Evaluation of the prevalence of dental agenesis through the use of orthopantomography in a sample of subjects residing in Lombardy and Piedmont regions.

AIM: Dental agenesis is one of the most frequent dental anomalies, with a prevalence varying from 1.6% to 36.5%, depending on the populations studied. The patient's age at diagnosis, sex, and ethnic differences are considered possible influenting factors that can explain such a wide range of prevalence. The objective of the study was to define the frequency of dental agenesis in a sample of subjects living in Piedmont and Lombardy regions of Italy. MATERIALS: X-rays, already taken for other diagnostic purposes, were collected. Orthopantomographies belonging to subjects born after 1995 and aged between 7.9 and 16.9 years were selected. It was assessed the presence of each tooth, except for third molars since they are frequently absent due to their variability. If a tooth was missing and the patient had additional radiographs, the other radiographs were evaluated to confirm the diagnosis or to rule out a delayed calcification or the presence of a malposition tooth. Results: Orthopantomographies were collected from 1,020 subjects and 98 of them presented agenesis, with a prevalence of 5% for females and 4.61% for males. The most affected teeth were 35 and 45, followed by 12 and 22. The lower arch was more frequently involved by agenesis: there were 107 teeth absent in the mandibular arch and 83 in the maxillary arch.

Evaluation of an aSi-EPID with flattening filter free beams: applicability to the GLAaS algorithm for portal dosimetry and first experience for pretreatment QA of RapidArc.

PURPOSE: To demonstrate the feasibility of portal dosimetry with an amorphous silicon mega voltage imager for flattening filter free (FFF) photon beams by means of the GLAaS methodology and to validate it for pretreatment quality assurance of volumetric modulated arc therapy (RapidArc). METHODS: The GLAaS algorithm, developed for flattened beams, was applied to FFF beams of nominal energy of 6 and 10 MV generated by a Varian TrueBeam (TB). The amorphous silicon electronic portal imager [named mega voltage imager (MVI) on TB] was used to generate integrated images that were converted into matrices of absorbed dose to water. To enable GLAaS use under the increased dose-per-pulse and dose-rate conditions of the FFF beams, new operational source-detector-distance (SDD) was identified to solve detector saturation issues. Empirical corrections were defined to account for the shape of the profiles of the FFF beams to expand the original methodology of beam profile and arm backscattering correction. GLAaS for FFF beams was validated on pretreatment verification of RapidArc plans for three different TB linacs. In addition, the first pretreatment results from clinical experience on 74 arcs were reported in terms of γ analysis. RESULTS: MVI saturates at 100 cm SDD for FFF beams but this can be avoided if images are acquired at 150 cm for all nominal dose rates of FFF beams. Rotational stability of the gantry-imager system was tested and resulted in a minimal apparent imager displacement during rotation of 0.2 ± 0.2 mm at SDD = 150 cm. The accuracy of this approach was tested with three different Varian TrueBeam linacs from different institutes. Data were stratified per energy and machine and showed no dependence with beam quality and MLC model. The results from clinical pretreatment quality assurance, provided a gamma agreement index (GAI) in the field area for six and ten FFF beams of (99.8 ± 0.3)% and (99.5 ± 0.6)% with distance to agreement and dose difference criteria set to 3 mm/3% with 2 mm/2% thresholds, GAI resulted (95.7.0 ± 2.3)% and (97.2 ± 2.1)%. CONCLUSIONS: The GLAaS methodology, introduced in clinical practice for conventional flattened photon beams for machine, IMRT, and RapidArc quality assurance, was successfully adapted for FFF beams of Varian TrueBeam Linac. The detector saturation effects could be eliminated if the portal images acquired at 150 cm for all nominal dose rates of FFF beams.

Dosimetric evaluation of photon dose calculation under jaw and MLC shielding.

PURPOSE: The accuracy of photon dose calculation algorithms in out-of-field regions is often neglected, despite its importance for organs at risk and peripheral dose evaluation. The present work has assessed this for the anisotropic analytical algorithm (AAA) and the Acuros-XB algorithms implemented in the Eclipse treatment planning system. Specifically, the regions shielded by the jaw, or the MLC, or both MLC and jaw for flattened and unflattened beams have been studied. METHODS: The accuracy in out-of-field dose under different conditions was studied for two different algorithms. Measured depth doses out of the field, for different field sizes and various distances from the beam edge were compared with the corresponding AAA and Acuros-XB calculations in water. Four volumetric modulated arc therapy plans (in the RapidArc form) were optimized in a water equivalent phantom, PTW Octavius, to obtain a region always shielded by the MLC (or MLC and jaw) during the delivery. Doses to different points located in the shielded region and in a target-like structure were measured with an ion chamber, and results were compared with the AAA and Acuros-XB calculations. Photon beams of 6 and 10 MV, flattened and unflattened were used for the tests. RESULTS: Good agreement between calculated and measured depth doses was found using both algorithms for all points measured at depth greater than 3 cm. The mean dose differences (± 1SD) were -8% ± 16%, -3% ± 15%, -16% ± 18%, and -9% ± 16% for measurements vs AAA calculations and -10% ± 14%, -5% ± 12%, -19% ± 17%, and -13% ± 14% for Acuros-XB, for 6X, 6 flattening-filter free (FFF), 10X, and 10FFF beams, respectively. The same figures for dose differences relative to the open beam central axis dose were: -0.1% ± 0.3%, 0.0% ± 0.4%, -0.3% ± 0.3%, and -0.1% ± 0.3% for AAA and -0.2% ± 0.4%, -0.1% ± 0.4%, -0.5% ± 0.5%, and -0.3% ± 0.4% for Acuros-XB. Buildup dose was overestimated with AAA, while Acuros-XB gave results more consistent with measurements. From RapidArc plan analysis the average difference between calculation and measurement in the shielded region was -0.3% ± 0.4% and -2.5% ± 1.2% for AAA and Acuros-XB, respectively, relative to the mean target dose value (1.6% ± 2.3%, -12.7% ± 4.0% if relative to each local value). These values were compared with the corresponding differences in the target structure: -0.7% ± 2.3% for AAA, and -0.5% ± 2.3% for Acuros-XB. CONCLUSIONS: The two algorithms analyzed showed encouraging results in predicting out-of-field region dose for clinical use.

Critical appraisal of volumetric-modulated arc therapy compared with electrons for the radiotherapy of cutaneous Kaposi's sarcoma of lower extremities with bone sparing.

OBJECTIVE: To evaluate the use of volumetric-modulated arc therapy [VMAT, RapidArc® (RA); Varian Medical Systems, Palo Alto, CA] for the treatment of cutaneous Kaposi's sarcoma (KS) of lower extremities with adequate target coverage and high bone sparing, and to compare VMAT with electron beam therapy. METHODS: 10 patients were planned with either RA or electron beams. The dose was prescribed to 30 Gy, 10 fractions, to mean the planning target volume (PTV), and significant maximum dose to bone was limited to 30 Gy. Plans were designed for 6-MV photon beams for RA and 6 MeV for electrons. Dose distributions were computed with AcurosXB® (Varian Medical Systems) for photons and with a Monte Carlo algorithm for electrons. RESULTS: V(90%) was 97.3±1.2 for RA plans and 78.2±2.6 for electrons; similarly, V(107%) was 2.5±2.2 and 37.7±3.4, respectively. RA met coverage criteria. Concerning bone sparing, D(2%) was 29.6±1.1 for RA and 31.0±2.4 for electrons. Although acceptable for bone involvement, pronounced target coverage violations were obtained for electron plans. Monitor units were similar for electrons and RA, although for the latter they increased when superior bone sparing was imposed. Delivery times were 12.1±4.0 min for electrons and 4.8±1.3 min for the most modulated RA plans. CONCLUSION: High plan quality was shown for KS in the lower extremities using VMAT, and this might simplify their management in comparison with the more conventional usage of electrons, particularly in institutes with limited staff resources and heavy workloads. ADVANCES IN KNOWLEDGE: VMAT is also dosimetrically extremely advantageous in a typology of treatments where electron beam therapy is mainly considered to be effective owing to the limited penetration of the beams.

Small field segments surrounded by large areas only shielded by a multileaf collimator: comparison of experiments and dose calculation.

PURPOSE: Complex radiotherapy fields delivered using a tertiary multileaf collimator (MLC) often feature small open segments surrounded by large areas of the beam only shielded by the MLC. The aim of this study was to test the ability of two modern dose calculation algorithms to accurately calculate the dose in these fields which would be common, for example, in volumetric modulated arc treatment (VMAT) and study the impact of variations in dosimetric leaf gap (DLG), focal spot size, and MLC transmission in the beam models. METHODS: Nine test fields with small fields (0.6-3 cm side length) surrounded by large MLC shielded areas (secondary collimator 12 × 12 cm(2)) were created using a 6 MV beam from a Varian Clinac iX linear accelerator with 120 leaf MLC. Measurements of output factors and profiles were performed using a diamond detector (PTW) and compared to two dose calculations algorithms anisotropic analytical algorithm [(AAA) and Acuros XB] implemented on a commercial radiotherapy treatment planning system (Varian Eclipse 10). RESULTS: Both calculation algorithms predicted output factors within 1% for field sizes larger than 1 × 1 cm(2). For smaller fields AAA tended to underestimate the dose. Profiles were predicted well for all fields except for problems of Acuros XB to model the secondary penumbra between MLC shielded fields and the secondary collimator. A focal spot size of 1 mm or less, DLG 1.4 mm and MLC transmission of 1.4% provided a generally good model for our experimental setup. CONCLUSIONS: AAA and Acuros XB were found to predict the dose under small MLC defined field segments well. While DLG and focal spot affect mostly the penumbra, the choice of correct MLC transmission will be essential to model treatments such as VMAT accurately.

Definition of parameters for quality assurance of flattening filter free (FFF) photon beams in radiation therapy.

PURPOSE: Flattening filter free (FFF) beams generated by medical linear accelerators have recently started to be used in radiotherapy clinical practice. Such beams present fundamental differences with respect to the standard filter flattened (FF) beams, making the generally used dosimetric parameters and definitions not always viable. The present study will propose possible definitions and suggestions for some dosimetric parameters for use in quality assurance of FFF beams generated by medical linacs in radiotherapy. METHODS: The main characteristics of the photon beams have been analyzed using specific data generated by a Varian TrueBeam linac having both FFF and FF beams of 6 and 10 MV energy, respectively. RESULTS: Definitions for dose profile parameters are suggested starting from the renormalization of the FFF with respect to the corresponding FF beam. From this point the flatness concept has been translated into one of "unflatness" and other definitions have been proposed, maintaining a strict parallelism between FFF and FF parameter concepts. CONCLUSIONS: Ideas for quality controls used in establishing a quality assurance program when introducing FFF beams into the clinical environment are given here, keeping them similar to those used for standard FF beams. By following the suggestions in this report, the authors foresee that the introduction of FFF beams into a clinical radiotherapy environment will be as safe and well controlled as standard beam modalities using the existing guidelines.

Moderate hypofractionation and simultaneous integrated boost with volumetric modulated arc therapy (RapidArc) for prostate cancer. Report of feasibility and acute toxicity.

PURPOSE: In the present study, the acute toxicity profiles for prostate patients treated with simultaneous integrated boost (SIB) with volumetric modulated arcs in a hypofractionated regime are reported. PATIENTS AND METHODS: A total of 70 patients treated with RapidArc between May 2010 and September 2011 were retrospectively evaluated. Patients were stratified into low (36%), intermediate (49%), and high-risk (16%) groups. Target volumes (expanded to define the planning volumes (PTV)) were clinical target volume (CTV) 1: prostate; CTV2: CTV1 + seminal vesicles; CTV3: CTV2 + pelvic nodes. Low-risk patients received 71.4 Gy to PTV1; intermediate-risk 74.2 Gy to PTV1 and 61.6 or 65.5 Gy to PTV2; high-risk 74.2 Gy to PTV1, 61.6 or 65.5 Gy to PTV2, and 51.8 Gy to PTV3. All treatments were in 28 fractions. The median follow-up was 11 months (range 3.5-23 months). The acute rectal, gastrointestinal (GI) and genitourinary (GU) toxicities were scored according to EORTC/RTOG scales. RESULTS: Acute toxicities were recorded for the GU [G0 = 31/70 (44%), G1 = 22/70 (31%); G2 = 16/70 (23%); G3 = 1/70 (1%)], the rectum [G0 = 46/70 (66%); G1 = 12/70 (17%); G2 = 12/70 (17%); no G3], and the GI [G0 = 54/69 (77%); G1 = 11/69 (16%); G2 = 4/69 (6%); no G3]. Median time to rectal, GU, and GI toxicities were 27, 30, and 33 days, respectively. Only the GI toxicity correlated with stage and pelvic irradiation. Univariate analysis presented significant correlations between GI toxicity and intestinal irradiation (V(50 Gy) and V(60 Gy)). In the multivariate analysis, the only significant dosimetric variable was V(50 Gy) for the intestinal cavity. CONCLUSION: Moderate hypofractionation with SIB and RapidArc was shown to be safe, with acceptable acute toxicity. Longer follow-up is needed to assess late toxicity and clinical outcome.

Chest wall radiotherapy with volumetric modulated arcs and the potential role of flattening filter free photon beams.

PURPOSE: The goal of the work was to assess the role of RapidArc treatments in chest wall irradiation after mastectomy and determine the potential benefit of flattening filter free beams. METHODS AND MATERIAL: Planning CT scans of 10 women requiring post-mastectomy chest wall radiotherapy were included in the study. A dose of 50 Gy in 2 Gy fractions was prescribed. Organs at risk (OARs) delineated were heart, lungs, contralateral breast, and spinal cord. Dose-volume metrics were defined to quantify the quality of concurrent treatment plans assessing target coverage and sparing of OARs. Plans were designed for conformal 3D therapy (3DCRT) or for RapidArc with double partial arcs (RA). RapidArc plans were optimized for both conventional beams as well as for unflattened beams (RAF). The goal for this planning effort was to cover 100% of the planning target volume (PTV) with ≥ 90% of the prescribed dose and to minimize the volume inside the PTV receiving > 105% of the dose. The mean ipsilateral lung dose was required to be lower than 15 Gy and V(20 Gy) < 22%. Contralateral organ irradiation was required to be kept as low as possible. RESULTS: All techniques met planning objectives for PTV and for lung (3DCRT marginally failed for V(20 Gy)). RA plans showed superiority compared to 3DCRT in the medium to high dose region for the ipsilateral lung. Heart irradiation was minimized by RAF plans with ~4.5 Gy and ~15 Gy reduction in maximum dose compared to RA and 3DCRT, respectively. RAF resulted in superior plans compared to RA with respect to contralateral breast and lung with a reduction of ~1.7 Gy and 1.0 Gy in the respective mean doses. CONCLUSION: RapidArc treatment resulted in acceptable plan quality with superior ipsilateral tissue sparing compared to traditional techniques. Flattening filter free beams, recently made available for clinical use, might provide further healthy tissue sparing, particularly in contralateral organs, suggesting their applicability for large and complex targets.

Quality assurance of RapidArc in clinical practice using portal dosimetry.

OBJECTIVE: Quality assurance data from five centres were analysed to assess the reliability of RapidArc radiotherapy delivery in terms of machine and dosimetric performance. METHODS: A large group of patients was treated with RapidArc radiotherapy and treatment data recorded. Machine quality assurance was performed according to Ling et al (Int J Radiat Oncol Biol Phys 2008;72:575-81). In addition, treatment to a typical clinical case was delivered biweekly as a constancy check. Pre-treatment dosimetric validation of plan delivery was performed for each patient. All measurements and computations were performed at the depth of the maximum dose in water according to the GLAaS method using electronic portal imaging device measurements. Evaluation was carried out according to a gamma agreement index (GAI, the percentage of field area passing the test); the threshold dose difference was 3% and the threshold distance to agreement was 3 mm. RESULTS: A total of 275 patients (395 arcs) were included in the study. Mean delivery parameters were 31.0±20.0° (collimator angle), 4.7±0.5° s(-1) (gantry speed), 343±134 MU min(-1) (dose rate) and 1.6±1.4 min (beam-on time) for prescription doses ranging from 1.8 to 16.7 Gy/fraction. Mean deviations from the baseline dose rate and gantry speed ranged from -0.61% to 1.75%. Mean deviations from the baseline for leaf speed variation ranged from -0.73% to 0.41%. The mean GAI of repeated clinical fields was 99.2±0.2%. GAI varied from 84.7% to 100%; the mean across all patients was 97.1±2.4%. CONCLUSION: RapidArc can provide a reliable and accurate delivery of radiotherapy for a variety of clinical conditions.

Management of unilateral condylar fracture in a 9.6-year-old female.

BACKGROUND: Fractures represent a particular kind of pathology in children, as they take place within a rapidly growing organism. Condylar fractures must be focused upon not only as a cause of direct damage to the bone structure, but also with regards to future disorders in the dentofacial development, skeletal deformities and articular dysfunctions. The treatment aims at restoring function, occlusion, and symmetry. Aim of this paper is to emphasise, through the description of a case report, the need for correct diagnosis and the importance of a functional treatment by means of early muscle activation, in order to prevent any consequences on facial development. CASE REPORT: A case of a 9.6-year-old female with monocondylar and intracapsular fracture following a car accident is described. In accordance with the literature, the patient did not undergo surgical treatment, but followed a functional orthodontic protocol. The significant symptoms reduction and the rapid improvement of mandibular functions confirm the excellent healing potential in paediatric age, while the X-ray evaluations 1 year and 3.7 years later testify the condylar reshaping. Since the latter can continue over many years, the clinical and radiological follow-ups of the patient will have to cover the entire growth period.

Testing the portal imager GLAaS algorithm for machine quality assurance.

BACKGROUND: To report about enhancements introduced in the GLAaS calibration method to convert raw portal imaging images into absolute dose matrices and to report about application of GLAaS to routine radiation tests for linac quality assurance procedures programmes. METHODS: Two characteristic effects limiting the general applicability of portal imaging based dosimetry are the over-flattening of images (eliminating the "horns" and "holes" in the beam profiles induced by the presence of flattening filters) and the excess of backscattered radiation originated by the detector robotic arm supports. These two effects were corrected for in the new version of GLAaS formalism and results are presented to prove the improvements for different beams, detectors and support arms. GLAaS was also tested for independence from dose rate (fundamental to measure dynamic wedges). With the new corrections, it is possible to use GLAaS to perform standard tasks of linac quality assurance. Data were acquired to analyse open and wedged fields (mechanical and dynamic) in terms of output factors, MU/Gy, wedge factors, profile penumbrae, symmetry and homogeneity. In addition also 2D Gamma Evaluation was applied to measurement to expand the standard QA methods. GLAaS based data were compared against calculations on the treatment planning system (the Varian Eclipse) and against ion chamber measurements as consolidated benchmark. Measurements were performed mostly on 6 MV beams from Varian linacs. Detectors were the PV-as500/IAS2 and the PV-as1000/IAS3 equipped with either the robotic R- or Exact- arms. RESULTS: Corrections for flattening filter and arm backscattering were successfully tested. Percentage difference between PV-GLAaS measurements and Eclipse calculations relative doses at the 80% of the field size, for square and rectangular fields larger than 5 x 5 cm2 showed a maximum range variation of -1.4%, + 1.7% with a mean variation of <0.5%. For output factors, average percentage difference between GLAaS and Eclipse (or ion chamber) data was -0.4 +/- 0.7 (-0.2 +/- 0.4) respectively on square fields. Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: 0.1 +/- 1.0, 0.7 +/- 0.8, 0.1 +/- 0.4 (1.0 +/- 1.4, -0.3 +/- 0.2, -0.1 +/- 0.2) respectively. Similar minimal deviations were observed for flatness and symmetry. For Dynamic wedges, percentage difference of MU/Gy between GLAaS and Eclipse (or ion chamber) was: -1.1 +/- 1.6 (0.4 +/- 0.7). Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: 0.4 +/- 1.6, -1.5 +/- 1.8, -0.1 +/- 0.3 (-2.2 +/- 2.3, 2.3 +/- 1.2, 0.8 +/- 0.3) respectively. For mechanical wedges differences of transmission factors were <1.6% (Eclipse) and <1.1% (ion chamber) for all wedges. Minimum, maximum and average percentage difference between GLAaS and Eclipse (or ion chamber) data in the flattened field region were: -1.3 +/- 0.7, -0.7 +/- 0.7, -0.2 +/- 0.2 (-0.8 +/- 0.8, 0.7 +/- 1.1, 0.2 +/- 0.3) respectively. CONCLUSION: GLAaS includes now efficient methods to correct for missing "horns" and "holes" induced by flattening filter in the beam and to compensate for excessive backscattering from the support arm. These enhancements allowed to use GLAaS based dosimetric measurement to perform standard tasks of Linac quality assurance with reliable and consistent results. This fast method could be applied to routine practice being also fast in usage and because it allows the introduction of new analysis tools in routine QA by means, e.g., of the Gamma Index analysis.

Comparison of advanced irradiation techniques with photons for benign intracranial tumours.

BACKGROUND AND PURPOSE: The potential benefits and limitations of different radiation techniques (stereotactic arc therapy (SRS/T), intensity modulated radiotherapy (IMRT), helical tomotherapy (HT), Cyberknife and intensity-modulated multiple arc therapy (AMOA)) have been assessed using comparative treatment planning methods on twelve patients presenting with 'benign' brain tumours. MATERIALS AND METHODS: Plans for five acoustic neurinomas, five meningiomas and two pituitary adenomas were computed to generate dose distributions for all modalities using a common CT dataset to delineate planning target volume and organs at risk. RESULTS: HT, AMOA and IMRT resulted superior to SRS/T and Cyberknife for target coverage. For the first group V(95%) ranged from 98% to 100%, minimum dose ranged from 91% to 96% and standard deviation from 0.84% to 1.67%. For organs at risk all techniques respected planning objectives with a tendency of Cyberknife and SRS/T to better spare the brain stem and the healthy brain tissue (e.g., V(20Gy) of 2.0% and 2.3%, respectively, compared to 3.1-5.0% for the other techniques). AMOA is in general preferable to IMRT for all OARs. Conformity index (CI(95)) was better for HT and Cyberknife (both 1.8) and less for AMOA and IMRT (3.9 and 3.0, respectively). CONCLUSION: All techniques provided good OAR sparing and primarily differed in target coverage indices. For the class of tumours investigated in this report, HT, AMOA and IMRT had better target coverage with HT providing the best combination of indeces. Between AMOA and IMRT, target coverage was comparable and, considering organs at risk, AMOA was slightly preferable.

Interference with complement regulatory molecules as a possible therapeutic strategy in HIV infection.

Drugs which inhibit different stages of the HIV infection process, such as cell entry through CD4 and chemokine receptors, production of double stranded DNA from the HIV genome and maturation of newly produced viruses, are now proposed for AIDS therapy. None of these treatments, however, solve the problem of complete HIV eradication and the frequent appearance of mutants displaying drug resistance. We have recently detailed a strategy describing how HIV protects itself from the human complement and propose that interference of this resistance could be a possible target for therapy.

Presence of autoantibodies against complement regulatory proteins in relapsing-remitting multiple sclerosis.

Complement was proposed to play an important role in the onset of Multiple Sclerosis (MS) lesions by inducing physical damage to myelin-producing cells. Every somatic cell is however endowed with a repertoire of membrane-bound molecules which normally down-regulate the complement activation cascade (Regulators of Complement Activation, RCA) and therefore protect cells from complement-dependent lysis. We show here that antibodies against two complement regulatory molecules expressed in the membrane of human cells (CD46 and CD59) are present in sera from relapsing-remitting MS patients in the acute phase, that they are directed against the active site of the RCA molecules and that they inactivate their regulatory function, thus providing a mechanism by which cells of the nervous system might be damaged in a complement-dependent fashion during the acute MS phase. Moreover, we found that most of these sera also contain antibodies reacting with an epitope of the transmembrane glycoprotein of HIV which is conserved in most retroviruses; this may support the hypothesis that self-reacting antibodies might have arisen in these patients as an immune response after retroviral infection or expression of endogenous retroviral proteins.

Role of complement in HIV infection.

In human plasma, HIV activates the complement system, even in the absence of specific antibodies. Complement activation would, however, be harmful to the virus if the reactions were allowed to go to completion, since their final outcome would be virolysis. This is avoided by complement regulatory molecules, which either are included in the virus membrane upon budding from the infected cells (e.g. DAF/CD55) or are secondarily attached to HIV envelope glycoproteins as in the case of factor H. By using this strategy of interaction with complement components, HIV takes advantage of human complement activation for enhancement of infectivity, for follicular localization, and for broadening its target cell range at the same time that it displays an intrinsic resistance against the lytic action of human complement. This intrinsic resistance to complement-mediated virolysis can be overcome by monoclonal antibodies inhibiting recruitment of human factor H to the virus surface, suggesting a new therapeutic principle.

A "complement-ary" AIDS vaccine.

The human immunodeficiency virus uses the human complement system to its advantage. Is it possible to turn the tables with a vaccine?

Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55).

Activation of the human complement system leads to complement deposition on human immunodeficiency virus (HIV) and HIV-infected cells without causing efficient complement-mediated lysis. Even in the presence of HIV-specific antibodies, only a few particles are destroyed, demonstrating that HIV is intrinsically resistant to human complement. Here we report that, in addition to decay accelerating factor (DAF) being partially responsible, human complement factor H (CFH), a humoral negative regulator of complement activation, is most critical for this resistance. In the presence of HIV-specific antibodies, sera devoid of CFH (total genetic deficiency or normal human serum depleted of CFH by affinity chromatography) lysed free virus and HIV-infected but not uninfected cells. In the presence of CFH, lysis of HIV was only obtained when binding of CFH to gp41 was inhibited by a monoclonal antibody against a main CFH-binding site in gp41. Since CFH is an abundant protein in serum, and high local concentration of CFH can be obtained at the surface of HIV as the result of specific interactions of CFH with the HIV envelope, it is proposed that the resistance of HIV and HIV-infected cells against complement-mediated lysis in vivo is dependent on DAF and CFH and can be overcome by suppressing this protection. Neutralization of HIV may be achieved by antibodies against DAF and, more importantly, antibodies against CFH-binding sites on HIV envelope proteins.

HIV glycoprotein 41 and complement factor H interact with each other and share functional as well as antigenic homology.

We have shown that complement factor H (CFH) interacts with HIV-1 at the level of the sequence Env 105-119, contained in the C1 domain of gp120. CFH interaction with HIV was evident only after dissociation of the Env complex induced by exposure to sCD4. We hypothesized that CFH could act as a gp41 analog in the interaction with Env 105-119. A panel of partially overlapping, synthetic peptides reproducing the extracellular portion of gp41 was therefore used to compete the binding of CFH to Env 105-119. Three sets of peptides that competed this interaction were identified. These peptides defined a region of functional homology between the gp41 molecule and CFH (Env 580-600), and two regions of interaction (Env 620-640 and Env 650-670). In addition to this, a monoclonal antibody directed against peptide Env 580-600 and a polyclonal mouse antiserum raised against recombinant gp41 were shown to recognize CFH in Western blots and ELISA, respectively, also defining a region of antigenic homology between gp41 and CFH. These data provide evidence for interaction and molecular mimicry between an HIV structural protein and a negative regulator of the complement pathway. We show here that CFH can interact with both HIV Env proteins, suggesting a possible and efficient mechanism of downregulation of the complement cascade at the surface of infected cells.