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(Chest. 2001;120:662-666.)
© 2001 American College of Chest Physicians

The Role of Passive Immunization in HIV-Positive Patients*

A Case Report

Veljko Veljkovic, PhD; Radmila Metlas, PhD; Djorde Jevtovic, PhD and William W. Stringer, MD, FCCP

* From the Institute VINCA (Dr. Veljkovic), Belgrade, Yugoslavia; Diapharm (Dr. Metlas), Guernsey, England; AIDS Clinic (Dr. Jevtovic), Institute for Infectious and Tropical Diseases, Belgrade, Yugoslavia; and UCLA School of Medicine (Dr. Stringer), Harbor-UCLA Medical Center, Torrance, CA.

Correspondence to: William W. Stringer, MD, FCCP, Interim Chair, Department of Medicine, Chief, General Internal Medicine, Associate Professor of Medicine, UCLA School of Medicine, Harbor-UCLA Medical Center, 1000 West Carson St, Box 459, Torrance, CA 90509


   Abstract
TOP
 Abstract
Introduction
 Rationale for Clinical...
 Case Report
 Discussion
 References
 
An HIV-positive patient presented with pulmonary tuberculosis as her AIDS-defining diagnosis in 1993 and was effectively treated with 12 months of standard antituberculosis medications (isoniazide, rifampin, and pyrazinamide for 2 months). She received zidovudine for 6 weeks at the time of her diagnosis; however, because of patient preference, she has not received subsequent standard HIV medications (7 years). Her CD4 count at the time of diagnosis (1993) was 297/µL. Monthly passive immunotherapy was administered (fresh frozen plasma from HIV-negative blood donors with a significant titer for the anti-vasoactive intestinal peptide [VIP]/NTM antibody) from December 1993 to June 1994. Her CD4 count increased to > 400/µL during the passive immunotherapy and has remained stable for the past 6 years. The rational for the use of anti-VIP/NTM antibodies preparations in HIV, the possible mode of action of anti-VIP/NTM antibodies, the use of Ig preparations, and the role of exercise as a natural source of anti-VIP/NTM antibodies are discussed. This case report supports the potential therapeutic use of anti-VIP antibodies for treatment of HIV disease.

Key Words: aerobic exercise • AIDS • anti-vasoactive intestinal peptide/NTM antibodies • HIV • Ig preparations • passive immunization • tuberculosis


   Introduction
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 Abstract
 Introduction
Rationale for Clinical...
 Case Report
 Discussion
 References
 
Despite

Abbreviations: AZT = zidovudine; OC = oral candidiasis; OD = optical density; TB = tuberculosis; VIP = vasoactive intestinal polypeptide\. enormously costly clinical and scientific efforts worldwide, the AIDS pandemic continues to spread at an alarming rate due to the lack of a safe and effective AIDS vaccine. Current HIV therapy is also quite toxic, expensive, and increasingly less effective due to the generation of more aggressive resistant HIV strains. Thus, clinicians are faced with an urgent need for effective, less toxic, nondrug-related therapies for HIV disease. Among the most promising approaches are those directed toward better utilization of the natural capacities of the host immune system against HIV.


   Rationale for Clinical Experiment Design
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 Abstract
 Introduction
 Rationale for Clinical...
Case Report
 Discussion
 References
 
The earliest clinical trials of passive immunization in HIV-positive patients provided conclusive evidence that antibodies to HIV-1 clear virus from the bloodstream to an undetectable level (by polymerase chain reaction) and maintains long-term neutralization of viremia.1 2 These preliminary results have accelerated further research, resulting in development of therapeutic immune preparations containing a mix of concentrated anti-HIV-1 antibodies derived from the healthy HIV-infected individuals (HIV hyperimmune globulin) 3 4 5 6 or immunized animals (porcine-derived hyperimmune Ig to HIV-1).7

Neurath and coworkers8 have reported differences in the spectrum of antibodies against HIV-1 gp120 in two groups of HIV-infected individuals, those who remained healthy for at least 10 years, and those who developed AIDS within 5 years of the onset of infection. They found that antibodies which recognized the peptide 280–306 derived from C-terminus of the second conserved region (C2) of gp120 of the HIV-1 isolate BH10 were significantly more prevalent in asymptomatic carriers than in AIDS patients. It has been speculated that absence or disappearance of these antibodies may represent a possible factor contributing to the development of AIDS.8 The origin of these antibodies remains unclear because the domain 280–306 of the C2 region is nonimmunogenic in humans.9 10 Based on the structural and informational similarities between the peptide RSANFTDNAKTIIVQLNESVEIN (peptide NTM) encompassing residues 280–302 of HIV-1 gp120 and the human vasoactive intestinal polypeptide (VIP), it has been proposed that antibodies identified by Neurath and coworkers represent natural anti-VIP autoantibodies.11 It has also been demonstrated that sera from HIV-negative asthma patients contains high titers of natural anti-VIP antibodies with peptide NTM reactivity.12

Correlation between the titer of VIP/NTM reactive antibodies and AIDS progression indicates that these antibodies may be an important factor in control of the disease. Using the above information, we considered the possibility of applying passive immunization, based on these antibodies, as a therapy for HIV disease. One of the important questions concerning this therapy concerned the possible source of the human VIP/NTM antibodies. Paul and Said13 reported the presence of anti-VIP autoantibodies in normal HIV-negative human sera. Starting from these results, we have screened sera collected from 393 HIV-negative blood donors by enzyme-linked immunosorbent assay based on the peptide NTM. Results of this analysis demonstrated that approximately 5% (21 of 393 donors) of the tested sera contain significant titer of the anti-VIP/NTM antibodies corresponding to optical density (OD) value > (OD mean + 2 SD); (Fig 1 ). Based on these results we decided to use selected normal HIV-negative sera containing high titer of the natural VIP/NTM reactive antibodies for passive immunization therapy of an HIV patient.



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  		Figure 1.. Reactivity to VIP in sera collected from 393 healthy, HIV-negative blood donors. Twenty-one of 393 donors (5.3%) exceeded (by 2 SD) the average OD of 0.275.

 

   Case Report
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 Abstract
 Introduction
 Rationale for Clinical...
 Case Report
Discussion
 References
 
A 35-year-old female IV drug user presented with pulmonary tuberculosis (TB) as her index AIDS diagnosis in November 1993. The clinical pattern of TB was typical of the reactivation, with chest radiography showing left upper lobe infiltration. The subsequent culture revealed Mycobacterium tuberculosis with a sensitive organism. The standard anti-TB therapy (isoniazide, rifampin, and pyrazinamide for 2 months) was effective and completed in November 1994 (12 of months of therapy). At the time of diagnosis (November 1993), her CD4 cell count was 297/µL (26.8%), her p24 antigen was negative, and her hematologic parameters allowed the introduction of zidovudine (AZT) therapy.

She was treated with oral AZT for 6 weeks after her diagnosis, and she remained clinically stable; however, mild oral candidiasis (OC) developed. During this period of AZT therapy, her CD4 cell count decreased to 253/µL (17.7%). Due to patient dissatisfaction with AZT treatment and the fall in her CD4 count, an alternative treatment was offered to the patient. She accepted, and AZT treatment was discontinued.

Treatment
The passive immunization protocol used for this patient was presented and approved by the local institutional review board (AIDS Clinic, Institute for Infectious and Tropical Diseases, Belgrade, Yugoslavia). One thousand milliliters of fresh frozen plasma selected from HIV-negative blood donors with a significant titer for the anti-VIP/NTM antibody (Fig 1) was administrated monthly for 6 consecutive months (from December 30, 1993, to June 20, 1994).

Laboratory Findings
The reactivity of patient’s serum to the peptides NTM and VIP was initially weak (OD < 0.25, a level of reactivity that corresponds to normal HIV-negative sera), but rose significantly after the immunotherapy infusions (OD, > 0.6). Subsequently, it remained high (OD, 0.65 to 0.73) until July 1995. Her CD4 count rose from a pretreatment value of 253 µ/L to 413/µL and 560/µL after 22 weeks and 32 weeks, respectively. In September 1995, it was 452/µL, peaked to 920/µL in July 1996, and decreased to 411/µL in May 1997 (Fig 2 ). It is important to point out that the percentage of CD4 cells, which represents an important predictor of development of AIDS,10 increased although her total CD4 count decreased (Fig 2) . Her viral load was 125,000 copies per milliliter (Amplicor System; Roche Diagnostics; Indianapolis, IN) on June 1994.



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  		Figure 2.. Change in the CD4 count per microliter and the CD4 fraction (percentage) for the first 1,750 days (5 years) after the initial (6 months) immunotherapy.

 
During the last 2 years, her CD4 count has been stable around 400/µL (last value May 1999). Figure 3 shows the marked increases in neutralizing anti-V3 antibody concentration with passive infusion therapy in this patient. Note the parallel increases in CD4% and total CD4 count during this period of therapy (Fig 2) .



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  		Figure 3.. Increases in neutralizing anti-V3 antibody concentration during the first 150 days of passive infusion therapy in the subject.

 
Follow-up
Even though pulmonary TB usually occurs relatively early in the course of HIV infection, with CD4 count well above 200/µL, it is clear that reactivation of a latent TB infection is related to early (subclinical) HIV-induced immunodeficiency. Most AIDS patients will continue to have progression of their immune deficiencies if untreated, especially when other signs of immune dysfunction are present (eg, OC). Using the definition of AIDS prior to the use of pulmonary TB as an AIDS-defining event, the median time to progression to AIDS after OC was 70 weeks among patients who are not receiving antiretroviral therapy, while > 80% of patients with OC would develop AIDS after 3 years. Therefore, we consider this case unusual, as she has not progressed after > 6 years from OC and TB and her CD4 cell count remained > 400/µL for > 5 years. Her last CD4 cell count was in May 1999, as she has been reluctant to undergo further laboratory examination. She remains disease free without symptoms at the time of this case report and receives regular office evaluations. Her OC is under control with intermittent fluconazole therapy.


   Discussion
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 Abstract
 Introduction
 Rationale for Clinical...
 Case Report
 Discussion
References
 
Possible Mode of Action of NTM/VIP-Reactive Antibodies
One of important obstacles in control of HIV infection by the host immune system relates to the phenomenon of "deceptive imprinting."14 According to this theory, immediately after HIV infection, immunodominant epitopes of HIV produce selective pressure on the immune system, which induces and maintains its deceptive state. Therefore, the immune system is only able to recognize those HIV variants carrying epitopes that are identical or very close to the "original antigenic sin" presented initially after infection. In this way, later variants that evolve from the first autologous virus are unrecognized by the immune system and escape neutralization. At this point, since the immune system is prevented from appropriately addressing the HIV infection, it starts to produce natural autoantibodies that are able to neutralize the virus by attacking its sensitive and highly conserved sites (C-terminus of the second conserve conserved region of gp120). The putative protective role of anti-VIP/NTM antibodies could be attributed to the multipathway mode of action, including the following: (1) blocking the "secondary interaction" between HIV-1 gp120 and CD4 molecule,15 16 17 (2) impairing HIV infectivity,18 19 20 (3) blocking intermolecular interaction within the oligomeric envelope complex,21 (4) inactivation of gp120 by its proteolysis with the anti-VIP/NTM antibodies,22 23 and/or (5) maintenance of the immune network dynamic.24 25

Therapy With HIV-Positive vs HIV-Negative Plasma and Ig Preparations
Despite the initial optimism based on a promising preliminary clinical results (especially in prevention of HIV-1 transmission from mother to child), passive immunotherapy is not a common intervention in current HIV therapy. The principle problem appears to be the therapeutic component (neutralizing anti-V3 antibodies) present in plasma and Ig preparations collected from HIV-positive individuals. The V3-loop as a principal neutralizing determinant of HIV-1 gp120 elicits type-specific but not group-specific antibodies.26 This means that efficacy of this therapy potentially depends on the "immunologic compatibility" between HIV-1 isolates from donor(s) and acceptor (patient). There are data that point out the possibility that antibodies elicited by V3-loop, as well as by some epitopes from gp41, may be potentially harmful rather than protective, because they can enhance HIV-1 infection.27 28 29 30 It has been also reported that gp120 protein structure might encode idiotopes. In this way idiotope-bearing gp120, either soluble or expressed in multiple form on the surface of the cell, can influence the immune response in idiotype Id-anti-Id fashion.24 25 31 32 These data, together with other harmful effects of anti-gp120 antibodies, have been reviewed,33 pointing out the significant therapeutic advantage of HIV-negative plasma preparations enriched with anti-VIP/NTM antibodies in comparison with application of HIV Ig.

Exercise as a Natural Source of VIP/NTM Reactive Antibodies
Although infusion therapy appears promising in this case report, other less invasive mechanisms to produce high titers of VIP/NTM reactive antibodies may be feasible. An interesting article by Paul and Said in 198813 showed that autoantibodies to VIP were present in plasma from 29.6% of healthy (non-HIV-positive) human subjects who habitually performed aerobic muscular exercise (running, cycling, swimming, aerobic dancing, and/or weight training, three or more workouts per week for a year or more prior to study entry), compared to 2.3% of healthy subjects who did not. The antigenic stimulus for the formation of these autoantibodies could not be identified from their data; however, acute exercise has been shown to be associated with a brisk increase plasma levels of VIP.34 35 It is certainly plausible to theorize that these antibodies may have been produced in response to increased VIP levels during exercise.

Aerobic exercise training has been demonstrated in a number of studies to have beneficial effects in HIV-positive individuals, including increased fitness (as measured by lactic acidosis threshold and maximal oxygen uptake)36 and improvements in skin test reactivity to Candida antigen, without adverse effects on CD4 counts or viral loads.37 Finally, quality of life is significantly improved with aerobic exercise training relative to a nonexercising control group.

Therefore, passive infusion and aerobic exercise would both appear to be very promising adjunctive therapies for HIV infection. Indeed, aerobic exercise may prove to be an ideal nondrug adjunctive therapy to increase the titer of anti-VIP/NTM antibodies, improve immune status, aerobic fitness, and quality of life in HIV-positive individuals. Passive infusion and aerobic exercise training to increase the titer of anti-VIP/NTM antibodies would appear to warrant further investigation in HIV-positive individuals.


   Footnotes
 
Drs. Veljkovic and Metlas are affiliated with Diapharm, Guernsey, England.

Received for publication August 30, 2000. Accepted for publication January 5, 2001.


   References
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 Abstract
 Introduction
 Rationale for Clinical...
 Case Report
 Discussion
 References
 

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