Case 13

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CASE 13

You have been Anthony’s general practitioner since childhood. Other than the usual run of minor childhood disorders, there has been nothing of note in his medical history. Both parents and a younger sibling are well. He is currently 22 years of age and is home for the summer, on vacation from college. Anthony had called your office, requesting a complete physical examination, and, as a precursor to that visit, you have ordered a series of routine tests, including serum blood cell counts and electrolyte determinations, chest radiograph, and urinalysis. The day before the appointment the laboratory results become available and show, somewhat surprisingly to you, a marked increase in some liver enzymes (transaminases) and an elevated bilirubin level. Physical examination of this young man when he did come in revealed, not surprisingly, a mild jaundice, with some tenderness at the liver edge. There were no other significant abnormalities, although you also note some healing bruises and pinpricks in the forearm. He seems to be sniffing a lot, as though he has a perpetual postnasal drip, and he seems to be somewhat more edgy in your presence than usual. How are you going to open up a conversation? What do you want to address? Do you have significant concerns?

QUESTIONS FOR GROUP DISCUSSION

1. Given the conglomeration of findings, how are you going to open up a conversation to address the overriding concern of drug use/abuse?
2. Cocaine may explain the sniffles and edginess, but resolving track marks and liver disease should alert you to intravenous drug use. As such, you should request serologic tests to determine if this patient has been exposed to a number of infections. For which infectious agents would you request an antibody titer?
3. At early stages of infection, serologic tests often provide false-negative results. Explain why this is so, and how one would confirm these results and the principle underlying the confirmatory tests.
4. Anthony’s confirmatory test was positive for HIV. Draw a schematic illustrating HIV infection of a CD4+ T cell. See Figure 13-2. Identify gp120, gp41, CD4, and the chemokine receptor. Also, explain the term “facilitated HIV infection in trans.” (Hint: What is the role of DC-SIGN in HIV infection?)
5. When Anthony was informed that he was HIV positive, he asked his physician if he could begin highly active retroviral therapy (HAART). What is the underlying principle of the drugs that constitute HAART? Explain why antiretroviral therapy (HAART) is effective by illustrating the steps these drugs target during productive viral infection of a cell.
6. As Anthony’s physician, you realize that you have to convince him that there are limitations to HAART. Discuss the advantages and disadvantages of HAART.
7. In addition to the advantages and disadvantages of HAART, you also explain to your patient that the “hit hard, hit early” slogan does not represent the current recommendations regarding when to commence therapy. What are the generally accepted guidelines for commencing HAART therapy?
8. HIV has evolved a number of viral evasive strategies. Describe several of these and explain how these contribute to viral persistence in a normal individual such that individuals develop acquired immunodeficiency syndrome (AIDS).
9. Interleukin (IL)-2 is a growth factor for T cells. Therefore, it seems reasonable to consider IL-2 as a therapeutic agent to expand the population of CD4+ T cells, which are the primary target of HIV infection. However, clinical trials have shown that IL-2 therapy can actually lead to an increase in viral load. Despite this, some advocates of IL-2 therapy argue that therapy with this cytokine in the presence of HAART is a good idea. Explain.
10. Describe the various approaches in attempts to develop an effective HIV vaccine and explain why an effective HIV vaccine is not likely in the immediate future.
image

FIGURE 13-2 Structure of human immunodeficiency virus-1 (HIV-1). An HIV virion is shown interacting with a CD4+ T cell. HIV interacts first with the primary receptor, CD4, via its envelope glycoprotein, gp120. Binding to CD4 creates a complex that allows gp120 to bind to CCR5 or CXCR4. Following this binding, gp41, which is a fusion protein, enters the cell membrane to initiate fusion of the viral envelope and subsequent delivery of the viral proteins and genome into the cell.

(From Abbas A, Lichtman A: Cellular and Molecular Immunology, 5th ed. Philadelphia, Saunders, 2003; Modified from front cover, The New Face of AIDS. Science 272:1841–2102, 1996. © Terese Winslow.)

RECOMMENDED APPROACH

Implication/Analysis of Family History

There is nothing remarkable about the family history and because you have been Anthony’s physician since childhood you are more concerned about recent lifestyle changes now that he is attending college.

Implications/Analysis of Clinical History

You should be concerned about the conglomeration of findings and need to find out if they are all symptomatic of the same problem. An overriding concern here is drug use/abuse. Cocaine may explain the sniffles and edginess, but the evidence for resolving track marks and liver disease should alert you to intravenous drug use. Anthony admits to intravenous drug use, although he claims it was a short period (less than 2 weeks) and that he has not had heroin for more than a month. Unfortunately it seems as though there was at least one episode of shared needle use. Further questioning reveals a recent history of fever (lasted >10 days ˜2 weeks ago) but no cough and no hematuria. There is no candidiasis. He casually mentions that he had diarrhea for days after he got home, attributing that to eating at a pretty run-down roadside café when he was driving home for the holidays.

Implications/Analysis of Laboratory Investigation

Based on the clinical history, physical examination (track marks on the arm, healing bruises, jaundice), and laboratory test results (elevated liver enzymes) you should be concerned about hepatitis and HIV infection. These infections are increased, depending on the setting in which intravenous drug use is occurring.

Additional Laboratory Tests

A complete blood cell count with differential was requested, along with enzyme-linked immunosorbent assays (ELISAs) to detect anti-hepatitis (A/B/C) antibodies. Additionally, a repeat liver enzyme assessment was ordered. The white blood cell count and differential was normal, and there was no evidence of anti–hepatitis B or anti–hepatitis C antibodies. However, there was evidence for hepatitis A seroconversion (anti-hepatitis A antibodies). Repeat blood work suggested the liver tests were normalizing. HIV serology was negative. At this stage you are a little more relieved.

Recognizing, however, that in the early stages of infection there are significant false-negative results in viral diagnostic tests that are based on antibody detection, you order more sensitive tests (viral load using nucleic acid amplification, e.g., polymerase chain reaction) for HIV and both hepatitis B and C. In most individuals the viral load (number of viral particles in circulation) is highest just before seroconversion. The viral load analysis for HIV comes back positive.

DIAGNOSIS

On the basis of the nucleic acid amplification tests, Anthony is informed that he is infected with HIV, the causative agent of acquired immunodeficiency disease (AIDS). Anthony’s CD4+ T cell count will need to be monitored. As the number of CD4+ T cells decreases, the number of opportunistic infections increases (Fig. 13-1).

image

FIGURE 13-1 Section of duodenum from HIV-infected patient with opportunistic infection by Cryptosporidium. Note small spherical bodies (schizonts) on the surface epithelium, weakly staining with hematoxylin and eosin (×400). The lamina propria is heavily infiltrated with plasma cells.

THERAPY

Highly active antiretroviral therapy (HAART) is the treatment of choice for HIV-infected patients. This drug regimen includes two antinucleoside analogue inhibitors and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. Even though the use of HAART is not a controversial issue, the “when” to initiate therapy is highly debated. This controversy follows the realization that the “hit hard, hit early” slogan of the mid 1990s does not lead to the eradication of the virus in patients despite long term, and early, drug therapy. HIV is detectable in latent infected cells even after prolonged therapy, and so the approach to drug therapy has had to be modified.

Advantages and Disadvantages of HAART

There are advantages and disadvantages to HAART. In patients receiving HAART, plasma HIV RNA levels fall to below the level of detection within 2 to 6 months. There is an increase in CD4+ T cell count and therefore delayed progression to AIDS. As well, in some cases HAART is accompanied by enlargement of the thymus. Whether this enlargement is due to regeneration of the thymus and active thymopoiesis or from the migration of peripheral blood cells into the thymus is currently being addressed using in vivo TREC (T cell receptor excision circles) assay of thymic function (see Case 2). On the down side, hepatotoxicity is a serious consideration, as is the development of viral variants that are resistant to the drugs. Additionally, HAART therapy does not eliminate HIV from resting memory CD4+ T cells carrying an integrated copy of the viral genome. Therefore, on discontinuation of HAART, viral load measures (plasma HIV-1 RNA) become significant when the latently infected cells are activated even by stimulatory molecules normally present in lymphoid tissues.

Patient Compliance with Treatment

The emergence of variants that are resistant to the ongoing drug therapy is substantially increased by the lack of patient adherence. In some cases this may reflect a regimen too complicated for the patient, a very large number of pills, or poor tolerance to the medication. In other cases, the patient’s desire for such intense treatment is not sufficient to merit adherence to therapy.

When to Begin Therapy

The question still remains as to when to begin therapy. Issues at stake are whether viral load or CD4+ T cell count should be used as a guideline for initiating therapy. Even those that advocate using CD4+ T cell count as the marker for therapy do not agree as to what that CD4+ T cell number should be. Those that believe that therapy should be initiated when the CD4+ T cell count falls below 200 cells/μL support their argument by emphasizing the reduced time for toxicity, enhanced quality of life before therapy, and a decrease in potential for viral resistance.

On the other hand, those that believe that therapy should be initiated when CD4+ T cell count is 350 cells/μL argue that initiating therapy at this time prevents irreversible immune damage, minimizes the spread of HIV to more restricted sites (e.g., central nervous system), and minimizes the potential for development of more virulent HIV. The initiation of HAART when the CD4+ T cell count is less than 350 cells/μL, or sooner if the HIV RNA load is higher than 5000 copies/mL, is another option that is under consideration. Once drug therapy is initiated, patient adherence and viral load should be monitored regularly.

Role of Cytokines in Therapy

Although HAART is changing the course of HIV infections, the reality is that the toxicity of the drugs and the emergence of drug-resistant escape mutants indicate that immunologic therapies should be pursued. Furthermore, the realization that discontinuation of therapy results in a rebound of viral burden emphasizes the need for immunologic forms of therapy.

Clinical trials have focused on those cytokines that would restore the patient’s cells (e.g., granulocyte-macrophage colony-stimulating factor [GM-CSF] for myeloid cells; IL-2, a growth factor for T cells; IL-12, to enhance polarization of T cell development toward CD4+ Th1 cells). Whereas larger randomized trials have been initiated for some of the therapies, others have been shown to actually cause an increase in plasma viral load. In vitro studies have shown that latently infected cells are activated and induce viral replication in the presence of some cytokines (e.g., IL-2, IL-6, and tumor necrosis factor-α).

Those who advocate the use of IL-2 as therapy to increase the number of CD4+ T cells in conjunction with HAART suggest that the IL-2 would activate latent cells with the net effect being their eradication, while the patient is protected by HAART. Implicit assumptions in this approach are that the virus strains are not resistant to HAART and that all the latent cells are CD4+ T cells. Recall that some cells that do not express CD4 can be infected after binding to galactosyl ceramide.

Another cytokine, IL-15, has been recommended for immunotherapy, based on the advantage that it does not enhance HIV replication but does play an important role in NK cell and CD8+ T cell cytotox-icity, CD4+ Th1 cell development, and activation of dendritic cells, monocytes, and neutrophils.

Vaccines

A number of pharmaceutical firms (e.g., VaxGen, Aventis Pasteur, Wyeth, Chiron, GlaxoSmithKline) are presently engaged in human trials for an HIV vaccine using various vectors and vaccine strategies. Ideally, a vaccine stimulates the immune system such that sterilizing immunity results (i.e., exposure to the virus fails to establish an ongoing infection in the immunized host). At this time, however, a vaccine that slows down or inhibits HIV replication would be beneficial to the millions of people infected with HIV.

Recombinant Protein Vaccines

From a historical point of view, it is not surprising that the early attempts at vaccine development used a recombinant form of the HIV envelope protein, gp120. After all, a recombinant vaccine for hepatitis B has been very effective. The ineffectiveness of the HIV vaccines is due, in part, to the fact that the neutralizing antibodies formed were specific for laboratory strains of HIV. In other vaccines, several anti-HIV antibodies developed, but these were not neutralizing. In general, neutralizing antibodies are not generated until late in the course of the HIV infection.

Recombinant Viruses and DNA Vectors

It also became evident early on that an effective vaccine would need to generate anti-HIV specific cytotoxic CD8+ T cells. Traditionally, this has been achieved by using attenuated viruses as vaccines (e.g., measles, mumps, rubella), but the risks associated with reversion to wild-type virus eliminate this as an option for HIV. Rather, recombinant DNA techniques have been used to insert HIV genes in the genome of nonlethal viruses from which genes relevant for viral production have been removed (e.g., canary poxvirus, adeno-associated virus). Because the principal function of these modified viruses is to ensure that HIV genes enter the cell cytosol, this can also be accomplished using microparticles containing HIV nucleic acids.

Once the genetic material is in the cell, it can be transcribed and translated into proteins. The proteins generated are hydrolyzed by the proteasome and the fragments translocated to the endoplasmic reticulum where they encounter class I MHC molecules and form complexes that are subsequently expressed on the surface of the cell. CD8+ T cells that recognize the complexes will be activated if the appropriate co-stimulatory molecules are also present. Unfortunately, these vaccines have not been particularly effective in generating either strong cytotoxic T cell or antibody responses. A modified approach, the “prime, boost” approach, has been used in attempts to enhance the response. In this approach, the vector is administered in the initial vaccine and this is followed by a protein injection weeks later.

Antigen-Pulsed Dendritic Cells

Several studies have shown that HIV-positive patients have fewer dendritic cells and that these cells have a reduced capacity to activate T cells. In the absence of antigen presentation, T cells cannot be activated, and so it has been suggested that this is one of the reasons why the immune system cannot clear HIV infection. To address this issue in an animal model, cytokine-treated (GM-CSF, IL-4) dendritic cells were pulsed with inactivated simian immunodeficiency virus and then injected into rhesus monkeys. Reports from this study are impressive; however, whether this approach would be efficacious or feasible for human vaccines is the focus of several investigations.

Vaccine Failures: “Original Antigenic Sin”

Despite the vast amount of research and various clinical trials, an effective vaccine is not likely in the near future. One of the reasons for this is the high frequency of mutations that escape detection by activated cytotoxic T cells and by anti-HIV antibodies.

Because mutations can occur early in the course of the disease, the activated cytotoxic T cells are no longer effective, yet immune response to escape mutants is much weaker than that to the primary HIV isolate (“original antigenic sin”). Antibody responses to the initial epitopes have also been reported to dominate. In addition to a blunted response to the escape mutants, the decrease in CD4+ T cells hampers cytotoxic T cell development (and antibody responses) because both require cognate interaction with, and cytokines derived from, CD4+ T cells.

ETIOLOGY OF AIDS: HUMAN IMMUNODEFICIENCY VIRUS

The human immunodeficiency virus type 1 (HIV) is the causative agent of AIDS, a disease in which the patient’s CD4+ T cell count is so drastically reduced that the patient becomes susceptible to numerous opportunistic infections. Transmission occurs from one person to another via infected body fluids (e.g., semen, blood). Retroviruses are enveloped single-stranded RNA viruses, whose genome encodes several proteins, including reverse transcriptase that reverse transcribes the RNA to double-stranded DNA. Activation of the infected cell is required for integration (random) of the double-stranded DNA into the genome. This double-stranded viral DNA is integrated into the host chromosome, where it can remain in a latent phase for years as a provirus until the cell is activated to replicate. Because the HIV provirus is integrated into the host chromosome, all the progeny of the infected cells will also have the provirus in their genome.

Cell Infection

Cell Surface Receptors

Productive infection requires that HIV binds to both a primary receptor, CD4, and a co-receptor CCR5 or CXCR4 on the target cell. CCR5 and CXCR4 are chemokine receptors that are targeted by different HIV strains (Fig. 13-2). CCR5 is used primarily by macrophage (M) tropic strains, whereas CXCR4 is used primarily by T cell (T) tropic strains. HIV interacts first with the primary receptor, CD4, via its envelope glycoprotein, gp120. Binding to CD4 creates a complex that allows gp120 to bind to CCR5 or CXCR4. After this binding, gp41, which is a fusion protein, enters the cell membrane to initiate fusion of the viral envelope and subsequent delivery of the viral proteins and genome into the cell. Under some circumstances, HIV can infect cells that do not express CD4 (e.g., endothelial cells, microglial cells) by binding galactosyl ceramide.

“Facilitated Infection In Trans”: Role of DC-SIGN

In context of HIV infection, the term facilitated infection in trans refers to the transfer of HIV from a dendritic cell surface molecule, DC-SIGN (dendritic cell–specific ICAM-3 grabbing nonintegrin), to CD4 on a target cell. In an emerging model, dendritic cells play an important role in the establishment of primary HIV infection by capturing viral particles in peripheral mucosal tissues and transporting them to the secondary lymphoid tissues.

In this model, capture occurs when DC-SIGN, a lectin, on dendritic cells binds HIV gp120 with high affinity, internalizes the complex into an acidic compartment, and recycles back to the surface where the HIV can be transferred to CD4+ T cells. Although studies indicate that internalization into an acidic compartment is essential for subsequent in trans infection, the strategies employed to evade degradation in the endocytic vacuole have not been determined.

Productive infection of CD4+ T cells, however, requires that T cells be activated. T cell activation occurs when antigen-specific receptors interact with complexes of class II MHC-antigen peptide on the surface of antigen-presenting cells. Therefore, antigen processing of HIV must also occur. The simplest explanation that would allow both events to occur is that DC-SIGN complexes are internalized via endocytic vesicles that escape fusion with lysosomes, while HIV particles internalized after binding to primitive pattern receptors are handled via the well-described pathway of antigen processing and cell surface expression with class II MHC.

Interaction of dendritic cells with CD4+ T cells in secondary lymphoid tissues via antigen-specific T cell receptors, co-stimulatory molecules, and adhesive molecules would bring the DC-SIGN-HIV complexes into close proximity to CD4, thereby facilitating infection (i.e., facilitated infection in trans) of the T cells.

DC-SIGN was first identified as a molecule that bound intercellular adhesive molecules (ICAM)-2 and -3 with greater affinity than leukocyte function antigen (LFA)-1, the previously known receptor for these adhesive molecules. ICAM-2 is expressed on both resting and activated vascular endothelium, as well as resting T cells. ICAM-3 is expressed also on resting T cells, as well as other leukocytes.

HIV Evasive Strategies

The failure of the immune system to eradicate HIV infection in previously healthy individuals is testament to the various immune strategies that are employed by the virus. The effectiveness of these immune evasive strategies is underscored when one considers that, despite the millions of people infected worldwide, there is not a single documented case of infection being eradicated by the immune system. This is unique in the world of viruses where, despite epidemics that kill millions of people (e.g., influenza viruses), a substantial number of the population can eliminate the infection. This holds true, even for devastating Ebola virus infections.

An understanding of the evasive strategies used by HIV may be critical for the development of therapeutic interventions. Mutagenesis, inhibition of class I MHC expression, and inhibition/downregulation of CD4 expression are well documented HIV strategies that either allow HIV to thwart the immune system or allow it to persist and replicate more effectively.

Mutagenesis of Viral Proteins

Retroviruses have an RNA genome that is converted to double-stranded DNA by the action of viral reverse transcriptase, a polymerase that has no proofreading activity, and so this leads to a very high error rate during this process. Existing antibodies do not recognize these “new” antigens, and activated T cells do not recognize the antigenic peptides that are displayed with MHC on the cell surface. In some cases, the mutated peptides cannot associate with existing MHC alleles, or they bind MHC with very low affinity, thereby reducing the stability of the MHC-peptide complex. Responses to the mutated viruses are typically blunted. In the absence of MHC-peptide recognition, T cell activation does not occur.

Downregulation of Class I Expression

Downregulation of class I MHC expression is a relatively common viral evasive strategy, but the mechanisms by which this is achieved vary from virus to virus. In HIV, downregulation of class I MHC is attributed to the action of the HIV regulatory protein, Nef, because its presence, or absence, in the HIV genome affects expression of class I MHC on the cell surface, a requirement for activation of cytotoxic T cells. At least two different mechanisms have been reported to explain this effect; the first is that Nef increases the endocytosis of surface class I MHC; the other is that Nef redirects class I MHC from the Golgi to the cytosol, or sequesters the complex in the Golgi. Irrespective of the mechanism, a decrease in the class I MHC-HIV peptides expressed on the infected cell surface will hinder recognition and targeting by cytotoxic T cells. Interestingly, the amount of class I MHC expressed on a cell surface has been shown to depend on the particular Nef allele encoded by a particular viral variant.

Downregulation of CD4

Nef has also been reported to play a role in the enhanced endocytosis of cell surface CD4 and rerouting from the Golgi apparatus, which results in decreased cell surface expression. How a reduction in CD4 expression benefits the virus is speculative because HIV (via gp120) must bind to CD4 to gain entry into the cell. What has been postulated is that a decrease in CD4 would reduce further HIV entry and hence avoid superinfection, which would be cytopathic to the cell. Alternatively, a reduction in CD4 cell surface expression reduces the likelihood of syncytia formation (by syncytium-inducing viruses), a phenomenon in which the gp120 embedded in the host cell membrane binds to other cells expressing CD4 such that cell fusion results. Syncytia can consist of four to five T cells that are effectively eliminated from immune responses.

Blocking Apoptosis of Infected Cells

Cells infected with HIV will ultimately undergo apoptosis, but productive infection and viral persistence necessitates that apoptosis be delayed at least until viral assembly and budding from the cell has occurred. In addition to its role in downregulating CD4 and class I MHC molecules, the Nef protein has been shown to prevent apoptosis of infected cells via interaction with cytosolic kinases.

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