Immunological aspects of allergy and anaphylaxis part 27

Vernal conjunctivitis is a chronic, bilateral conjunctival inflammatory disease found primarily in young males with history of atopy during spring months. Initial symptom onset is before puberty, and symptoms dissipate by the third decade of life. In severe cases, vernal conjunctivitis can lead to corneal scarring and permanent vision loss. Histopathologically, conjunctival infiltration with basophils, eosinophils, plasma cells, lymphocytes, and macrophages characterizes vernal conjunctivitis. With this cellular milieu, it appears that vernal conjunctivitis is a combined immediate and delayed-type hypersensitivity reaction.

Immunological aspects of allergy and anaphylaxis part 26

Perrennial allergic conjunctivitis, in contrast, is associated with a persistent increase in the number of these allergic cell types throughout the year as well as specific IgE (dust, mold, animal dander) found in the tears of affected individuals.

Immunological aspects of allergy and anaphylaxis part 25

Inflammatory markers include up-regulation of intercellular adhesion molecules such as ICAM-1. Increased levels of helper T cell 2 subset (TH2) cytokines, including IL-4, are found in the eye tissues during allergy season. Clinically, the conjunctiva is red, with a clear  discharge . The  eye is almost uniformly  pruritic. Seasonal allergic  conjunctivitis is commonly associated  with rhinitis, but it may be the predominant symptom of allergy.

Immunological aspects of allergy and anaphylaxis part 24

Seasonal allergic conjunctivitis is the most common form of allergic ocular disease. Changes in the conjunctiva include a visible increase in the type and number of cells provoking allergy symptoms, usually in spring  and in fall. The aforementioned cell types, such as mast cells and eosinophils, interact and release a variety of allergic mediators when exposed to seasonal aeroallergens such as tree or grass pollen. Preformed  mediators are released in an immediate phase, and newly  formed mediators appear approxomately eight to twenty-four hours after exposure. These mediators have overlapping biological functions that contribute to the typical ocular itching, redness, and watery discharge associated with allergic eye disease.

Immunological aspects of allergy and anaphylaxis part 23

CLINICAL DISEASE STATES

Allergic eye disease consists of four overlapping conditions, including:

• seasonal and perennial allergic conjunctivitis
• vernal conjunctivitis
• giant papillary conjunctivitis
• atopic keratoconjunctivitis

Distinct immunological changes occuring at the conjunctival surface give rise to the clinical spectrum seen in accular allergy.

Immunological aspects of allergy and anaphylaxis part 22

ALLERGIC CONJUNCTIVITIS

The eye, one of the initial exposure interfaces for allergens, is a common site for allergic disorders. Symptoms can range from mild eye itching to chronic  cataracts and blindness. These disorders are differentiated by their clinical presentation as well as by the nature of immunological changes occuring  in the conjunctival surface. Ocular allergic inflammation is typically associated with IgE-mediated  mast cell activation. Mast cell-derived mediators (eg histamine, proteases, leukotrienes, and cytokines) initiate a cascade of events that culminate in the infiltration and migration of inflammatory leukocytes (neutrophils, eosinophils, and lymphocytes) to the ocular tissue. This trafficking of inflammatory cells requires attraction of these cells initiated by chemokines, and directed migration of the inflammatory cells out the bloodstream to the surface epithelium using adhesion molecules and their receptors.

Immunological aspects of allergy and anaphylaxis part 21

Anaphylactic reactions involve an immunological mechanism. However, there are subsets of reactions clinically indistinc from anaphylaxis, which occur in a non-IgE-mediated fashion. In these anaphylactoid reactions, certain substances such as morphine and other agents such as radiocontrast media are common triggers. In contrast to IgE-mediated anaphylaxis, prior exposure is generally not required. In non-IgE anaphylaxis, some patients with selective absence of IgA demonstrate anaphylactic symptoms following transfusion of IgA-containing plasma. Physiological changes such as exercise, emotions and overheating  can provoke symptoms  in patients with  cholinergic anaphylactoid  reaction. In this rare condition, an increase in  core body temperature causes a rise in plasma histamine  from mast cells. This disease is an exaggerated form of urticaria. In all cases, no single pathogenic mechanism has been defined, but it is likely that direct mast cell activation accounts for most of these disorders; complement activations has also been reported.

Immunological aspects of allergy and anaphylaxis part 20

In recent years, natural rubber latex has been recognized as a source of anaphylaxis. Exposure can occur through contact or inhalation, and various scenarios of exposure include surgical procedures, dental exams, or sexual intercourse with latex condoms. Health care workers and spina bifida patients are particularly at risk. IgE antibodies to latex antigen Hev b1 have been demonstrated by immunoassay and are felt to play a pathogenic role in this clinical entity.

Immunological aspects of allergy and anaphylaxis part 19

Foods, including nuts and crustaceans (ie shrimp), are frequently the cause of anaphylactic reactions. With exercise-induced anaphylaxis, certain foods that are normally tolerated such as celery, apples, and shrimp can induce anaphylaxis when ingestion is followed by exercise.

Immunological aspects of allergy and anaphylaxis part 18

Insect venom, another common cause of anaphylaxis, accounts for approximately forty to fifty deaths each year in the United States. The Hymenoptera order, including hornets, wasps, honeybees, and yellow jack-ets, contains the most common allergenic species. Immunotherapy is 90 to 95 % effective after five years of therapy.

Immunological aspects of allergy and anaphylaxis part 17

Skin testing using a commercially available benzylpenicilloyl polylysine conjugate may be used to predict the likeli-hood of an immediate-type reactions. Skin testing cannot predict non-IgE-mediated reactions; therefore, a thorough history to determine the necessity for skin testing is important.

Immunological aspects of allergy and anaphylaxis part 16

Penicilline,  the prototypic beta-lactam antibiotic, is the most frequent cause of anaphylaxis in humans. The reaction occurs when the compound is covalently bound to tissue carrier proteins to form drug-protein conjugates known as haptens. Ninety-five percent of tissue- bound penicillin is haptenized as benzylpenicilloyl, termed the major antigenic determinant. IgE antibodies directed at this hapten appear to be implicated in type I hyperensitivity reactions.

Immunological aspects of allergy and anaphylaxis part 15

REPRESENTATIVE AGENTS CAUSING ANAPHYLAXIS

Multiple substances have been implicated as possible causes of anaphylaxis. The most common substances include drugs, specifically low-molecular-weight compounds. In most cases, the parenteral mode of administration is implicated, although oral, inhaled, and even cutaneous exposure can induce anaphylaxis as well.

Immunological aspects of allergy and anaphylaxis part 15

REPRESENTATIVE AGENTS CAUSING ANAPHYLAXIS

Multiple substances have been implicated as possible causes of anaphylaxis. The most common substances include drugs, specifically low-molecular-weight compounds. In most cases, the parenteral mode of administration is implicated, although oral, inhaled, and even cutaneous exposure can induce anaphylaxis as well.

Immunological aspects of allergy and anaphylaxis part 14

EXPERIMENTAL MODEL

Animal models have been use to understand various manifestations of anaphylaxis. Circulatory collapse typically occurs in dogs, rabbits may suffer acute pulmonary hypertension, and guinea pigs may experience acute respiratory obstruction. These reactions are classically mediated by the interaction of IgE, the high-affinity IgE receptor found on mast cells and histamine. However, findings from several rodent studies suggest an alternative pathway involving the Ig receptor, macrophages, platelets and platelet-activating factor may be more important in anaphylaxis than previously realized. Strait and colleagues immunized wild-type, IgE-deficient and mast cell-deficient mice using goat antimouse IgD antibody. This technique induced mastocytosis and a large response to goat antigen (IgG) with increased IgE and IgG production. After fourteen days, they challenged the mice with antigen (goat IgG) or rat  antimouse IgE monoclonal antibody (mAb). The severity of anaphylaxis was gauged by changes in body temperature, physical activity, and mortality. Findings  in this experimental model included similar anaphylactic responses regardless of anti-IgE, mAb-induced, or goat IgG antigen challenge.

Immunological aspects of allergy and anaphylaxis part 13

Treatment of anaphylaxis is aimed at restoring blood pressure, decreasing tissue edema, and reversing bronchospasm. Subcutaneous or intravenous epinephrine, oral or intravenous antihistamines, and systemic steroids are the mainstay of treatment. Patients should be monitored for at least six to twelve hours because late-phase reactions are possible.

Immunological aspects of allergy and anaphylaxis part 12

Clinically, these reactions lead to:

• Airway and laringeal edema and bronchospasm with potential for complete asphyxiation
• Gastrointestinal tract smooth muscle contraction, causing pain, vomiting, and diarrhea
• Blood vessel dilatation with potential for progression to circulatory collapse
• Cutaneous vascular permeability, resulting in flushing, urticaria, and angioedema

Immunological aspects of allergy and anaphylaxis part 11

In the immediate phase, preformed enzymes and toxic mediators such as histamine, tryptase, and heparin are the predominant bioactive substances released. Acting on H1 and H2 receptors, histamine promotes multiple effects such as increased vascular permeability, vasodilatation, constriction of bronchial smooth muscle, and increased mucous secretion.

Immunological aspects of allergy and anaphylaxis part 10

Generally, antigen-spesific IgE antibodies on mast cells, or basophils, interact with previously encountered antigens mediating anaphylaxis. Mast cells are found in large numbers beneath cutaneous and mucosal surfaces and are closely associated with blood vessels and peripheral nerves. Basophils, most closely related to eosinophils, function similarly to mast cells. Basophils are present in the circulation, while mast cells are present only in tissue but in much greater numbers. When either of these cells types is triggered, a biphasic release of mediators occurs. The pathophysiology of anaphylaxis is clinically defined by the physiological effects of the immediate-phase and late-phase mediators on the target organs. By definition, anaphylaxis involves the cardiovascular, respiratory, gastrointestinal, or epidermal system; in most cases, multiple organs are involved.

Immunological aspects of allergy and anaphylaxis part 9

SYSTEMIC ANAPHYLAXIS AND ANAPHYLACTOID REACTIONS

Systemic anaphylaxis represents the clinical manifestation of type I hypersensitivity that occurs when a specific antigen and a homocytotrophic antibody interact. The reaction can be sudden and progress rapidly, often without a clear cause. Death can occur because of vascular collapse or airway obstruction. The term anaphylaxis is derived from the Greek ana, meaning backward, and phylaxis, meaning protection. Poiter and Richet coined the term in 1902 after sea anemone antigen injected into a previously tolerant dog caused a fatal reaction instead of the expected immunological protection, or prophylaxis.

Immunological aspects of allergy and anaphylaxis part 8

Although atopy has a strong genetic component, environtmental factors best explain the recent global trend toward increased prevalence of allergic disease. Predictive factors include the following:

• decreased exposure to infectious disease during early childhood
• changes in diet
• higher levels of allergen exposure
• increased environtmental pollution

Of these factors, variances in exposure to infectious disease appear to have the greatest correlation with atopy. Epidemioligical studies point out a negative association between atopic disease in children and a history of measles or hepatitis A virus infection. It is hypothesized that infections such as these tilt the production of cytokines toward interferon gamma (IFN-γ) and the TH1 cytokines, thereby decreasing production of TH2 allergic cytokines such as IL-4. This theory's attractiveness may be its ability to explain the global increase in atopy due to decreased infection rates in Westernized regions with aggressive vaccination programs.

Immunological aspects of allergy and anaphylaxis part 7

Genetic studies of atopic families have identified regions on chromosome 11q and 5q that affect IgE production. Chromosome 5 contains multiple genes, including those for IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor. Eosinophil survival and mast cell proliferation are just a few pro-allergic effects of these cytokines. Chromosome 11 encodes the beta subunit of the high-affinity IgE receptor. Increased expression of this receptor on mast cells leads to more vehement response to small numbers of antigens. This increased expression explains how exposure to minute amounts of allergen, such as venom from a stinging insect, can produce systemic anaphylaxis.

Immunological aspects of allergy and anaphylaxis part 6

Inhalation of most proteins does not cause IgE-mediated responses, whereas a limited number of small protein allergens can elicit such reactions. Although the mechanism of allergic induction is not completely clear, some general principles have emerged. Allergens presented transmucosally at very low doses induce IgE responses by TH2 cells. This subset of cells produces the primary cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13). These interleukins interact with receptors on B lymphocyte cell surfaces, which promote class switching to the IgE antibody subclass. The subsequent class switch produces antigen-specific IgE antibodies with specifity toward common allergens such as pollen, animal dander, food, or venom.

Immunological aspects of allergy and anaphylaxis part 5

Our current understanding of the development of an IgE response favors a TH2 T-cell induction. When specific inhaled, ingested, or absorbed proteins, or allergens, appropriately stimulate this subset of the T-cell population, a series of cellular reactions occurs that leads to IgE antibody production.

Immunological aspects of allergy and anaphylaxis part 4

ATOPY

Clinical allergic diseases  are predominately type I, or IgE mediated. Approximately 40% of people in Western nations are inclined toward an exaggerated IgE response to multiple environtmental allergens such as pollen  or animal dander. This allergic state, known as atopy, is the result of multiple genetic and environmental factors.

Immunological aspects of allergy and anaphylaxis part 3

ALLERGIC HYPERSENSITIVITY

In 1964, Gell and Coombs classified four types of immunologically mediated hypersensitivity states. The majority of disease states encountered in the clinical practice of allergy are related to type I, or immediate type hypersensitivity. In this model, an allergen interacts with preformed IgE on the surface of a mast cell or basophil. This interaction causes cross-linking of the FceRI receptor and release of multiple mediators, including histamine, leukotriens, and various interleukins. Depending on the relative localization of release, clinical states such as allergic asthma, allergic rhinitis, or systemic anaphylaxis occur. Of the remaining clinical allergy hypersensitivity states, type IV, or delayed-type hypersensitivity, is most common. In this type, T-cell antigen receptors on TH1 or TH2 lymphocytes bind to tissue antigens, causing clonal expansion of lymphocytes and release of pro-inflammatory lymphokines. Distinc clinical entities such as contact dermatitis (eg, poison ivy) or tuberculin skin test sensitivity in pulmonary tuberculosis may occur relative to the site of the tissue antigen.

Immunological aspects of allergy and anaphylaxis part 2

Allergic reaction may be found in up to 20% of the general US population, but by the age 6, 40% of the children in the United States have some sort of allergic problems. Although most of these children have respiratory problems, such as allergic rhinitis or bronchial asthma, many of those with allergies may also have atopic reactions to foods or medications. As antigens are slowly introduced into an infant's environtment or diet, the child's propensity to deal with these new substances may not be developed. In addition, children's airways are small, their gastrointestinal tracts are not developed, and their immune systems are not ready to meet the challenges of these newly introduced proteins called allergens. Most responses are Gell and Coombs type 1 or immediate hypersensitivity reaction.

Immunological aspects of allergy and anaphylaxis part 1

Adverse responses to otherwise innocuous substances we are exposed to constitute the crux of allergic reactions. Reaction to exposure to these substances may vary from a slight rash, easily treated with an antihistamine, leukotrien modifier, or corticosteroid cream, to a multisystemic reaction, with catastrophic consequences or anaphylaxis.

IMMUNOLOGY OF HIV INFECTIONS part 39

These are, however, to be considered as first-generation vaccines. The ultimate goal will be to produce an effective preventive vaccine. This will require new thinking about vaccine approaches, innovative solutions, and persistence, but the total prevention of this devastating disease is a worthwhile goal.

IMMUNOLOGY OF HIV INFECTIONS part 38

Thus, the need for a safe, effective, inexpensive vaccine to prevent further spread of the infection becomes an increasingly important goal. Unfortunately, most of the vaccine trials to date have not been successful in this regard, and many investigators  have turned their attention to vaccines that, if given early in the infection, may protect individuals from developing AIDS. A number of these vaccines show promise and are in various stages of clinical or nonhuman primate trials.

IMMUNOLOGY OF HIV INFECTIONS part 37

FUTURE DIRECTIONS FOR RESEARCH

The use of antiretroviral combination regimes has made significant advances in the treatment of HIV infections in industrialized countries. However, these treatments are expensive and would only reach a limited number of infected individuals, especially in developing countries where most of the epidemic is occuring.

IMMUNOLOGY OF HIV INFECTIONS part 36

CELLULAR VACCINES

While the original recombinant HIV vaccines used vaccinia virus and were well tolerated, safety considerations in immunodeficient hosts has led investigators to substitute the canarypox virus for the vaccinia virus. However, the immunogenicity of the pox-virus-based vaccines in humans has been relatively modest with less than 35% of the vaccinees scoring positive for T-cell responses. In contrast, replication-defective  adenovirus type 5 (ad5) appears  to be one of the most promising    live virus vectors for HIV vaccines. Merck has used this complex and showed that 50% of the volunteers had significantly longlasting CD8 T-cell responses to HIV-1 peptides. A trivalent recombinant ad5-gag/pol/nef complex has been engineered and retested in human volunteers. A phase II trial of this candidate is being investigated in 1,200 men and 400 women at high risk of exposure to HIV infection who will be followed for three years.

IMMUNOLOGY OF HIV INFECTIONS part 35

CELLULAR VACCINES

Vaccines have been based on this strategy with particular emphasis on the use of naked DNA vaccines and live recombinant vectors, for example, naked DNA vaccines expressing the HIV-1 gag gene and either IL-12 or IL-15, which was developed by Wyeth and is presently in several phase I trials in the United states, Brazil, and Thailand. DNA vaccines have been found  to be most useful as priming vaccines in prime-boost strategies, using live recombinant vaccines for booster immunization,

IMMUNOLOGY OF HIV INFECTIONS part 34

CELLULAR VACCINES

A strong and specific T-cell immune response in the absence of broadly neutralizing antibodies may blunt the initial viremia, even if the infection is not completely prevented. Thus, more recent vaccine efforts have been directed toward stimulating the cellular  immune response. Particular attention has been paid to those vaccines that induce an HIV-specific CD8 CTL response whose role in the control of virus load and evolution of disease has been well documented in the macaque model. Although the T-cell vaccines do not prevent the HIV infection, they do help vaccines who get infected to control viral replication and reduce viral loads, thus resulting in less risk of transmission of the disease to seronegative partners.

IMMUNOLOGY OF HIV INFECTIONS part 33

SUBUNIT VACCINES

Most of the research efforts in HIV vaccines have gone into the subunit vaccines involving the gp120 envelope proteins, which also includes the GP41 domain. Both of these proteins do elicit neutralizing antibodies to the homologous vaccine strain but not to heterologous primary isolates in the animal model. Despite these caveats, two large scale phase III clinical trials of this type of vaccine have been carried out involving 7,500 high-risk individuals. Neither of these trials showed a significant reduction in HIV infection in the vaccinated individuals. Neither of these trials showed a significant reduction in HIV infection in the vaccinated individuals, even with continuous booster shots during the three-year trial. A number of other trials involving trimeric gp140, a DNA vaccine encoding a V2-deleted gp 140 and other combinations, are in various phases, but the results are not known at present.

IMMUNOLOGY OF HIV INFECTIONS part 32

INACTIVATED VIRAL VACCINES

A second approach has been to inactivated the domains of two nucleocapsid protein zinc fingers. This has been achieved by treating these complexes with mild oxidation or alkylation procedures, which completely inactivates both HIV-1 and SIV but keeps the envelope glycoprotein spikes intact and functional. Studies in the SIV macaque model revealed that monkeys vaccinated with the inactivated virus were not protected against infection with the wild-type virus, but the level of SIV viremia were low and there was  no depletion of CD4 T cells.

IMMUNOLOGY OF HIV INFECTIONS part 31

INACTIVATED VIRAL VACCINES

Although the initial results with inactivated vaccine were negative with high doses of formalin treatment (loss of antigenicity of the viral envelope proteins), it was quickly discovered that by using low doses of formalin, the antigenicity of the envelope proteins was preserved. This preparation was capable of inducing viral neutralizing  antibodies in both mice and nonhuman primates. This area is presently being actively pursued, but the problem will be overcoming the rapidly changing antigens of the wild-type virus

IMMUNOLOGY OF HIV INFECTIONS part 30

Yes,other report by Chakraborty and colleagues indicate that superinfection may be not so high. They studied fourteen HIV seroconcordant couples (ie, partners were independently infected  with different HIV-1 strains) with high risk of re-exposure to the virus. Phylogenetic analyses based on pol and env global sequences obtained from more than a 100 longitudinal plasma samples over one to four years failed to detect HIV-1 superinfection in this cohort patients. They conclude that chronic HIV infection seems to confer protection against superinfection with a second HIV-1 strain. Obviously, more work needs to be done to determine what factors are responsible for superinfection in some individuals and protection in others, both at high risk of reinfection.

IMMUNOLOGY OF HIV INFECTIONS part 29

Several reports raise the question whether these attenuated vaccines will give the broad protection so eagerly sought. As Anne Piantadosi and colleagues (2007) have pointed out, HIV-1 superinfection (reinfection) does not always protect against other strains. In their studies, they screened a cohort of high-risk Kenyan women by comparing partial gag and envelope sequences over a five-year period, beginning with the primary infection.  Of thirty-seven women screened, seven were found to have superinfections, including cases in which both viruses were from the same HIV-1 subtype A. In five cases, the superinfecting strain was detected in only one of the two genomes examined, suggesting that recombination has had time to develop and mature. Supporting this claim was an earlier report by Altfeld et al. in Nature in which this superinfection occured despite broad CD8 T-cell responses (twenty-five distinc epitopes) to many HIV viral proteins. They conclude that superinfection can occur in the setting of a strong and broadly directed virus-specific CD8 T-cell response.

IMMUNOLOGY OF HIV INFECTIONS part 28

LIVE ATTENUATED VACCINES

The observation that NEF strains could offer protection against  challenge with pathogenic SIV infections in rhesus macaques served as the model for the use of this type of attenuated vaccine. However, this mutant's drawback is that it produces a lifelong persistent viral infection in the host. The positive side is that although the attenuated vaccine does not prevent infection with a wild-type SIV infection, it does prevent that infection from going on to produce the disease AIDS. Thus, this approach does not appear feasible now. However, what is being explored is the nature of the protective immune response in these monkeys after infection with the attenuated virus.

IMMUNOLOGY OF HIV INFECTIONS part 27

VACCINE CANDIDATES

There have been many attempts to construct a vaccine that is both protective and has a low cost of production; yet, there is still not a promising candidate. Part of the problem is that to be effective the vaccine has to be given early or before exposure to the virus. Ideally a vaccine could prevent the disease entirely or at least shut down the viremia phase. For the sake of convenience, we have listed the vaccine approaches separately with their promises and caveats.

IMMUNOLOGY OF HIV INFECTIONS part 26

The genome of HIV is a single-stranded positive small RNA molecule, approximately 9.5 kbs in length and encodes the typical retrovirus proteins Gag further divided into  M(matrix), C(capsid), and N(nucleocapsid); Pol, cleaved into protease, reverse transcriptase, and integrase; and ENV 160 kD glycoprotein, divided into an external gp120  and a transmembrane gp41 subunit that together form    trimeric spikes on the surface of the virion. Furthermore, the HIV genome encodes a variety of nonstructural proteins such as transactivation protein (Tat) splice regulator protein (Rev) and accessory proteins such as Nef, Vpr, and Vpn.

IMMUNOLOGY OF HIV INFECTIONS part 25

Two types of HIV have been described: HIV-1 and HIV-2, the latter being less virulent, less transmissible, and confined mostly to West Africa. HIV-1 is phylogenetically close to SIVcpz commensural virus in chimpanzees, which probably arose as a specific transmission event from chimps to humans. However, SIVmac is the etiological  agent of simian AIDS and has many of the features of HIV AIDS. HIV-1 is further divided into three major  groups: M(major), O(outliner), and N(non M or O). Most of the strains responsible for the AIDS epidemic belong to the M group, and this group has been divided into ten different subgroups known as clades (A-K).

IMMUNOLOGY OF HIV INFECTIONS part 24

Before we go to the actual vaccine candidates, some knowledge of the structure of the HIV is warranted. HIV, together with the simian, feline, and bovine immunodeficiency viruses (SIV, FIV, and BIV) all belong to the genus lentevirus in the family of retroviridae. These viruses characteristically produce slowly progressive infections, and the replications depends on an active reverse transcriptase enzyme to transform the viral RNA genome into a proviral DNA copy that integrates into the host cell chromosome. This step provides the enormous genetic diversity of HIV isolates in the infected cell, since the reverse transcriptase step is often fraught with errors in replication.

IMMUNOLOGY OF HIV INFECTIONS part 23

VACCINES TO PREVENT HIV INFECTION

Despite the many efforts to develop a safe and effective vaccine against HIV infection, the results to date have been negative or controversial at best.  Among the reasons for this state of affairs have been the enormous  genetic  diversity of the virus and the unique features of the HIV envelope protein. One thing we have learned from studies of HIV pathogenesis, however, has been that a vaccine that induces a strong and specific T-cell immune response in the absence of broadly neutralizing antibodies may blunt initial viremia, even if the infection is not completely prevented. Moreover, they may prevent the mass destruction  of CD4 T cells, thereby helping to control the infection and prolong disease-free survival.

IMMUNOLOGY OF HIV INFECTIONS part 22

The real problem with the monkey models is that experiments to evaluate vaccine efficacy requires challenging the vaccinated animals with high doses of virus to get 100% infection, that is, 10(3)-10(5) TCID50 equivalent to 5x10(7) SIV RNA copies/ml. This is in marked contrast to natural exposure to HIV in humans wherein the doses of 10(3) HIV RNA copies/ml of seminal plasma have been reported. However, these results are quite different in mucosal challenge, wherein reported low doses (10-30 TCID50) with SIV results in the same viral and immunological kinetics of infection as high-dose challenges. Thus, this new type of mucosal challenge might change the results of preclinical vaccine efficacy studies in the future.

IMMUNOLOGY OF HIV INFECTIONS part 21

However, the problem has been whether these variants, like SHIV 89.6P, are relevant to HIV infections. For example, they exhibit an "X4" cellular tropism and are therefore easier to contain by vaccine-induced immune response than "R5" viruses such as SIV. If we could obtain SHIV strains with R5 tropism, this might be a better model to study.

IMMUNOLOGY OF HIV INFECTIONS part 20

A second animal model of HIV vaccine research is based on the use of SIV/HIV hybrid viruses that were enginered to carry the env gene from HIV into the content of the SIV genome. These viruses do replicate in rhesus macaques and after serial macaque passages do lead to the emergence of highly pathogenic SHIV variants that can wipe out circulating CD4 T cells within a few weeks and lead to a lethal immunodeficiency syndrome within a year of infection.

IMMUNOLOGY OF HIV INFECTIONS part 19

In fact, a significant obstacle in HIV vaccine research has been the difficulty in developing an appropriate animal model with many of the features of human HIV infection. The only animals susceptible to experimental infections with HIV are chimpanzees, Pantroglodytes, and pigtail macaques, Macaca nemestrina. These animals maintain low levels of persistent virus but do not develop clinical manifestations of AIDS. In contrast, Asian monkeys, especially rhesus monkeys from India, are highly susceptible to SIVmac infection and progressively develop an immunodeficiency syndrome that is similar to human AIDS. Plasma viral levels during acute and chronic SIVmac251 infection in these animals parallel those observed in humans, with some animals containing virus spontaneously and progressing to disease slowly as in HIV-1 infected human long-term nonprogressors. In contrast, others maintain high viral loads and behave like human rapid progresses. As in HIV-1 infected humans, the cellular immune response to SIVmac during acute and chronic disease differs significantly, and evidence of immune escape has been well documented. This is particularly true of the mucosal immune system, especially the many CD4 CCR5 T cells in the gut associated lymphoid tissue, the major site of the viral replications and of CD4 T-cell depletion in SIV-infected macaques. This also mimics the human diasease and thus the SIV macaque model is currently considered the most appropriate animal model for studies on potential protective immune responses against HIV.

IMMUNOLOGY OF HIV INFECTIONS part 18

ANIMAL MODELS OF HIV INFECTION

Although many questions concerned with HIV biology were first learned in cultured cell lines infected with HIV or SIV, it became obvious that these cultured lines did not truly mimic the wild-type infections seen in animal models, such as the SCID mouse, were developed  and were helpful but somewhat artificial and did not really mimic human disease.