiate and one to control cytokine pathways, (thechemical signals by which cells communicate). CD8 lymphocytes and other cells,which fight infection, (present but not functioning normally in AIDS patients),are rapidly restored to normal function. This drug regime opens new therapeuticoptions for the care of HIV patients, including those in advanced stages ofAIDS.
In addition, CD4 and CD8 lymphocyte numbers have statistically increased,and marked clinical improvements have been observed in all patients receivingtreatment with HRG214. These improvements include increase in appetite andstamina, as well as marked improvements in AIDS-related conditions such aschronic fatigue syndrome, diarrhea, malabsorption, and other HIV-relateddiseases. Cytolin Unlike current AIDS drugs, which attack HIV directly, Cytolinwould help the body’s immune system by correcting the immune system’sself-destruct mechanism that is triggered by an HIV infection. Cytolin is amonoclonal antibody designed to prevent one part of the immune system-aparticular type of “killer” CD8 cells-from attacking another part-CD4cells, the destruction of which results in AIDS.
Cytolin is designed to protectthe immune system’s natural defenses while antiviral drugs take the offensiveagainst HIV. Cytolin is to be given in a doctor’s office, most often as anadjunct to a combination of antiviral drugs. Combinations, or”cocktails,” of antiviral drugs have helped some patientssignificantly reduce the level of their HIV infection, improving their health. However, the side effects of antiviral drugs can be so significant that at least15 percent of patients cannot take them.
Even some patients who can tolerateantiviral therapy have continued to face declining health. Following injectionwith Cytolin, the patients demonstrated significantly reduced levels of HIVinfection and clinical signs of immune system recovery, including increasedlevels of disease fighting CD4 cells. Conclusion First of all, HIV attacks thevery cells that are responsible for the defense of the human body againstinvaders, the CD4+ T cells. However, HIV also targets other immune system cellswith CD4 on their surface. Not only are HIV replication and the spread of thevirus more efficient in activated cells, but chronic immune activation duringHIV disease may result in a massive stimulation of a person’s B cells, impairingthe ability of these cells to make antibodies against other pathogens. Chronicimmune activation also can result in a form of cellular suicide known asapoptosis, and in the increased production of signaling molecules calledcytokines that can themselves increase HIV replication.
This strategy shows thatHIV does not to invade the CD4+ cells to inflict damage to the immune system. The chronic immune activation not only impairs the ability of B cells to makepathogens against other cells, but it also results in apoptosis, and anincreased production of cytokines that may not only increase the HIV replicationbut also have other deleterious effects, such as the severe weight loss causedby increased levels of TNF-alpha. Now, finally researchers have found a twopotentially successful immunological treatments, HRG 214 and Cytolin. HRG 214neutralizes and inactivates essential steps in the replication cycle of HIV. Cytolin helps the immune system by correcting its self-destruct mechanism thatis triggered by an HIV infection. BibliographyPantaleo G, The qualitative nature of the primary immune response to HIVinfection is a prognosticator of disease progression independent of the initiallevel of plasma viremia.
Proc Natl Acad Sci USA 1997. – http://camelot. emmes. com/avctn/index.
htm- http://www. niaid. nih. gov/research/daids. htm – Kostirkis LG, Huang Y, Moore JP,et al.
A chemokine receptor CCR2 allele delays HIV-1 disease progression and isassociated with a CCR5 promoter mutation. Nat Med 1998; 4:350-3. – Cocchi F,DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P. Identification of RANTES,MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced byCD8+ T cells. Science 1995; 270:1811-5.
– Pantaleo G, Graziosi C, Demarest JF,et al. HIV infection is active and progressive in lymphoid issue during theclinically latent stage of disease. Nature 1993; 362:355-8. – Embretson J,Zupancic M, Ribas JL, et al.
Massive covert infection of helper T lymphocytesand macrophages by HIV during the incubation period of AIDS. Nature 1993;362:359-62. – HIV Pathogenesis and Viral Markers. HIV Clinical Management -Volume 2. ? 1999 Medscape, Inc.
– Junqueira, Carneiro, and Kelly. Functionelehistologie. Utrecht 1996. – Meer, J van der, et al.
Interne Geneeskunde. BohnStafleu Van Loghum
